Journal: J Mol Cell Cardiol

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Abstract

Peli1 contributes to myocardial ischemia/reperfusion injury by impairing autophagy flux via its E3 ligase mediated ubiquitination of P62.

Yang J, Tong T, Zhu C, Zhou M, ... Li J, Li Y
Autophagy flux is impaired during myocardial ischemia/reperfusion (M-I/R) via the accumulation of autophagosome and insufficient clearance, which exacerbates cardiomyocyte death. Peli1 (Pellion1) is a RING finger domain-containing ubiquitin E3 ligase that could catalyze the polyubiquitination of substrate proteins. Peli1 has been demonstrated to play an important role in ischemic cardiac diseases. However, little is known about whether Peli1 is involved in the regulation of autophagy flux during M-I/R. The present study investigated whether M-I/R induced impaired autophagy flux could be mediated through Peli1 dependent mechanisms. We induced M-I/R injury in wild type (WT) and Peli1 knockout mice and observed that M-I/R significantly decreased cardiac function that was associated with increased cardiac Peli1 expression and upregulated autophagy-associated protein LC3II and P62. In contrast, Peli1 knockout mice exhibited significant improvement of M-I/R induced cardiac dysfunction and decreased LC3II and P62 expression. Besides, inhibitors of autophagy also increased the infarct size in Peli1 knockout mice after 24 h of reperfusion. Mechanistic studies demonstrated that in vivo I/R or in vitro hypoxia/reoxygenation (H/R) markedly increased the Peli1 E3 ligase activity which directly promoted the ubiquitination of P62 at lysine(K)7 via K63-linkage to inhibit its dimerization and autophagic degradation. Co-immunoprecipitation and GST-pull down assay indicated that Peli1 interacted with P62 via the Ring domain. In addition, Peli1 deficiency also decreased cardiomyocyte apoptosis. Together, our work demonstrated a critical link between increased expression and activity of Peli1 and autophagy flux blockage in M-I/R injury, providing insight into a promising strategy for treating myocardium M-I/R injury.

Copyright © 2022. Published by Elsevier Ltd.

J Mol Cell Cardiol: 27 Sep 2022; 173:30-46
Yang J, Tong T, Zhu C, Zhou M, ... Li J, Li Y
J Mol Cell Cardiol: 27 Sep 2022; 173:30-46 | PMID: 36179399
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Abstract

KMT2B-dependent RFK transcription activates the TNF-α/NOX2 pathway and enhances ferroptosis caused by myocardial ischemia-reperfusion.

Cao Y, Luo F, Peng J, Fang Z, Liu Q, Zhou S
Epigenetic regulation such as histone modification is implicated in the pathogenesis of myocardial ischemia/reperfusion injury (MIRI). Lysine-specific methyltransferase 2B (KMT2B) is a histone H3 lysine 4 (H3K4) methyltransferase. This study aims at exploring the role of KMT2B-mediated histone modification in MIRI. Peripheral blood samples were collected from 30 patients with acute myocardial infarction (AMI) and 30 healthy volunteers for analyses of the expression levels of KMT2B, riboflavin kinase (RFK), tumor necrosis factor (TNF)-α, and NADPH oxidase 2 (NOX2). H9C2 cardiomyocytes or Sprague-Dawley rats were utilized for developing in vitro and in vivo models. To evaluate the effect of the aforementioned molecules on cellular damage and MIRI, short hairpin RNAs or overexpression plasmids were introduced into cardiomyocytes for gene silencing or overexpression and also, they were packaged into adenovirus vectors for in vivo interventions. Immunoprecipitation assays were conducted to assess the interactions between KMT2B and RFK and among RFK, NOX2 sub-unit p22phox, and TNF receptor 1-associated death domain protein. KMT2B, RFK, TNF-α, and NOX2 were notably upregulated in AMI patients. KMT2B knockdown resulted in considerably attenuated cell apoptosis and reduced myocardial infarct area. Additionally, the release of pro-inflammatory proteins and ferroptosis were suppressed. Furthermore, KMT2B could promote RFK gene transcription by upregulating H3 methylation levels and consequently activate the TNF-α/NOX2 axis, which was the possible mechanism underlying the role of KMT2B in MIRI. KMT2B motivates MIRI-induced cellular injury and ferroptosis by inducing RFK transcription and mediating the TNF-α/NOX2 axis.

Copyright © 2022. Published by Elsevier Ltd.

J Mol Cell Cardiol: 23 Sep 2022; epub ahead of print
Cao Y, Luo F, Peng J, Fang Z, Liu Q, Zhou S
J Mol Cell Cardiol: 23 Sep 2022; epub ahead of print | PMID: 36162497
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Abstract

Diabetes disturbs functional adaptation of the remote myocardium after ischemia/reperfusion.

Funk F, Kronenbitter A, Isić M, Flocke V, ... Krüger M, Schmitt JP
Diabetes mellitus type 2 is associated with adverse clinical outcome after myocardial infarction. To better understand the underlying causes we here investigated sarcomere protein function and its calcium-dependent regulation in the non-ischemic remote myocardium (RM) of diabetic mice (db/db) after transient occlusion of the left anterior descending coronary artery. Before and 24 h after surgery db/db and non-diabetic db/+ underwent magnetic resonance imaging followed by histological and biochemical analyses of heart tissue. Intracellular calcium transients and sarcomere function were measured in isolated cardiomyocytes. Active and passive force generation was assessed in skinned fibers and papillary muscle preparations. Before ischemia and reperfusion (I/R), beat-to-beat calcium cycling was depressed in diabetic cardiomyocytes. Nevertheless, contractile function was preserved owing to increased myofilament calcium sensitivity and higher responsiveness of myocardial force production to β-adrenergic stimulation in db/db compared to db/+. In addition, protein kinase C activity was elevated in db/db hearts leading to strong phosphorylation of the titin PEVK region and increased titin-based tension of myofilaments. I/R impaired the function of whole hearts and RM sarcomeres in db/db to a larger extent than in non-diabetic db/+, and we identified several reasons. First, the amplitude and the kinetics of cardiomyocyte calcium transients were further reduced in the RM of db/db. Underlying causes involved altered expression of calcium regulatory proteins. Diabetes and I/R additively reduced phospholamban S16-phosphorylation by 80% (P < 000.1) leading to strong inhibition of the calcium ATPase SERCA2a. Second, titin stiffening was only observed in the RM of db/+, but not in the RM of db/db. Finally, db/db myofilament calcium sensitivity and force generation upon β-adrenergic stimulation were no longer enhanced over db/+ in the RM. The findings demonstrate that impaired cardiomyocyte calcium cycling of db/db hearts is compensated by increased myofilament calcium sensitivity and increased titin-based stiffness prior to I/R. In contrast, sarcomere function of the RM 24 h after I/R is poor because both these compensatory mechanisms fail and myocyte calcium handling is further depressed.

Copyright © 2022. Published by Elsevier Ltd.

J Mol Cell Cardiol: 20 Sep 2022; epub ahead of print
Funk F, Kronenbitter A, Isić M, Flocke V, ... Krüger M, Schmitt JP
J Mol Cell Cardiol: 20 Sep 2022; epub ahead of print | PMID: 36150524
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Abstract

Identification of a novel cardiac epitope triggering T-cell responses in patients with myocardial infarction.

Hapke N, Heinrichs M, Ashour D, Vogel E, ... Frantz S, Ramos GC
T-cells contribute to pathophysiological processes in myocardial diseases, including myocardial infarction (MI) and heart failure (HF). Antigen-specificity is a hallmark of T-cell responses but the cardiac antigens that trigger heart-directed T-cell responses in patients have not yet been uncovered, thus posing a roadblock to translation. In the present exploratory study, we identified a peptide fragment of the beta-1 adrenergic receptor (ADRB1) that elicits CD4+ T-cell responses after myocardial infarction in patients with a defined HLA haplotype. Our observations may advance the development of tools to monitor other antigen-specific immune responses in patients.

Copyright © 2022. Published by Elsevier Ltd.

J Mol Cell Cardiol: 16 Sep 2022; epub ahead of print
Hapke N, Heinrichs M, Ashour D, Vogel E, ... Frantz S, Ramos GC
J Mol Cell Cardiol: 16 Sep 2022; epub ahead of print | PMID: 36122767
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Abstract

The role of autophagic cell death in cardiac disease.

Nah J, Zablocki D, Sadoshima J
Cardiomyocytes undergo various forms of cell death during heart disease such as myocardial infarction and heart failure. Understanding the mechanisms of cell death in cardiomyocytes is one of the most fundamental issues in the treatment of heart failure. Among the several kinds of cell death mechanisms, this review will focus on autophagy-related cardiomyocyte cell death. Although autophagy plays an essential role in mediating cellular quality control mechanisms for cell survival, dysregulation of autophagy can cause cell death, referred to as autophagy-dependent cell death or type II programmed cell death. The recent discovery of autosis as a modality of autophagy-dependent cell death with unique morphological and biochemical features has allowed us to broaden our understanding of the mechanistic role of autophagy in cell death. Here, we discuss autophagy-dependent cardiomyocyte cell death, including autosis, in pathophysiological conditions of the heart.

Copyright © 2022. Published by Elsevier Ltd.

J Mol Cell Cardiol: 06 Sep 2022; epub ahead of print
Nah J, Zablocki D, Sadoshima J
J Mol Cell Cardiol: 06 Sep 2022; epub ahead of print | PMID: 36084743
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Abstract

Direct proteomic and high-resolution microscopy biopsy analysis identifies distinct ventricular fates in severe aortic stenosis.

Brandenburg S, Otto L, Schönberger HL, Jacob CF, ... Lenz C, Lehnart SE
The incidence of aortic valve stenosis (AS), the most common reason for aortic valve replacement (AVR), increases with population ageing. While untreated AS is associated with high mortality, different hemodynamic subtypes range from normal left-ventricular function to severe heart failure. However, the molecular nature underlying four different AS subclasses, suggesting vastly different myocardial fates, is unknown. Here, we used direct proteomic analysis of small left-ventricular biopsies to identify unique protein expression profiles and subtype-specific AS mechanisms. Left-ventricular endomyocardial biopsies were harvested from patients during transcatheter AVR, and inclusion criteria were based on echocardiographic diagnosis of severe AS and guideline-defined AS-subtype classification: 1) normal ejection fraction (EF)/high-gradient; 2) low EF/high-gradient; 3) low EF/low-gradient; and 4) paradoxical low-flow/low-gradient AS. Samples from non-failing donor hearts served as control. We analyzed 25 individual left-ventricular biopsies by data-independent acquisition mass spectrometry (DIA-MS), and 26 biopsies by histomorphology and cardiomyocytes by STimulated Emission Depletion (STED) superresolution microscopy. Notably, DIA-MS reliably detected 2273 proteins throughout each individual left-ventricular biopsy, of which 160 proteins showed significant abundance changes between AS-subtype and non-failing samples including the cardiac ryanodine receptor (RyR2). Hierarchical clustering segregated unique proteotypes that identified three hemodynamic AS-subtypes. Additionally, distinct proteotypes were linked with AS-subtype specific differences in cardiomyocyte hypertrophy. Furthermore, superresolution microscopy of immunolabeled biopsy sections showed subcellular RyR2-cluster fragmentation and disruption of the functionally important association with transverse tubules, which occurred specifically in patients with systolic dysfunction and may hence contribute to depressed left-ventricular function in AS.

Copyright © 2022. Published by Elsevier Ltd.

J Mol Cell Cardiol: 06 Sep 2022; epub ahead of print
Brandenburg S, Otto L, Schönberger HL, Jacob CF, ... Lenz C, Lehnart SE
J Mol Cell Cardiol: 06 Sep 2022; epub ahead of print | PMID: 36084744
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Abstract

Remodelling of potassium currents underlies arrhythmic action potential prolongation under beta-adrenergic stimulation in hypertrophic cardiomyopathy.

Doste R, Coppini R, Bueno-Orovio A
Hypertrophic cardiomyopathy (HCM) patients often present an enhanced arrhythmogenicity that can lead to lethal arrhythmias, especially during exercise. Recent studies have indicated an abnormal response of HCM cardiomyocytes to β-adrenergic receptor stimulation (β-ARS), with prolongation of their action potential rather than shortening. The mechanisms underlying this aberrant response to sympathetic stimulation and its possible proarrhythmic role remain unknown. The aims of this study are to investigate the key ionic mechanisms underlying the HCM abnormal response to β-ARS and the resultant repolarisation abnormalities using human-based experimental and computational methodologies. We integrated and calibrated the latest models of human ventricular electrophysiology and β-ARS using experimental measurements of human adult cardiomyocytes from control and HCM patients. Our major findings include: (1) the developed in silico models of β-ARS capture the behaviour observed in the experimental data, including the aberrant response of HCM cardiomyocytes to β-ARS; (2) the reduced increase of potassium currents under β-ARS was identified as the main mechanism of action potential prolongation in HCM, rather than a more sustained inward calcium current; (3) action potential duration differences between healthy and HCM cardiomyocytes were increased upon β-ARS, while endocardial to epicardial differences in HCM cardiomyocytes were reduced; (4) models presenting repolarisation abnormalities were characterised by downregulation of the rapid delayed rectifier potassium current and the sodium‑potassium pump, while inward currents were upregulated. In conclusion, our results identify causal relationships between the HCM phenotype and its arrhythmogenic response to β-ARS through the downregulation of potassium currents.

Copyright © 2022. Published by Elsevier Ltd.

J Mol Cell Cardiol: 01 Sep 2022; epub ahead of print
Doste R, Coppini R, Bueno-Orovio A
J Mol Cell Cardiol: 01 Sep 2022; epub ahead of print | PMID: 36058298
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Abstract

Elucidating the role of the L-type calcium channel in excitability and energetics in the heart: The ISHR 2020 Research Achievement Award Lecture.

Hool LC
Cardiovascular disease continues to be the leading health burden worldwide and with the rising rates in obesity and type II diabetes and ongoing effects of long COVID, it is anticipated that the burden of cardiovascular morbidity and mortality will increase. Calcium is essential to cardiac excitation and contraction. The main route for Ca2+ influx is the L-type Ca2+ channel (Cav1.2) and embryos that are homozygous null for the Cav1.2 gene are lethal at day 14 postcoitum. Acute changes in Ca2+ influx through the channel contribute to arrhythmia and sudden death, and chronic increases in intracellular Ca2+ contribute to pathological hypertrophy and heart failure. We use a multidisciplinary approach to study the regulation of the channel from the molecular level through to in vivo CRISPR mutant animal models. Here we describe some examples of our work from over 2 decades studying the role of the channel under physiological and pathological conditions. Our single channel analysis of purified human Cav1.2 protein in proteoliposomes has contributed to understanding direct molecular regulation of the channel including identifying the critical serine involved in the \"fight or flight\" response. Using the same approach we identified the cysteine responsible for altered function during oxidative stress. Chronic activation of the L-type Ca2+ channel during oxidative stress occurs as a result of persistent glutathionylation of the channel that contributes to the development of hypertrophy. We describe for the first time that activation of the channel alters mitochondrial function (and energetics) on a beat-to-beat basis via movement of cytoskeletal proteins. In translational studies we have used this response to \"report\" mitochondrial function in models of cardiomyopathy and to test efficacy of novel therapies to prevent cardiomyopathy.

Copyright © 2022 The Author. Published by Elsevier Ltd.. All rights reserved.

J Mol Cell Cardiol: 27 Aug 2022; 172:100-108
Hool LC
J Mol Cell Cardiol: 27 Aug 2022; 172:100-108 | PMID: 36041287
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Abstract

Enhanced calcium release at specialised surface sites compensates for reduced t-tubule density in neonatal sheep atrial myocytes.

Smith CER, Pinali C, Eisner DA, Trafford AW, Dibb KM
Cardiac myocytes rely on transverse (t)-tubules to facilitate a rapid rise in calcium throughout the cell. However, despite their importance in triggering synchronous Ca2+ release, t-tubules are highly labile structures. They develop postnatally, increase in density during exercise training and are lost in diseases such as heart failure (HF). In the majority of settings, an absence of t-tubules decreases function. Here we show that despite reduced t-tubule density due to immature t-tubules, the newborn atrium is highly specialised to maintain Ca2+ release. To compensate for fewer t-tubules triggering a central rise in Ca2+, Ca2+ release at sites on the cell surface is enhanced in the newborn, exceeding that at all Ca2+ release sites in the adult. Using electron and super resolution microscopy to investigate myocyte ultrastructure, we found that newborn atrial cells had enlarged surface sarcoplasmic reticulum and larger, more closely spaced surface and central ryanodine receptor clusters. We suggest that these adaptations mediate enhanced Ca2+ release at the sarcolemma and aid propagation to compensate for reduced t-tubule density in the neonatal atrium.

Copyright © 2022. Published by Elsevier Ltd.

J Mol Cell Cardiol: 26 Aug 2022; epub ahead of print
Smith CER, Pinali C, Eisner DA, Trafford AW, Dibb KM
J Mol Cell Cardiol: 26 Aug 2022; epub ahead of print | PMID: 36038009
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Abstract

Mechanisms and strategies to promote cardiac xenotransplantation.

Garry DJ, Weiner JI, Greising SM, Garry MG, Sachs DH
End stage heart failure is a terminal disease, and the only curative therapy is orthotopic heart transplantation. Due to limited organ availability, alternative strategies have received intense interest for treatment of patients with advanced heart failure. Recent studies using gene-edited porcine organs suggest that cardiac xenotransplantation may provide a future source of organs. In this review, we highlight the historical milestones for cardiac xenotransplantation and the gene editing strategies designed to overcome immunological barriers, which have culminated in a recent cardiac pig-to-human xenotransplant. We also discuss recent results of studies on the engineering of human-porcine chimeric organs that may provide an alternative and complementary strategy to overcome some of the major immunological barriers to producing a new source of transplantable organs.

Copyright © 2022. Published by Elsevier Ltd.

J Mol Cell Cardiol: 25 Aug 2022; epub ahead of print
Garry DJ, Weiner JI, Greising SM, Garry MG, Sachs DH
J Mol Cell Cardiol: 25 Aug 2022; epub ahead of print | PMID: 36030840
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Abstract

Loss of Acta2 in cardiac fibroblasts does not prevent the myofibroblast differentiation or affect the cardiac repair after myocardial infarction.

Li Y, Li C, Liu Q, Wang L, ... Molkentin JD, Fu X
In response to myocardial infarction (MI), quiescent cardiac fibroblasts differentiate into myofibroblasts mediating tissue repair. One of the most widely accepted markers of myofibroblast differentiation is the expression of Acta2 which encodes smooth muscle alpha-actin (SMαA) that is assembled into stress fibers. However, the requirement of Acta2/SMαA in the myofibroblast differentiation of cardiac fibroblasts and its role in post-MI cardiac repair remained unknown. To answer these questions, we generated a tamoxifen-inducible cardiac fibroblast-specific Acta2 knockout mouse line. Surprisingly, mice that lacked Acta2 in cardiac fibroblasts had a normal post-MI survival rate. Moreover, Acta2 deletion did not affect the function or histology of infarcted hearts. No difference was detected in the proliferation, migration, or contractility between WT and Acta2-null cardiac myofibroblasts. Acta2-null cardiac myofibroblasts had a normal total filamentous actin level and total actin level. Acta2 deletion caused a significant compensatory increase in the transcription level of non-Acta2 actin isoforms, especially Actg2 and Acta1. Moreover, in myofibroblasts, the transcription levels of cytoplasmic actin isoforms were significantly higher than those of muscle actin isoforms. In addition, we found that myocardin-related transcription factor-A is critical for myofibroblast differentiation but is not required for the compensatory effects of non-Acta2 isoforms. In conclusion, the Acta2 deletion does not prevent the myofibroblast differentiation of cardiac fibroblasts or affect the post-MI cardiac repair, and the increased expression and stress fiber formation of non-SMαA actin isoforms and the functional redundancy between actin isoforms are able to compensate for the loss of Acta2 in cardiac myofibroblasts.

Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.

J Mol Cell Cardiol: 22 Aug 2022; 171:117-132
Li Y, Li C, Liu Q, Wang L, ... Molkentin JD, Fu X
J Mol Cell Cardiol: 22 Aug 2022; 171:117-132 | PMID: 36007455
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Abstract

The heart of cardiac reprogramming: The cardiac fibroblasts.

Ricketts SN, Qian L
Cardiovascular disease is the leading cause of death worldwide, outpacing pulmonary disease, infectious disease, and all forms of cancer. Myocardial infarction (MI) dominates cardiovascular disease, contributing to four out of five cardiovascular related deaths. Following MI, patients suffer adverse and irreversible myocardial remodeling associated with cardiomyocyte loss and infiltration of fibrotic scar tissue. Current therapies following MI only mitigate the cardiac physiological decline rather than restore damaged myocardium function. Direct cardiac reprogramming is one strategy that has promise in repairing injured cardiac tissue by generating new, functional cardiomyocytes from cardiac fibroblasts (CFs). With the ectopic expression of transcription factors, microRNAs, and small molecules, CFs can be reprogrammed into cardiomyocyte-like cells (iCMs) that display molecular signatures, structures, and contraction abilities similar to endogenous cardiomyocytes. The in vivo induction of iCMs following MI leads to significant reduction in fibrotic cardiac remodeling and improved heart function, indicating reprogramming is a viable option for repairing damaged heart tissue. Recent work has illustrated different methods to understand the mechanisms driving reprogramming, in an effort to improve the efficiency of iCM generation and create an approach translational into clinic. This review will provide an overview of CFs and describe different in vivo reprogramming methods.

Copyright © 2022 Elsevier Ltd. All rights reserved.

J Mol Cell Cardiol: 22 Aug 2022; 172:90-99
Ricketts SN, Qian L
J Mol Cell Cardiol: 22 Aug 2022; 172:90-99 | PMID: 36007393
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Abstract

Glutamine uptake and catabolism is required for myofibroblast formation and persistence.

Gibb AA, Huynh AT, Gaspar RB, Ploesch TL, ... Hill BG, Elrod JW
Background
Fibrosis and extracellular matrix remodeling are mediated by resident cardiac fibroblasts (CFs). In response to injury, fibroblasts activate, differentiating into specialized synthetic and contractile myofibroblasts producing copious extracellular matrix proteins (e.g., collagens). Myofibroblast persistence in chronic diseases, such as HF, leads to progressive cardiac dysfunction and maladaptive remodeling. We recently reported that an increase in αKG (alpha-ketoglutarate) bioavailability, which contributes to enhanced αKG-dependent lysine demethylase activity and chromatin remodeling, is required for myofibroblast formation. Therefore, we aimed to determine the substrates and metabolic pathways contributing to αKG biosynthesis and their requirement for myofibroblast formation.
Methods
Stable isotope metabolomics identified glutaminolysis as a key metabolic pathway required for αKG biosynthesis and myofibroblast formation, therefore we tested the effects of pharmacologic inhibition (CB-839) or genetic deletion of glutaminase (Gls1-/-) on myofibroblast formation in both murine and human cardiac fibroblasts. We employed immunofluorescence staining, functional gel contraction, western blotting, and bioenergetic assays to determine the myofibroblast phenotype.
Results
Carbon tracing indicated enhanced glutaminolysis mediating increased αKG abundance. Pharmacological and genetic inhibition of glutaminolysis prevented myofibroblast formation indicated by a reduction in αSMA+ cells, collagen gel contraction, collagen abundance, and the bioenergetic response. Inhibition of glutaminolysis also prevented TGFβ-mediated histone demethylation and supplementation with cell-permeable αKG rescued the myofibroblast phenotype. Importantly, inhibition of glutaminolysis was sufficient to prevent myofibroblast formation in CFs isolated from the human failing heart.
Conclusions
These results define glutaminolysis as necessary for myofibroblast formation and persistence, providing substantial rationale to evaluate several new therapeutic targets to treat cardiac fibrosis.

Copyright © 2022 Elsevier Ltd. All rights reserved.

J Mol Cell Cardiol: 18 Aug 2022; 172:78-89
Gibb AA, Huynh AT, Gaspar RB, Ploesch TL, ... Hill BG, Elrod JW
J Mol Cell Cardiol: 18 Aug 2022; 172:78-89 | PMID: 35988357
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Abstract

A perinuclear calcium compartment regulates cardiac myocyte hypertrophy.

Turcotte MG, Thakur H, Kapiloff MS, Dodge-Kafka KL
The pleiotropic Ca2+/calmodulin-dependent phosphatase calcineurin is a key regulator of pathological cardiac myocyte hypertrophy. The selective activation of hypertrophic calcineurin signaling under stress conditions has been attributed to compartmentation of Ca2+ signaling in cardiac myocytes. Here, perinuclear signalosomes organized by the scaffold protein muscle A-Kinase Anchoring Protein β (mAKAPβ/AKAP6β) are shown to orchestrate local Ca2+ transients, inducing calcineurin-dependent NFATc nuclear localization and myocyte hypertrophy in response to β-adrenergic receptor activation. Fluorescent biosensors for Ca2+ and calcineurin and protein kinase A (PKA) activity, both diffusely expressed and localized by nesprin-1α to the nuclear envelope, are used to define an autonomous mAKAPβ signaling compartment in adult and neonatal rat ventricular myocytes. Notably, β-adrenergic-stimulated perinuclear Ca2+ and PKA and CaN activity transients depended upon mAKAPβ expression, while Ca2+ elevation and PKA and CaN activity in the cytosol were mAKAPβ independent. Buffering perinuclear cAMP and Ca2+ prevented calcineurin-dependent NFATc nuclear translocation and myocyte hypertrophy, without affecting cardiac myocyte contractility. Additional findings suggest that the perinuclear Ca2+ transients were mediated by signalosome-associated ryanodine receptors regulated by local PKA phosphorylation. These results demonstrate the existence of a functionally independent Ca2+ signaling compartment in the cardiac myocyte regulating hypertrophy and provide a premise for targeting mAKAPβ signalosomes to prevent selectively cardiac hypertrophy in disease.

Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.

J Mol Cell Cardiol: 08 Aug 2022; 172:26-40
Turcotte MG, Thakur H, Kapiloff MS, Dodge-Kafka KL
J Mol Cell Cardiol: 08 Aug 2022; 172:26-40 | PMID: 35952391
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Abstract

PGE2 protects against heart failure through inhibiting TGF-β1 synthesis in cardiomyocytes and crosstalk between TGF-β1 and GRK2.

Fu J, Li L, Chen L, Su C, ... Yang X, Fu Q
Inflammation plays a central role in the development of heart failure. Prostaglandin E2 (PGE2) is a key mediator of the inflammatory process in the cardiovascular system. However, the role of PGE2 in heart failure is complex and controversial. A recent report suggested that PGE2 inhibits acute β adrenergic receptor (β-AR) stimulation-enhanced cardiac contractility. The aim of this study was to characterize the influence of PGE2 on chronic β-AR stimulation-induced heart failure. Male C57BL/6 J mice received isoproterenol (ISO) or vehicle for 4 weeks. PGE2 significantly reversed ISO-induced cardiac contractile dysfunction and remodeling. Mechanically, ventricular myocytes were found to be an important source of TGF-β1 in ISO-model and PGE2 ablated TGF-β1 synthesis in cardiomyocytes through inhibition of β-AR activated PKA-CREB signaling. Furthermore, PGE2 significantly suppressed TGF-β1-GRK2 crosstalk-induced pro-hypertrophy and pro-fibrotic signaling in cardiomyocytes and cardiac fibroblasts, respectively. Pharmacological inhibition of GRK2 also attenuated contractile dysfunction and cardiac hypertrophy and fibrosis in ISO-model. These studies elucidate a novel mechanism by which PGE2 reduces TGF-β1 synthesis and its downstream signaling in heart failure and identify PGE2 or TGF-β1-GRK2 crosstalk as plausible therapeutic targets for preventing or treating heart failure induced by chronic β-AR stimulation.

Copyright © 2022. Published by Elsevier Ltd.

J Mol Cell Cardiol: 04 Aug 2022; epub ahead of print
Fu J, Li L, Chen L, Su C, ... Yang X, Fu Q
J Mol Cell Cardiol: 04 Aug 2022; epub ahead of print | PMID: 35934102
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Abstract

Cardiomyocyte-specific loss of plasma membrane calcium ATPase 1 impacts cardiac rhythm and is associated with ventricular repolarisation dysfunction.

Wilson C, Stafford N, Zi M, Chelu A, ... Trafford AW, Cartwright EJ
Plasma membrane calcium ATPase 1 (PMCA1, Atp2b1) is emerging as a key contributor to cardiac physiology, involved in calcium handling and myocardial signalling. In addition, genome wide association studies have associated PMCA1 in several areas of cardiovascular disease including hypertension and myocardial infarction. Here, we investigated the role of PMCA1 in basal cardiac function and heart rhythm stability. Cardiac structure, heart rhythm and arrhythmia susceptibility were assessed in a cardiomyocyte-specific PMCA1 deletion (PMCA1CKO) mouse model. PMCA1CKO mice developed abnormal heart rhythms related to ventricular repolarisation dysfunction and displayed an increased susceptibility to ventricular arrhythmias. We further assessed the levels of cardiac ion channels using qPCR and found a downregulation of the voltage-dependent potassium channels, Kv4.2, with a corresponding reduction in the transient outward potassium current which underlies ventricular repolarisation in the murine heart. The changes in heart rhythm were found to occur in the absence of any structural cardiomyopathy. To further assess the molecular changes occurring in PMCA1CKO hearts, we performed proteomic analysis. Functional characterisation of differentially expressed proteins suggested changes in pathways related to metabolism, protein-binding, and pathways associated cardiac function including β-adrenergic signalling. Together, these data suggest an important role for PMCA1 in basal cardiac function in relation to heart rhythm control, with reduced cardiac PMCA1 expression resulting in an increased risk of arrhythmia development.

Copyright © 2022. Published by Elsevier Ltd.

J Mol Cell Cardiol: 01 Aug 2022; epub ahead of print
Wilson C, Stafford N, Zi M, Chelu A, ... Trafford AW, Cartwright EJ
J Mol Cell Cardiol: 01 Aug 2022; epub ahead of print | PMID: 35926724
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Abstract

Genetic and functional analyses of TBX4 reveal novel mechanisms underlying pulmonary arterial hypertension.

Yoshida Y, Uchida K, Kodo K, Shibata H, ... Takahashi T, Yamagishi H
Background
Pulmonary arterial hypertension (PAH) is a fatal disease, with approximately 10% of cases associated with genetic variants. Recent genetic studies have reported pathogenic variants in the TBX4 gene in patients with PAH, especially in patients with childhood-onset of the disease, but the pathogenesis of PAH caused by TBX4 variant has not been fully uncovered.
Methods
We analysed the TBX4 gene in 75 Japanese patients with sporadic or familial PAH using a PCR-based bidirectional sequencing method. Detected variants were evaluated using in silico analyses as well as in vitro analyses including luciferase assay, immunocytochemistry and chromatin immunoprecipitation (ChIP) whether they have altered function. We also analysed the function of TBX4 using mouse embryonic lung explants with inhibition of Tbx4 expression.
Results
Putative pathogenic variants were detected in three cases (4.0%). Our in vitro functional analyses revealed that TBX4 directly regulates the transcriptional activity of fibroblast growth factor 10 (FGF10), whereas the identified TBX4 variant proteins failed to activate the FGF10 gene because of disruption of nuclear localisation signal or poor DNA-binding affinity. Furthermore, ex vivo inhibition of Tbx4 resulted in insufficiency of lung morphogenesis along with specific downregulation of Tie2 and Kruppel-like factor 4 expression.
Conclusion
Our results implicate variants in TBX4 as a genetic cause of PAH in a subset of the Japanese population. Variants in TBX4 may lead to PAH through insufficient lung morphogenesis by disrupting the TBX4-mediated direct regulation of FGF10 signalling and pulmonary vascular endothelial dysfunction involving PAH-related molecules.

Copyright © 2022 Elsevier Ltd. All rights reserved.

J Mol Cell Cardiol: 29 Jul 2022; 171:105-116
Yoshida Y, Uchida K, Kodo K, Shibata H, ... Takahashi T, Yamagishi H
J Mol Cell Cardiol: 29 Jul 2022; 171:105-116 | PMID: 35914404
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Abstract

Improved Ca release synchrony following selective modification of I and phase 1 repolarization in normal and failing ventricular myocytes.

Fowler ED, Wang N, Hezzell MJ, Chanoit G, Hancox JC, Cannell MB
Loss of ventricular action potential (AP) early phase 1 repolarization may contribute to the impaired Ca2+ release and increased risk of sudden cardiac death in heart failure. Therefore, restoring AP phase 1 by augmenting the fast transient outward K+ current (Itof) might be beneficial, but direct experimental evidence to support this proposition in failing cardiomyocytes is limited. Dynamic clamp was used to selectively modulate the contribution of Itof to the AP and Ca2+ transient in both normal (guinea pig and rabbit) and in failing rabbit cardiac myocytes. Opposing native Itof in non-failing rabbit myocytes increased Ca2+ release heterogeneity, late Ca2+ sparks (LCS) frequency and AP duration. (APD). In contrast, increasing Itof in failing myocytes and guinea pig myocytes (the latter normally lacking Itof) increased Ca2+ transient amplitude, Ca2+ release synchrony, and shortened APD. Computer simulations also showed faster Ca2+ transient decay (mainly due to fewer LCS), decreased inward Na+/Ca2+ exchange current and APD. When the Itof conductance was increased to ~0.2 nS/pF in failing cells (a value slightly greater than seen in typical human epicardial myocytes), Ca2+ release synchrony improved and AP duration decreased slightly. Further increases in Itof can cause Ca2+ release to decrease as the peak of the bell-shaped ICa-voltage relationship is passed and premature AP repolarization develops. These results suggest that there is an optimal range for Itof enhancement that may support Ca2+ release synchrony and improve electrical stability in heart failure with the caveat that uncontrolled Itof enhancement should be avoided.

Copyright © 2022. Published by Elsevier Ltd.

J Mol Cell Cardiol: 28 Jul 2022; epub ahead of print
Fowler ED, Wang N, Hezzell MJ, Chanoit G, Hancox JC, Cannell MB
J Mol Cell Cardiol: 28 Jul 2022; epub ahead of print | PMID: 35908686
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Abstract

GRK2 in cardiovascular disease and its potential as a therapeutic target.

Ferrero KM, Koch WJ
Cardiovascular diseases (CVDs) represent the leading cause of death globally. Despite major advances in the field of pharmacological CVD treatments, particularly in the field of heart failure (HF) research, case numbers and overall mortality remain high and have trended upwards over the last few years. Thus, identifying novel molecular targets for developing HF therapeutics remains a key research focus. G protein-coupled receptors (GPCRs) are critical myocardial signal transducers which regulate cardiac contractility, growth, adaptation and metabolism. Additionally, GPCR dysregulation underlies multiple models of cardiac pathology, and most pharmacological therapeutics currently used in HF target these receptors. Currently-approved treatments have improved patient outcomes, but therapies to stop or reverse HF are lacking. A recent focus on GPCR intracellular-regulating proteins such as GPCR kinases (GRKs) has uncovered GRK2 as a promising target for combating HF. Current literature strongly establishes increased levels and activity of GRK2 in multiple models of CVD. Additionally, the GRK2 interactome includes numerous proteins which interact with differential domains of GRK2 to modulate both beneficial and deleterious signaling pathways in the heart, indicating that these domains can be targeted with a high level of specificity unique to various cardiac pathologies. These data support the premise that GRK2 should be at the forefront of a novel investigative drug search. This perspective reviews cardiac GPCRs, describes the structure and functions of GRK2 in cardiac function and maladaptive pathology, and summarizes the ongoing and future research for targeting this critical kinase across cellular, animal and human models of cardiac dysfunction and HF.

Copyright © 2022. Published by Elsevier Ltd.

J Mol Cell Cardiol: 22 Jul 2022; epub ahead of print
Ferrero KM, Koch WJ
J Mol Cell Cardiol: 22 Jul 2022; epub ahead of print | PMID: 35878706
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Abstract

Integrins in cardiac fibrosis.

Li R, Frangogiannis NG
Cells sense mechanical stress and changes in their matrix environment through the integrins, a family of heterodimeric surface receptors that bind to extracellular matrix ligands and trigger cytoskeletal remodeling, while transducing a wide range of intracellular signals. Integrins have been extensively implicated in regulation of inflammation, repair and fibrosis in many different tissues. This review manuscript discusses the role of integrin-mediated cascades in myocardial fibrosis. In vitro studies have demonstrated that β1 and αv integrins play an important role in fibrogenic conversion of cardiac fibroblast, acting through direct stimulation of FAK/Src cascades, or via accentuation of growth factor signaling. Fibrogenic actions of αv integrins may be mediated, at least in part, through pericellular activation of latent TGF-β stores. In vivo evidence supporting the role of integrin heterodimers in fibrotic cardiac remodeling is limited to associative evidence, and to experiments using pharmacologic inhibitors, or global loss-of-function approaches. Studies documenting in vivo actions of integrins on fibroblasts using cell-specific strategies are lacking. Integrin effects on leukocytes may also contribute to the pathogenesis of fibrotic myocardial responses by mediating recruitment and activation of fibrogenic macrophages. The profile and role of integrins in cardiac fibrosis may be dependent on the underlying pathologic condition. Considering their cell surface localization and the availability of small molecule inhibitors, integrins may be attractive therapeutic targets for patients with heart failure associated with prominent fibrotic remodeling.

Copyright © 2022. Published by Elsevier Ltd.

J Mol Cell Cardiol: 21 Jul 2022; epub ahead of print
Li R, Frangogiannis NG
J Mol Cell Cardiol: 21 Jul 2022; epub ahead of print | PMID: 35872324
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Abstract

Current knowledge of pyroptosis in heart diseases.

Gao Y, Shi H, Dong Z, Zhang F, Sun A, Ge J
Pyroptosis is a form of pro-inflammatory, necrotic cell death mediated by proteins of the gasdermin family. Various heart diseases, including myocardial ischemia/reperfusion injury, myocardial infarction, and heart failure, involve cardiomyocyte and non-myocyte pyroptosis. Cardiomyocyte pyroptosis also causes the release of pro-inflammatory cytokines. Recent studies have confirmed that pyroptosis is predominantly triggered by both the canonical and non-canonical inflammasome pathways, which independently facilitate caspase-1 or caspase-11/4/5 activation and gasdermin D (GSDMD) cleavage. Cardiac fibroblast and myeloid cell pyroptosis also contributes to the pathogenesis and development of heart diseases. This review summarizes the recent studies on pyroptosis in heart diseases and discusses the associated therapeutic targets.

Copyright © 2022. Published by Elsevier Ltd.

J Mol Cell Cardiol: 19 Jul 2022; epub ahead of print
Gao Y, Shi H, Dong Z, Zhang F, Sun A, Ge J
J Mol Cell Cardiol: 19 Jul 2022; epub ahead of print | PMID: 35868567
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Abstract

Engineering stem cell therapeutics for cardiac repair.

Fang J, Li JJ, Zhong X, Zhou Y, ... Cheng K, Li S
Cardiovascular disease is the leading cause of death in the world. Stem cell-based therapies have been widely investigated for cardiac regeneration in patients with heart failure or myocardial infarction (MI) and surged ahead on multiple fronts over the past two decades. To enhance cellular therapy for cardiac regeneration, numerous engineering techniques have been explored to engineer cells, develop novel scaffolds, make constructs, and deliver cells or their derivatives. This review summarizes the state-of-art stem cell-based therapeutics for cardiac regeneration and discusses the emerged bioengineering approaches toward the enhancement of therapeutic efficacy of stem cell therapies in cardiac repair. We cover the topics in stem cell source and engineering, followed by stem cell-based therapies such as cell aggregates and cell sheets, and biomaterial-mediated stem cell therapies such as stem cell delivery with injectable hydrogel, three-dimensional scaffolds, and microneedle patches. Finally, we discuss future directions and challenges of engineering stem cell therapies for clinical translation.

Copyright © 2022 Elsevier Ltd. All rights reserved.

J Mol Cell Cardiol: 18 Jul 2022; 171:56-68
Fang J, Li JJ, Zhong X, Zhou Y, ... Cheng K, Li S
J Mol Cell Cardiol: 18 Jul 2022; 171:56-68 | PMID: 35863282
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Abstract

Deficiency of cystathionine gamma-lyase promotes aortic elastolysis and medial degeneration in aged mice.

Zhu J, Wang Y, Rivett A, Li H, ... Wang R, Yang G
Enzymatic degradation of elastin by matrix metalloproteinases (MMPs) leads to the permanent dilation of aortic wall and constitutes the most prominent characters of aortic aneurysm and aging-related medial degeneration. Hydrogen sulfide (H2S) as a gasotransmitter exhibits a wide variety of cardio-protective functions through its anti-inflammatory and anti-oxidative actions. Cystathionine gamma-lyase (CSE) is a main H2S-generating enzyme in cardiovascular system. The regulatory roles of CSE/H2S system on elastin homeostasis and blood vessel degeneration have not yet been explored. Here we found that aged CSE knockout mice had severe aortic dilation and elastic degradation in abdominal aorta and were more sensitive to angiotensin II-induced aortic elastolysis and medial degeneration. Administration of NaHS would protect the mice from angiotensin II-induced inflammation, gelatinolytic activity, elastin fragmentation, and aortic dilation. In addition, human aortic aneurysm samples had higher inflammatory infiltration and lower expression of CSE. In cultured smooth muscle cells (SMCs), TNFα-induced MMP2/9 hyperactivity and elastolysis could be attenuated by exogenously applied NaHS or CSE overexpression while further deteriorated by complete knockout of CSE. It was further found that H2S inhibited MMP2 transcription by posttranslational modification of Sp1 via S-sulfhydration. H2S also directly suppressed MMP hyperactivity by S-sulfhydrating the cysteine switch motif. Taken together, this study revealed the involvement of CSE/H2S system in the pathogenesis of aortic elastolysis and medial degeneration by maintaining the inactive form of MMPs, suggesting that CSE/H2S system can be a target for the prevention of age-related medial degeneration and treatment of aortic aneurysm.

Copyright © 2022 Elsevier Ltd. All rights reserved.

J Mol Cell Cardiol: 14 Jul 2022; 171:30-44
Zhu J, Wang Y, Rivett A, Li H, ... Wang R, Yang G
J Mol Cell Cardiol: 14 Jul 2022; 171:30-44 | PMID: 35843061
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Abstract

Induction of GLI1 by miR-27b-3p/FBXW7/KLF5 pathway contributes to pulmonary arterial hypertension.

Wang Q, Chai L, Zhang Q, Wang J, ... Xie X, Li M
Glioma-associated oncogene homolog 1 (GLI1), a zinc-finger transcription factor, is upregulated in tumors and promotes cancer cell proliferation and migration. However, whether GLI1 involves in pulmonary artery smooth muscle cells (PASMCs) proliferation and migration and the detailed molecular mechanisms underlying GLI1 in pulmonary arterial hypertension (PAH) are not yet clear. Primary cultured rat PASMCs and monocrotaline (MCT)-induced PAH rats model were applied to address these issues in the present study. We found that the expression of GLI1 was significantly increased in endothelin-1 (ET-1) treated PASMCs, accompanied with the activation of microRNA (miR)-27b-3p/F-box and WD repeat domain containing 7 (FBXW7)/kruppel-like factor 5 (KLF5)/GLI1 pathway through endothelin-1 receptor type A (ETAR). Elevated miR-27b-3p suppressed FBXW7 expression, which led to KLF5 accumulation by decreasing its ubiquitinated degradation, KLF5 further induced GLI1 upregulation leading to PASMCs proliferation and migration. In addition, in MCT-induced PAH rats, targeting ETAR/miR-27b-3p/FBXW7/KLF5/GLI1 pathway effectively prevented the pulmonary vascular remodeling and the development of PAH in rats. Our study indicates that interfering ETAR/miR-27b-3p/FBXW7/KLF5/GLI1 signaling axis might have a potential value in the prevention and treatment of PAH.

Copyright © 2022 Elsevier Ltd. All rights reserved.

J Mol Cell Cardiol: 07 Jul 2022; 171:16-29
Wang Q, Chai L, Zhang Q, Wang J, ... Xie X, Li M
J Mol Cell Cardiol: 07 Jul 2022; 171:16-29 | PMID: 35810662
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Abstract

Insights on aortic aneurysm and dissection: Role of the extracellular environment in vascular homeostasis.

Wang Y, Gao P, Li F, Du J
Aortic aneurysm and dissection (AAD) is a life-threatening medical condition associated with high morbidity and mortality rates. Important mechanisms underlying AAD are the dysregulation of vascular homeostasis and adverse remodeling. Vascular homeostasis maintains normal physiological function. Various physical, chemical, biological, and other internal or external environmental changes dysregulate vascular homeostasis, leading to vascular degeneration and aggravated aortic injury. This process is dependent on the communication between homeostatic mechanisms and the extracellular environment, such as local inflammatory cytokines, vasoactive substances, and hemodynamics. In this article, we summarize recent reports by Chinese researchers who studied the pathogenic mechanisms of AAD mainly from the perspective of communication of the extracellular environment with vascular homeostasis and improving diagnostic methods and therapeutic options for patients with AAD. This review aims to provide a roadmap for AAD that encompasses its pathogenesis and clinical aspects. We hope to facilitate future studies on the development of effective treatments and preventive therapies, and thus improve patient outcomes.

Copyright © 2022. Published by Elsevier Ltd.

J Mol Cell Cardiol: 04 Jul 2022; epub ahead of print
Wang Y, Gao P, Li F, Du J
J Mol Cell Cardiol: 04 Jul 2022; epub ahead of print | PMID: 35798048
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This program is still in alpha version.