<div><h4>Visualization of cardiac thick filament dynamics in ex vivo heart preparations.</h4><i>Kelly CM, Martin JL, Coseno M, Previs MJ</i><br /><b>Rationale</b><br />Cardiac muscle cells are terminally differentiated after birth and must beat continually throughout one\'s lifetime. This mechanical process is driven by the sliding of actin-based thin filaments along myosin-based thick filaments, organized within sarcomeres. Despite costly energetic demand, the half-life of the proteins that comprise the cardiac thick filaments is ~10 days, with individual molecules being replaced stochastically, by unknown mechanisms.<br /><b>Objectives</b><br />To allow for the stochastic replacement of molecules, we hypothesized that the structure of thick filaments must be highly dynamic in vivo.<br /><b>Methods and results</b><br />To test this hypothesis in adult mouse hearts, we replaced a fraction of the endogenous myosin regulatory light chain (RLC), a component of thick filaments, with GFP-labeled RLC by adeno-associated viral (AAV) transduction. The RLC-GFP was properly localized to the heads of the myosin molecules within thick filaments in ex vivo heart preparations and had no effect on heart size or actin filament siding in vitro. However, the localization of the RLC-GFP molecules was highly mobile, changing its position within the sarcomere on the minute timescale, when quantified by fluorescence recovery after photobleaching (FRAP) using multiphoton microscopy. Interestingly, RLC-GFP mobility was restricted to within the boundaries of single sarcomeres. When cardiomyocytes were lysed, the RLC-GFP remained strongly bound to myosin heavy chain, and the intact myosin molecules adopted a folded, compact configuration, when disassociated from the filaments at physiological ionic conditions.<br /><b>Conclusions</b><br />These data demonstrate that the structure of the thick filament is highly dynamic in the intact heart, with a rate of molecular exchange into and out of thick filaments that is ~1500 times faster than that required for the replacement of molecules through protein synthesis or degradation.<br /><br />Copyright © 2023. Published by Elsevier Ltd.<br /><br /><small>J Mol Cell Cardiol: 01 Nov 2023; epub ahead of print</small></div>

<div><h4>The characteristics of proliferative cardiomyocytes in mammals.</h4><i>Yang X, Li L, Zeng C, Wang WE</i><br /><AbstractText>Better understanding of the mechanisms regulating the proliferation of pre-existing cardiomyocyte (CM) should lead to better options for regenerating injured myocardium. The absence of a perfect research model to definitively identify newly formed mammalian CMs is lacking. However, methodologies are being developed to identify and enrich proliferative CMs. These methods take advantages of the different proliferative states of CMs during postnatal development, before and after injury in the neonatal heart. New approaches use CMs labeled in lineage tracing animals or single cell technique-based CM clusters. This review aims to provide a timely update on the characteristics of the proliferative CMs, including their structural, functional, genetic, epigenetic and metabolic characteristics versus non-proliferative CMs. A better understanding of the characteristics of proliferative CMs should lead to the mechanisms for inducing endogenous CMs to self-renew, which is a promising therapeutic strategy to treat cardiac diseases that cause CM death in humans.</AbstractText><br /><br />Copyright © 2023. Published by Elsevier Ltd.<br /><br /><small>J Mol Cell Cardiol: 31 Oct 2023; 185:50-64</small></div>

<div><h4>Clustering properties of the cardiac ryanodine receptor in health and heart failure.</h4><i>Waddell HMM, Mereacre V, Alvarado FJ, Munro ML</i><br /><AbstractText>The cardiac ryanodine receptor (RyR2) is an intracellular Ca<sup>2+</sup> release channel vital for the function of the heart. Physiologically, RyR2 is triggered to release Ca<sup>2+</sup> from the sarcoplasmic reticulum (SR) which enables cardiac contraction; however, spontaneous Ca<sup>2+</sup> leak from RyR2 has been implicated in the pathophysiology of heart failure (HF). RyR2 channels have been well documented to assemble into clusters within the SR membrane, with the organisation of RyR2 clusters recently gaining interest as a mechanism by which the occurrence of pathological Ca<sup>2+</sup> leak is regulated, including in HF. In this review, we explain the terminology relating to key nanoscale RyR2 clustering properties as both single clusters and functionally grouped Ca<sup>2+</sup> release units, with a focus on the advancements in super-resolution imaging approaches which have enabled the detailed study of cluster organisation. Further, we discuss proposed mechanisms for modulating RyR2 channel organisation and the debate regarding the potential impact of cluster organisation on Ca<sup>2+</sup> leak activity. Finally, recent experimental evidence investigating the nanoscale remodelling and functional alterations of RyR2 clusters in HF is discussed with consideration of the clinical implications.</AbstractText><br /><br />Copyright © 2023. Published by Elsevier Ltd.<br /><br /><small>J Mol Cell Cardiol: 25 Oct 2023; epub ahead of print</small></div>

<div><h4>Glimepiride, a novel soluble epoxide hydrolase inhibitor, protects against heart failure via increasing epoxyeicosatrienoic acids.</h4><i>Zhao C, Jiang X, Peng L, Zhang Y, ... Chen C, Wang DW</i><br /><b>Background</b><br />Epoxyeicosatrienoic acids (EETs), which exert multiple endogenous protective effects, are hydrolyzed into less active dihydroxyeicosatrienoic acids (DHETs) by soluble epoxide hydrolase (sEH). However, commercial drugs related to EETs or sEH are not yet in clinical use.<br /><b>Methods</b><br />Firstly, the plasma concentration of EETs and DHETs of 316 patients with heart failure (HF) were detected and quantitated by liquid chromatography-tandem mass spectrometry. Then, transverse aortic constriction (TAC)-induced HF was introduced in cardiomyocyte-specific Ephx2<sup>-/-</sup> mice. Moreover, Western blot, real-time PCR, luciferase reporter, ChIP assays were employed to explore the underlying mechanism. Finally, multiple sEH inhibitors were designed, synthesized, and validated in vitro and in vivo.<br /><b>Results</b><br />The ratios of DHETs/EETs were increased in the plasma from patients with HF. Meanwhile, the expression of sEH was upregulated in the heart of patients and mice with HF, especially in cardiomyocytes. Cardiomyocyte-specific Ephx2<sup>-/-</sup> mice ameliorated cardiac dysfunction induced by TAC. Consistently, Ephx2 knockdown protected Angiotensin II (AngII)-treated cardiomyocytes via increasing EETs in vitro. Mechanistically, AngII could enhance the expression of transcript factor Krüppel-like factor 15 (KLF15), which in turn upregulated sEH. Importantly, glimepiride was identified as a novel sEH inhibitor, which benefited from the elevated EETs during HF.<br /><b>Conclusions</b><br />Glimepiride attenuates HF in mice in part by increasing EETs.<br /><b>Clinical trial identifier</b><br />NCT03461107 (https://clinicaltrials.gov).<br /><br />Copyright © 2023. Published by Elsevier Ltd.<br /><br /><small>J Mol Cell Cardiol: 21 Oct 2023; 185:13-25</small></div>

<div><h4>Computational insight into energy control balance by Ca and cAMP-PKA signaling in pacemaker cells.</h4><i>Mazgaoker S, Yaniv Y</i><br /><AbstractText>Cyclic adenosine monophosphate (cAMP(-protein kinase A (PKA) signaling controls sinoatrial node cell (SANC) function by affecting the degree of coupling between Ca<sup>2+</sup> and membrane clocks. PKA is known to phosphorylate ionic channels, Ca<sup>2+</sup> pump and release from the sarcoplasmic reticulum, and enzymes controlling ATP production in the mitochondria. While the PKA cytosolic targets in SANC have been extensively explored, its mitochondrial targets and its ability to maintain SANC energetic balance remain to be elucidated. To investigate the role of PKA in SANC energetics, we tested three hypotheses: (i) PKA is an important regulator of the ATP supply-to-demand balance, (ii) Ca<sup>2+</sup> regulation of energetics is important for maintenance of NADH level and (iii) abrupt reduction in ATP demand first reduces the AP firing rate and, after dropping below a certain threshold, leads to a reduction in ATP. To gain mechanistic insights into the ATP supply-to-demand matching regulators, a modified model of mitochondrial energy metabolism was integrated into our coupled-clock model that describes ATP demand. Experimentally, increased ATP demand was accompanied by maintained ATP and NADH levels. Ca<sup>2+</sup> regulation of energetics was found to be important in the maintenance of NADH and PKA regulation was found to be important in the maintenance of intracellular ATP and the increase in oxygen consumption. PKA inhibition led to a biphasic reduction in AP firing rate, with the first phase being rapid and ATP-independent, while the second phase was slow and ATP-dependent. Thus, SANC energy balance is maintained by both Ca<sup>2+</sup> and PKA signaling.</AbstractText><br /><br />Copyright © 2023. Published by Elsevier Ltd.<br /><br /><small>J Mol Cell Cardiol: 20 Oct 2023; epub ahead of print</small></div>

<div><h4>Characterization of heterozygous and homozygous mouse models with the most common hypertrophic cardiomyopathy mutation MYBPC3 in the Netherlands.</h4><i>Hilderink S, Schuldt M, Goebel M, Jansen V, ... van der Velden J, Kuster DWD</i><br /><AbstractText>Hypertrophic cardiomyopathy (HCM) is frequently caused by mutations in the cardiac myosin binding protein-C (cMyBP-C) encoding gene MYBPC3. In the Netherlands, approximately 25% of patients carry the MYBPC3<sub>c.2373InsG</sub> founder mutation. Most patients are heterozygous (MYBPC3<sup>+/InsG</sup>) and have highly variable phenotypic expression, whereas homozygous (MYBPC3<sup>InsG/InsG</sup>) patients have severe HCM at a young age. To improve understanding of disease progression and genotype-phenotype relationship based on the hallmarks of human HCM, we characterized mice with CRISPR/Cas9-induced heterozygous and homozygous mutations. At 18-28 weeks of age, we assessed the cardiac phenotype of Mybpc3<sup>+/InsG</sup> and Mybpc3<sup>InsG/InsG</sup> mice with echocardiography, and performed histological analyses. Cytoskeletal proteins and cardiomyocyte contractility of 3-4 week old and 18-28 week old Mybpc3<sub>c.2373InsG</sub> mice were compared to wild-type (WT) mice. Expectedly, knock-in of Mybpc3<sub>c.2373InsG</sub> resulted in the absence of cMyBP-C and our 18-28 week old homozygous Mybpc3<sub>c.2373InsG</sub> model developed cardiac hypertrophy and severe left ventricular systolic and diastolic dysfunction, whereas HCM was not evident in Mybpc3<sup>+/InsG</sup> mice. Mybpc3<sup>InsG/InsG</sup> cardiomyocytes also presented with slowed contraction-relaxation kinetics, to a greater extent in 18-28 week old mice, partially due to increased levels of detyrosinated tubulin and desmin, and reduced cardiac troponin I (cTnI) phosphorylation. Impaired cardiomyocyte contraction-relaxation kinetics were successfully normalized in 18-28 week old Mybpc3<sup>InsG/InsG</sup> cardiomyocytes by combining detyrosination inhibitor parthenolide and β-adrenergic receptor agonist isoproterenol. Both the 3-4 week old and 18-28 week old Mybpc3<sup>InsG/InsG</sup> models recapitulate HCM, with a severe phenotype present in the 18-28 week old model.</AbstractText><br /><br />Copyright © 2023. Published by Elsevier Ltd.<br /><br /><small>J Mol Cell Cardiol: 14 Oct 2023; epub ahead of print</small></div>

<div><h4>Loss of TIMP3, but not TIMP4, exacerbates thoracic and abdominal aortic aneurysm.</h4><i>Hu M, Meganathan I, Zhu J, MacArthur R, Kassiri Z</i><br /><b>Aims</b><br />Aorta exhibits regional heterogeneity (structural and functional), while different etiologies for thoracic and abdominal aortic aneurysm (TAA, AAA) are recognized. Tissue inhibitor of metalloproteinases (TIMPs) regulate vascular remodeling through different mechanisms. Region-dependent functions have been reported for TIMP3 and TIMP4 in vascular pathologies. We investigated the region-specific function of these TIMPs in development of TAA versus AAA.<br /><b>Methods & results</b><br />TAA or AAA was induced in male and female mice lacking TIMP3 (Timp3<sup>-/-</sup>), TIMP4 (Timp4<sup>-/-</sup>) or in wildtype (WT) mice by peri-adventitial elastase application. Loss of TIMP3 exacerbated TAA and AAA severity in males and females, with a greater increase in proteinase activity, smooth muscle cell phenotypic switching post-AAA and -TAA, while increased inflammation was detected in the media post-AAA, but in the adventitia post-TAA. Timp3<sup>-/-</sup> mice showed impaired intimal barrier integrity post-AAA, but a greater adventitial vasa-vasorum branching post-TAA, which could explain the site of inflammation in AAA versus TAA. Severity of TAA and AAA in Timp4<sup>-/-</sup> mice was similar to WT mice. In vitro, Timp3 knockdown more severely compromised the permeability of human aortic EC monolayer compared to Timp4 knockdown or the control group. In aneurysmal aorta specimens from patients, TIMP3 expression decreased in the media in AAA, and in adventitial in TAA specimens, consistent with the impact of its loss in AAA versus TAA in mice.<br /><b>Conclusion</b><br />TIMP3 loss exacerbates inflammation, adverse remodeling and aortic dilation, but triggers different patterns of remodeling in AAA versus TAA, and through different mechanisms.<br /><br />Copyright © 2023 Elsevier Ltd. All rights reserved.<br /><br /><small>J Mol Cell Cardiol: 14 Oct 2023; 184:61-74</small></div>

<div><h4>Profibrotic COVID-19 subphenotype exhibits enhanced localized ER-dependent HSP47 expression in cardiac myofibroblasts in situ.</h4><i>Jacobs ER, Ross GR, Padilla N, Pan AY, ... Rui H, Benjamin IJ</i><br /><AbstractText>We recently described a subgroup of autopsied COVID-19 subjects (~40%), termed \'profibrotic phenotype,\' who exhibited clusters of myofibroblasts (Mfbs), which were positive for the collagen-specific chaperone heat shock protein 47 (HSP47<sup>+</sup>) in situ. This report identifies increased, localized (hot spot restricted) expression of αSMA, COLα1, POSTN and FAP supporting the identity of HSP47<sup>+</sup> cells as myofibroblasts and characterizing a profibrotic extracellular matrix (ECM) phenotype. Coupled with increased GRP78 in COVID-19 subjects, these data could reflect induction of the unfolded protein response for mitigation of proteostasis (i.e., protein homeostasis) dysfunction in discrete clusters of cells. ECM shifts in selected COVID-19 subjects occur without significant increases in either global trichrome positive staining or myocardial injury based quantitively on standard H&E scoring. Our findings also suggest distinct mechanism(s) for ECM remodeling in the setting of SARS-CoV-2 infection. The ratio of CD163<sup>+</sup>/CD68<sup>+</sup> cells is increased in hot spots of profibrotic hearts compared with either controls or outside of hot spots in COVID-19 subjects. In sum, matrix remodeling of human COVID-19 hearts in situ is characterized by site-restricted profibrotic mediated (e.g., HSP47<sup>+</sup> Mfbs, CD163<sup>+</sup> Mφs) modifications in ECM (i.e., COLα1, POSTN, FAP), with a strong correlation between COLα1 and HSP47<sup>+</sup>cells within hot spots. Given the established associations of viral infection (e.g., human immunodeficiency virus; HIV), myocardial fibrosis and sudden cardiac death, early screening tools (e.g., plasma biomarkers, noninvasive cardiac magnetic resonance imaging) for diagnosis, monitoring and treatment of fibrotic ECM remodeling are warranted for COVID-19 high-risk populations.</AbstractText><br /><br />Copyright © 2023. Published by Elsevier Ltd.<br /><br /><small>J Mol Cell Cardiol: 13 Oct 2023; epub ahead of print</small></div>

<div><h4>CaMKII, \'jack of all trades\' in inflammation during cardiac ischemia/reperfusion injury.</h4><i>Zhang W, Dong E, Zhang J, Zhang Y</i><br /><AbstractText>Myocardial infarction and revascularization cause cardiac ischemia/reperfusion (I/R) injury featuring cardiomyocyte death and inflammation. The Ca<sup>2+</sup>/calmodulin dependent protein kinase II (CaMKII) family are serine/ threonine protein kinases that are involved in I/R injury. CaMKII exists in four different isoforms, α, β, γ, and δ. In the heart, CaMKIIδ is the predominant isoform，with multiple splicing variants, such as δB, δ<sub>C</sub> and δ9. During I/R, elevated intracellular Ca<sup>2+</sup> concentrations and reactive oxygen species activate CaMKII. In this review, we summarized the regulation and function of CaMKII in multiple cell types including cardiomyocytes, endothelial cells, and macrophages during I/R. We conclude that CaMKII mediates inflammation in the microenvironment of the myocardium, resulting in cell dysfunction, elevated inflammation, and cell death. However, different CaMKII-δ variants exhibit distinct or even opposite functions. Therefore, reagents/approaches that selectively target specific CaMKII subtypes and variants are needed for evaluating and counteracting the exact role of CaMKII in I/R injury and developing effective treatments against I/R injury.</AbstractText><br /><br />Copyright © 2023. Published by Elsevier Ltd.<br /><br /><small>J Mol Cell Cardiol: 07 Oct 2023; epub ahead of print</small></div>

<div><h4>Caveolae-associated cAMP/Ca-mediated mechano-chemical signal transduction in mouse atrial myocytes.</h4><i>Medvedev RY, Turner DGP, DeGuire FC, Leonov V, ... Bondarenko VE, Glukhov AV</i><br /><AbstractText>Caveolae are tiny invaginations in the sarcolemma that buffer extra membrane and contribute to mechanical regulation of cellular function. While the role of caveolae in membrane mechanosensation has been studied predominantly in non-cardiomyocyte cells, caveolae contribution to cardiac mechanotransduction remains elusive. Here, we studied the role of caveolae in the regulation of Ca<sup>2+</sup> signaling in atrial cardiomyocytes. In Langendorff-perfused mouse hearts, atrial pressure/volume overload stretched atrial myocytes and decreased caveolae density. In isolated cells, caveolae were disrupted through hypotonic challenge that induced a temporal (<10 min) augmentation of Ca<sup>2+</sup> transients and caused a rise in Ca<sup>2+</sup> spark activity. Similar changes in Ca<sup>2+</sup> signaling were observed after chemical (methyl-β-cyclodextrin) and genetic ablation of caveolae in cardiac-specific conditional caveolin-3 knock-out mice. Acute disruption of caveolae, both mechanical and chemical, led to the elevation of cAMP level in the cell interior, and cAMP-mediated augmentation of protein kinase A (PKA)-phosphorylated ryanodine receptors (at Ser<sup>2030</sup> and Ser<sup>2808</sup>). Caveolae-mediated stimulatory effects on Ca<sup>2+</sup> signaling were abolished via inhibition of cAMP production by adenyl cyclase antagonists MDL12330 and SQ22536, or reduction of PKA activity by H-89. A compartmentalized mathematical model of mouse atrial myocytes linked the observed changes to a microdomain-specific decrease in phosphodiesterase activity, which disrupted cAMP signaling and augmented PKA activity. Our findings add a new dimension to cardiac mechanobiology and highlight caveolae-associated cAMP/PKA-mediated phosphorylation of Ca<sup>2+</sup> handling proteins as a novel component of mechano-chemical feedback in atrial myocytes.</AbstractText><br /><br />Copyright © 2023. Published by Elsevier Ltd.<br /><br /><small>J Mol Cell Cardiol: 05 Oct 2023; epub ahead of print</small></div>

<div><h4>Current optimized strategies for stem cell-derived extracellular vesicle/exosomes in cardiac repair.</h4><i>Wu R, Hu X, Wang J</i><br /><AbstractText>Ischemic heart diseases remain the leading cause of death globally, and stem cell-based therapy has been investigated as a potential approach for cardiac repair. Due to poor survival and engraftment in the cardiac ischemic milieu post transplantation, the predominant therapeutic effects of stem cells act via paracrine actions, by secreting extracellular vesicles (EVs) and/or other factors. Exosomes are nano-sized EVs of endosomal origin, and now viewed as a major contributor in facilitating myocardial repair and regeneration. However, EV/exosome therapy has major obstacles before entering clinical settings, such as limited production yield, unstable biological activity, poor homing efficiency, and low tissue retention. This review aims to provide an overview of the biogenesis and mechanisms of stem cell-derived EV/exosomes in the process of cardiac repair and discuss the current advancements in different optimized strategies to produce high-yield EV/exosomes with higher bioactivity, or engineer them with improved homing efficiency and therapeutic potency. In particular, we outline recent findings toward preclinical and clinical translation of EV/exosome therapy in ischemic heart diseases, and discuss the potential barriers in regard to clinical translation of EV/exosome therapy.</AbstractText><br /><br />Copyright © 2023. Published by Elsevier Ltd.<br /><br /><small>J Mol Cell Cardiol: 04 Oct 2023; 184:13-25</small></div>

<div><h4>Nonsense mediated decay factor UPF3B is associated with cMyBP-C haploinsufficiency in hypertrophic cardiomyopathy patients.</h4><i>Burkart V, Kowalski K, Disch A, Hilfiker-Kleiner D, ... Kraft T, Montag J</i><br /><AbstractText>Hypertrophic cardiomyopathy (HCM) is the most prevalent inherited cardiac disease. Up to 40% of cases are associated with heterozygous mutations in myosin binding protein C (cMyBP-C, MYBPC3). Most of these mutations lead to premature termination codons (PTC) and patients show reduction of functional cMyBP-C. This so-called haploinsufficiency most likely contributes to disease development. We analyzed mechanisms underlying haploinsufficiency using cardiac tissue from HCM-patients with truncation mutations in MYBPC3 (MYBPC3<sub>trunc</sub>). We compared transcriptional activity, mRNA and protein expression to donor controls. To differentiate between HCM-specific and general hypertrophy-induced mechanisms we used patients with left ventricular hypertrophy due to aortic stenosis (AS) as an additional control. We show that cMyBP-C haploinsufficiency starts at the mRNA level, despite hypertrophy-induced increased transcriptional activity. Gene set enrichment analysis (GSEA) of RNA-sequencing data revealed an increased expression of NMD-components. Among them, Up-frameshift protein UPF3B, a regulator of NMD was upregulated in MYBPC3<sub>trunc</sub> patients and not in AS-patients. Strikingly, we show that in sarcomeres UPF3B but not UPF1 and UPF2 are localized to the Z-discs, the presumed location of sarcomeric protein translation. Our data suggest that cMyBP-C haploinsufficiency in HCM-patients is established by UPF3B-dependent NMD during the initial translation round at the Z-disc.</AbstractText><br /><br />Copyright © 2023. Published by Elsevier Ltd.<br /><br /><small>J Mol Cell Cardiol: 03 Oct 2023; epub ahead of print</small></div>

<div><h4>Activation of neurokinin-III receptors modulates human atrial TASK-1 currents.</h4><i>Wiedmann F, Paasche A, Nietfeld J, Kraft M, ... Frey N, Schmidt C</i><br /><b>Rationale</b><br />The neurokinin-III receptor was recently shown to regulate atrial cardiomyocyte excitability by inhibiting atrial background potassium currents. TASK-1 (hK<sub>2P</sub>3.1) two-pore-domain potassium channels, which are expressed atrial-specifically in the human heart, contribute significantly to atrial background potassium currents. As TASK-1 channels are regulated by a variety of intracellular signalling cascades, they represent a promising candidate for mediating the electrophysiological effects of the Gq-coupled neurokinin-III receptor.<br /><b>Objective</b><br />To investigate whether TASK-1 channels mediate the neurokinin-III receptor activation induced effects on atrial electrophysiology.<br /><b>Methods and results</b><br />In Xenopus laevis oocytes, heterologously expressing neurokinin-III receptor and TASK-1, administration of the endogenous neurokinin-III receptor ligands substance P or neurokinin B resulted in a strong TASK-1 current inhibition. This could be reproduced by application of the high affinity neurokinin-III receptor agonist senktide. Moreover, preincubation with the neurokinin-III receptor antagonist osanetant blunted the effect of senktide. Mutagenesis studies employing TASK-1 channel constructs which lack either protein kinase C (PKC) phosphorylation sites or the domain which is regulating the diacyl glycerol (DAG) sensitivity domain of TASK-1 revealed a protein kinase C independent mechanism of TASK-1 current inhibition: upon neurokinin-III receptor activation TASK-1 channels are blocked in a DAG-dependent fashion. Finally, effects of senktide on atrial TASK-1 currents could be reproduced in patch-clamp measurements, performed on isolated human atrial cardiomyocytes.<br /><b>Conclusions</b><br />Heterologously expressed human TASK-1 channels are inhibited by neurokinin-III receptor activation in a DAG dependent fashion. Patch-clamp measurements, performed on human atrial cardiomyocytes suggest that the atrial-specific effects of neurokinin-III receptor activation on cardiac excitability are predominantly mediated via TASK-1 currents.<br /><br />Copyright © 2023. Published by Elsevier Ltd.<br /><br /><small>J Mol Cell Cardiol: 02 Oct 2023; epub ahead of print</small></div>

<div><h4>Role of ventrolateral part of ventromedial hypothalamus in post-myocardial infarction cardiac dysfunction induced by sympathetic nervous system.</h4><i>Liu Z, Liu Z, Xu X, Zhou Y, ... Jiang H, Yu L</i><br /><AbstractText>Psychological stress has been recognized as a contributing factor to worsened prognosis in patients with cardiac failure following myocardial infarction (MI). Although the ventrolateral part of the ventromedial hypothalamus (VMHVL) has been implicated in emotional distress, its involvement in post-MI cardiac dysfunction remains largely unexplored. This study was designed to investigate the effect of the VMHVL activation in the MI rat model and its underlying mechanisms. Our findings demonstrate that activation of VMHVL neurons enhances the activity of the cardiac sympathetic nervous system through the paraventricular nucleus (PVN) and superior cervical ganglion (SCG). This activation leads to an elevation in catecholamine levels, which subsequently modulates myosin function and triggers the release of anti-inflammatory factors, to exacerbate the post-MI cardiac prognosis. The denervation of the superior cervical ganglion (SGN) effectively blocked the cardiac sympathetic effects induced by the VMHVL activation, and ameliorated the cardia fibrosis and dysfunction. Therefore, our study identified the role of the \"VMHVL-PVN-SCG\" sympathetic pathway in the post-MI heart, and proposed SGN as a promising strategy in mitigating cardiac prognosis in stressful rats.</AbstractText><br /><br />Copyright © 2023. Published by Elsevier Ltd.<br /><br /><small>J Mol Cell Cardiol: 30 Sep 2023; epub ahead of print</small></div>

<div><h4>A cardiac amino-terminal GRK2 peptide inhibits insulin resistance yet enhances maladaptive cardiovascular and brown adipose tissue remodeling in females during diet-induced obesity.</h4><i>Manaserh IH, Bledzka KM, Ampong I, Junker A, Grondolsky J, Schumacher SM</i><br /><AbstractText>Obesity and metabolic disorders are increasing in epidemic proportions, leading to poor outcomes including heart failure. With a growing recognition of the effect of adipose tissue dysfunction on heart disease, it is less well understood how the heart can influence systemic metabolic homeostasis. Even less well understood is sex differences in cardiometabolic responses. Previously, our lab investigated the role of the amino-terminus of GRK2 in cardiometabolic remodeling using transgenic mice with cardiac restricted expression of a short peptide, βARKnt. Male mice preserved insulin sensitivity, enhanced metabolic flexibility and adipose tissue health, elicited cardioprotection, and improved cardiac metabolic signaling. To examine the effect of cardiac βARKnt expression on cardiac and metabolic function in females in response to diet-induced obesity, we subjected female mice to high fat diet (HFD) to trigger cardiac and metabolic adaptive changes. Despite equivalent weight gain, βARKnt mice exhibited improved glucose tolerance and insulin sensitivity. However, βARKnt mice displayed a progressive reduction in energy expenditure during cold challenge after acute and chronic HFD stress. They also demonstrated reduced cardiac function and increased markers of maladaptive remodeling and tissue injury, and decreased or aberrant metabolic signaling. βARKnt mice exhibited reduced lipid deposition in the brown adipose tissue (BAT), but delayed or decreased markers of BAT activation and function suggested multiple mechanisms contributed to the decreased thermogenic capacity. These data suggest a non-canonical cardiac regulation of BAT lipolysis and function that highlights the need for studies elucidating the mechanisms of sex-specific responses to metabolic dysfunction.</AbstractText><br /><br />Copyright © 2023. Published by Elsevier Ltd.<br /><br /><small>J Mol Cell Cardiol: 13 Sep 2023; epub ahead of print</small></div>

<div><h4>BAK contributes critically to necrosis and infarct generation during reperfused myocardial infarction.</h4><i>Qin D, Jia XF, Hanna A, Lee J, ... Frangogiannis NG, Kitsis RN</i><br /><AbstractText>At least seven cell death programs are activated during myocardial infarction (MI), but which are most important in causing heart damage is not understood. Two of these programs are mitochondrial-dependent necrosis and apoptosis. The canonical function of the pro-cell death BCL-2 family proteins BAX and BAK is to mediate permeabilization of the outer mitochondrial membrane during apoptosis allowing apoptogen release. BAX has also been shown to sensitize cells to mitochondrial-dependent necrosis, although the underlying mechanisms remain ill-defined. Genetic deletion of Bax or both Bax and Bak in mice reduces infarct size following reperfused myocardial infarction (MI/R), but the contribution of BAK itself to cardiomyocyte apoptosis and necrosis and infarction has not been investigated. In this study, we use Bak-deficient mice and isolated adult cardiomyocytes to delineate the role of BAK in the pathogenesis of infarct generation and post-infarct remodeling during MI/R and non-reperfused MI. Generalized homozygous deletion of Bak reduced infarct size ~50% in MI/R in vivo, which was attributable primarily to decreases in necrosis. Protection from necrosis was also observed in BAK-deficient isolated cardiomyocytes suggesting that the cardioprotection from BAK loss in vivo is at least partially cardiomyocyte-autonomous. Interestingly, heterozygous Bak deletion, in which the heart still retains ~28% of wild type BAK levels, reduced infarct size to a similar extent as complete BAK absence. In contrast to MI/R, homozygous Bak deletion did not attenuate acute infarct size or long-term scar size, post-infarct remodeling, cardiac dysfunction, or mortality in non-reperfused MI. We conclude that BAK contributes significantly to cardiomyocyte necrosis and infarct generation during MI/R, while its absence does not appear to impact the pathogenesis of non-reperfused MI. These observations suggest BAK may be a therapeutic target for MI/R and that even partial pharmacological antagonism may provide benefit.</AbstractText><br /><br />Copyright © 2023. Published by Elsevier Ltd.<br /><br /><small>J Mol Cell Cardiol: 12 Sep 2023; epub ahead of print</small></div>

<div><h4>Does the small conductance Ca-activated K current I flow under physiological conditions in rabbit and human atrial isolated cardiomyocytes?</h4><i>Giommi A, Gurgel ARB, Smith GL, Workman AJ</i><br /><b>Background</b><br />The small conductance Ca<sup>2+</sup>-activated K<sup>+</sup> current (I<sub>SK</sub>) is a potential therapeutic target for treating atrial fibrillation.<br /><b>Aim</b><br />To clarify, in rabbit and human atrial cardiomyocytes, the intracellular [Ca<sup>2+</sup>]-sensitivity of I<sub>SK</sub>, and its contribution to action potential (AP) repolarisation, under physiological conditions.<br /><b>Methods</b><br />Whole-cell-patch clamp, fluorescence microscopy: to record ion currents, APs and [Ca<sup>2+</sup>]<sub>i</sub>; 35-37°C.<br /><b>Results</b><br />In rabbit atrial myocytes, 0.5 mM Ba<sup>2+</sup> (positive control) significantly decreased whole-cell current, from -12.8 to -4.9 pA/pF (P < 0.05, n = 17 cells, 8 rabbits). By contrast, the I<sub>SK</sub> blocker apamin (100 nM) had no effect on whole-cell current, at any set [Ca<sup>2+</sup>]<sub>i</sub> (~100-450 nM). The I<sub>SK</sub> blocker ICAGEN (1 μM: ≥2 x IC<sub>50</sub>) also had no effect on current over this [Ca<sup>2+</sup>]<sub>i</sub> range. In human atrial myocytes, neither 1 μM ICAGEN (at [Ca<sup>2+</sup>]<sub>i</sub> ~ 100-450 nM), nor 100 nM apamin ([Ca<sup>2+</sup>]<sub>i</sub> ~ 250 nM) affected whole-cell current (5-10 cells, 3-5 patients/group). APs were significantly prolonged (at APD<sub>30</sub> and APD<sub>70</sub>) by 2 mM 4-aminopyridine (positive control) in rabbit atrial myocytes, but 1 μM ICAGEN had no effect on APDs, versus either pre-ICAGEN or time-matched controls. High concentration (10 μM) ICAGEN (potentially I<sub>SK</sub>-non-selective) moderately increased APD<sub>70</sub> and APD<sub>90</sub>, by 5 and 26 ms, respectively. In human atrial myocytes, 1 μM ICAGEN had no effect on APD<sub>30-90</sub>, whether stimulated at 1, 2 or 3 Hz (6-9 cells, 2-4 patients/rate).<br /><b>Conclusion</b><br />I<sub>SK</sub> does not flow in human or rabbit atrial cardiomyocytes with [Ca<sup>2+</sup>]<sub>i</sub> set within the global average diastolic-systolic range, nor during APs stimulated at physiological or supra-physiological (≤3 Hz) rates.<br /><br />Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.<br /><br /><small>J Mol Cell Cardiol: 11 Sep 2023; epub ahead of print</small></div>

<div><h4>Myeloid-specific deletion of Capns1 attenuates myocardial infarction injury via restoring mitochondrial function and inhibiting inflammasome activation.</h4><i>Xiao Z, Wei X, Li M, Yang K, ... Liang Y, Ge J</i><br /><b>Background</b><br />Mitochondrial dysfunction of macrophage-mediated inflammatory response plays a key pathophysiological process in myocardial infarction (MI). Calpains are a well-known family of calcium-dependent cysteine proteases that regulate a variety of processes, including cell adhesion, proliferation, and migration, as well as mitochondrial function and inflammation. CAPNS1, the common regulatory subunit of calpain-1 and 2, is essential for the stabilization and activity of the catalytic subunit. Emerging studies suggest that calpains may serve as key mediators in mitochondria and NLRP3 inflammasome. This study investigated the role of myeloid cell calpains in MI.<br /><b>Methods</b><br />MI models were constructed using myeloid-specific Capns1 knockout mice. Cardiac function, cardiac fibrosis, and inflammatory infiltration were investigated. In vitro, bone marrow-derived macrophages (BMDMs) were isolated from mice. Mitochondrial function and NLRP3 activation were assessed in BMDMs under LPS stimulation. ATP5A1 knockdown and Capns1 knock-out mice were subjected to MI to investigate their roles in MI injury.<br /><b>Results</b><br />Ablation of calpain activities by Capns1 deletion improved the cardiac function, reduced infarct size, and alleviated cardiac fibrosis in mice subjected to MI. Mechanistically, Capns1 knockout reduced the cleavage of ATP5A1 and restored the mitochondria function thus inhibiting the inflammasome activation. ATP5A1 knockdown antagonized the protective effect of Capns1 mKO and aggravated MI injury.<br /><b>Conclusion</b><br />This study demonstrated that Capns1 depletion in macrophages mitigates MI injury via maintaining mitochondrial homeostasis and inactivating the NLRP3 inflammasome signaling pathway. This study may offer novel insights into MI injury treatment.<br /><br />Copyright © 2023. Published by Elsevier Ltd.<br /><br /><small>J Mol Cell Cardiol: 07 Sep 2023; 183:54-66</small></div>