CaMKII exacerbates heart failure progression by activating class I HDACs

https://doi.org/10.1016/j.yjmcc.2020.09.007Get rights and content

Highlights

  • CaMKII directly enhances HDAC1 and HDAC3 deacetylase activity.

  • CaMKII induces HDAC1 and HDAC3 expression in the heart.

  • CaMKII promotes HDAC1/HDAC2/Sin3a repressive complex formation.

  • Class I HDAC inhibitors improve CaMKII hyperactivity induced cardiac hypertrophy.

  • HDAC inhibitor recovers CaMKII hyperactivity induced autophagy genes downregulation.

Abstract

Background

Persistent cardiac Ca2+/calmodulin dependent Kinase II (CaMKII) activation plays an essential role in heart failure development. However, the molecular mechanisms underlying CaMKII induced heart failure progression remains incompletely understood. Histone deacetylases (HDACs) are critical for transcriptional responses to stress, and contribute to expression of pathological genes causing adverse ventricular remodeling. Class I HDACs, including HDAC1, HDAC2 and HDAC3, promote pathological cardiac hypertrophy, whereas class IIa HDACs suppress cardiac hypertrophy. While it is known that CaMKII deactivates class IIa HDACs to enhance cardiac hypertrophy, the role of CaMKII in regulating class I HDACs during heart failure progression is unclear.

Methods and results

CaMKII increases the deacetylase activity of recombinant HDAC1, HDAC2 and HDAC3 via in vitro phosphorylation assays. Phosphorylation sites on HDAC1 and HDAC3 are identified with mass spectrometry. HDAC1 activity is also increased in cardiac-specific CaMKIIδC transgenic mice (CaMKIIδC-tg). Beyond post-translational modifications, CaMKII induces HDAC1 and HDAC3 expression. HDAC1 and HDAC3 expression are significantly increased in CaMKIIδC-tg mice. Inhibition of CaMKII by overexpression of the inhibitory peptide AC3-I in the heart attenuates the upregulation of HDAC1 after myocardial infarction surgery. Importantly, a potent HDAC1 inhibitor Quisinostat improves downregulated autophagy genes and cardiac dysfunction in CaMKIIδC-tg mice. In addition to Quisinostat, selective class I HDACs inhibitors, Apicidin and Entinostat, HDAC3 specific inhibitor RGFP966, as well as HDAC1 and HDAC3 siRNA prevent CaMKII overexpression induced cardiac myocyte hypertrophy.

Conclusion

CaMKII activates class I HDACs in heart failure, which may be a central mechanism for heart failure progression. Selective class I HDACs inhibition may be a novel therapeutic avenue to alleviate CaMKII hyperactivity induced cardiac dysfunction.

Introduction

Heart failure is one of the leading causes of death worldwide and represents a major healthcare burden [1]. Novel mechanism based therapies for heart failure are in high demand. Neurohormonal hyperactivity including persistent activation of β-adrenergic and angiotensin II (AngII) signaling is one of the fundamental mechanisms of adverse ventricular remodeling and heart failure development. As such, neurohormonal inhibition is the cornerstone of current heart failure therapy [1]. Ca2+/calmodulin-dependent kinase II (CaMKII) is a direct downstream effector of β-adrenergic [2] and AngII signaling [3], promoting cardiac hypertrophy [[4], [5], [6]], oxidative stress [3,7], cell death [8,9], arrhythmia [10], inflammation [11] and fibrosis [12]. Importantly, CaMKII activity is persistently elevated in heart failure patients despite standard neurohormonal inhibition therapies [13]. Therefore, new strategies need to be developed to mitigate the adverse effects of CaMKII hyperactivity.

The molecular mechanisms of CaMKII mediated pathological cardiac hypertrophy remain poorly understood. CaMKII is known to inhibit class IIa histone deacetylases (HDACs) [14,15], such as HDAC4 and HDAC5. Class IIa HDACs prevent cardiac hypertrophy by the suppression of the pro-hypertrophic transcription factor myocyte enhancer factor-2 (MEF2) [16]. The inhibition of class IIa HDACs by CaMKII results in exacerbated cardiac hypertrophy. In contrast to class IIa HDACs, class I HDACs promote cardiac hypertrophy through a number of mechanisms, including the suppression of inositol polyphosphate-5-phosphatase f (Inpp5f) expression and subsequent inhibition of glycogen synthase kinase 3β (GSK3β) signaling [17], or the inhibition of dual-specificity phosphatase 5 (DUSP5), a nuclear phosphatase that negatively regulates ERK1/2 elicited cardiac hypertrophy [18], or by attenuating autophagy via activation of mTOR signaling [19]. Here we investigated whether CaMKII regulates class I HDACs and whether class I HDAC inhibitors, many of which are already in clinical use [20], could represent novel therapies to antagonize persistently elevated CaMKII activity in heart failure patients.

Section snippets

Animal models and procedures

Study procedures were approved by the Johns Hopkins University and University of Pittsburgh Animal Care and Use Committees in accordance with National Institutes of Health guidelines. Cardiac-specific CaMKIIδC transgenic mice (CaMKIIδC-tg) [21] and cardiac-specific transgenic mice overexpressing CaMKII inhibitory peptide (AC3-I) [4] were generated as reported previously. CaMKIIδC-tg mice with 17 fold increase of the amount of CaMKII rapidly progress to heart failure and premature death. At the

CaMKII directly enhances HDAC1 activity by phosphorylation

CaMKII regulates HDAC4 signaling, a class IIa HDAC, through phosphorylation. CaMKII mediated phosphorylation of HDAC4 initiates translocation of HDAC4 from the nucleus into the cytoplasm by binding to 14-3-3 protein [14]. Class I HDACs are predominantly located in nucleus. Class I HDACs possess much stronger deacetylase activity than class IIa HDACs [28]. We first examined whether CaMKII could modulate class I HDACs deacetylase activity through phosphorylation. Recombinant HDAC1, HDAC2 and

Discussion

Persistent CaMKII activation, either by canonical Ca2+/calmodulin activation or non-canonical oxidative activation [3], plays an essential role in pathological cardiac hypertrophy and adverse ventricular remodeling [[4], [5], [6]]. CaMKII is a direct downstream target of β-adrenergic signaling [2] and Gαq signaling [3] (Endothelin, Angiotensin II), and mediates neurohormonal hyperactivity driven cardiac myocyte death [8], cardiac hypertrophy [[4], [5], [6]], Ca2+ mishandling [29], and fibrosis [

Author contributions

M.Z., Conceptualization; Data curation; Formal analysis; Funding acquisition; Investigation; Methodology; Project administration; Resources; Software; Supervision; Validation; Visualization; Writing - original draft; Writing - review & editing.

X.Y., R.J.Z., Q.W., J.M.G, Data curation; Formal analysis; Investigation; Methodology;

M.A.R., conducted confocal imaging studies;

D.B, conducted echocardiography studies; Data curation; Formal analysis;

E.D.L, H.J., Data curation; Formal analysis;

N.F.,

Declaration of Competing Interest

None to report.

Acknowledgements

This work was supported by the National Institutes of Health grant K08 HL130604, American Heart Association Innovative Project Award #18IPA34170219, UPMC Competitive Research Fund (Dr. Ning Feng), and Samuel and Emma Winters Foundation (Dr. Manling Zhang). We thank the support of Center for Biologic Imaging at University of Pittsburgh, and the confocal microscope was supported by NIH S10OD019973.

We greatly appreciate Dr. Mark Anderson's scientific suggestions and critical review of the

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