CaMKII exacerbates heart failure progression by activating class I HDACs
Graphical abstract
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
References (50)
- et al.
Beta-adrenergic receptor signaling in the heart: role of CaMKII
J. Mol. Cell. Cardiol.
(2010) - et al.
A dynamic pathway for calcium-independent activation of CaMKII by methionine oxidation
Cell
(2008) Oxidant stress promotes disease by activating CaMKII
J. Mol. Cell. Cardiol.
(2015)- et al.
CaMKII is a nodal signal for multiple programmed cell death pathways in heart
J. Mol. Cell. Cardiol.
(2017) - et al.
Mechanism of recruitment of class II histone deacetylases by myocyte enhancer factor-2
J. Mol. Biol.
(2005) - et al.
Myocardial remodeling is controlled by myocyte-targeted gene regulation of phosphodiesterase type 5
J. Am. Coll. Cardiol.
(2010) - et al.
CaMKIIdelta isoforms differentially affect calcium handling but similarly regulate HDAC/MEF2 transcriptional responses
J. Biol. Chem.
(2007) - et al.
HDAC-dependent ventricular remodeling
Trends Cardiovasc. Med.
(2013) - et al.
Class II histone deacetylases act as signal-responsive repressors of cardiac hypertrophy
Cell
(2002) - et al.
Transgenic overexpression of Hdac3 in the heart produces increased postnatal cardiac myocyte proliferation but does not induce hypertrophy
J. Biol. Chem.
(2008)