Ca ²⁺ /Calmodulin-Dependent Protein Kinase IIδ and Protein Kinase D Overexpression Reinforce the Histone Deacetylase 5 Redistribution in Heart Failure

Abstract

Abstract-Cardiac hypertrophy and heart failure (HF) are associated with reactivation of fetal cardiac genes, and class II histone deacetylases (HDACs) (eg, HDAC5) have been strongly implicated in this process. We have shown previously that inositol trisphosphate, Ca 2ϩ /calmodulin-dependent protein kinase II (CaMKII), and protein kinase (PK)D are involved in HDAC5 phosphorylation and nuclear export in normal adult ventricular myocytes and also that CaMKII␦ and inositol trisphosphate receptors are upregulated in HF. Here we tested whether, in our rabbit HF model, nucleocytoplasmic shuttling of HDAC5 was altered either at baseline or in response to endothelin-1, which would indicate HDAC5 phosphorylation and transcription effects. The fusion protein HDAC5-green fluorescent protein (HDAC5-GFP) was more cytosolic in HF myocytes (F nuc /F cyto 3.3Ϯ0.3 vs 7.2Ϯ0.4 in control), and HDAC5 was more phosphorylated. Despite this baseline cytosolic HDAC5 shift, endothelin-1 produced more rapid HDAC5-GFP nuclear export in HF versus control myocytes. We also find that PKD and CaMKII␦ C expression and activation state are increased in both rabbit and human HF. Inhibition of either CaMKII or PKD in HF myocytes partially restored the HDAC5-GFP F nuc /F cyto toward control, and simultaneous inhibition restored F nuc /F cyto to that in control myocytes. Moreover, adenovirus-mediated overexpression of PKD, CaMKII␦ B , or CaMKII␦ C reduced baseline HDAC5 F nuc /F cyto in control myocytes (3.4Ϯ0.5, 3.8Ϯ0.5, and 5.2Ϯ0.5, respectively), approaching that seen in HF. We conclude that chronic upregulation and activation of inositol trisphosphate receptors, CaMKII, and PKD in HF shifts HDAC5 out of the nucleus, derepressing transcription of hypertrophic genes. This may directly contribute to the development and/or maintenance of HF.

The non-excitable smooth muscle: Calcium signaling and phenotypic switching during vascular disease

“…CaMKII δ isoforms couple to ERK1/2 signaling [1,47], and the δ 2 isoform was shown to specifically regulate VSMC migration [105,108]. Upregulation of CaMKII δ isoforms was shown to occur in models of cardiac hypertrophy and heart failure [23,166], as well as in regenerating skeletal muscle after injury [2].…”

Protein Kinase D3 Is a Pivotal Activator of Pathological Cardiac Hypertrophy by Selectively Increasing the Expression of Hypertrophic Transcription Factors

“…In the heart, PKD1 has been best characterized for its role in regulating myocardial contraction, cardiac hypertrophy and remodeling (27,28). PKD1 is a typical HDAC5 kinase and thus more relevant to HDAC5-MEF2 hypertrophic signaling (19,29). Mice with PKD1 ablation show substantial resistance to cardiac hypertrophy (30).…”

Emerging roles of inositol 1,4,5-trisphosphate signaling in cardiac myocytes

“…Indeed, it has been demonstrated that the release of perinuclear IP 3 -sensitive Ca 2+ stores promotes a CaMKII-dependent phosphorylation of histone deacetylase 5 (HDAC5) thereby causing it to be exported out of the nucleus [140]. Thus, perinuclear IP 3 -evoked Ca 2+ signals can derepress the expression of genes that underlie hypertrophic growth, such as those under the control of MEF2c [149]. It is well known that stimulation of myocytes with hormones that activate IP 3 production, e.g.…”