Function of PKD1 in pathological cardiac remodeling

Function of the stress-dependent kinase Protein Kinase D1 (PKD1) in pathological cardiac remodeling

The adult heart responds to biomechanical stress and neurohormonal signaling by hypertrophic growth, accompanied by fibrosis, and activation of a fetal gene program leading to a diminished cardiac function. Class II histone deacetylases (HDACs) are negative regulators of pathological cardiac remodeling via the myocyte enhancer factor-2 (MEF2) transcription factor, an activator of heart disease. Protein kinase D1 (PKD1) is a stress-responsive kinase that phosphorylates class II HDACs, resulting in their dissociation from MEF2 with subsequent activation of MEF2 target genes. Cardiac PKD1 is activated in response to arterial hypertension, pressure overload, and chronic neurohormonal activation. We generated mice with a conditional PKD1-null allele (PKD1 cKO). Mice with cardiomyocyte-specific deletion of PKD1 showed diminished cardiac hypertrophy, interstitial and perivascular fibrosis, and fetal gene activation as well as improved cardiac function in response to chronic pressure overload or chronic angiotensin II (Ang II; Figure 1) and adrenergic signaling. These findings demonstrate that PKD1 in cardiomyocytes plays a key role in mediating stress-dependent remodeling and reprogramming of gene expression in the adult heart. However, in addition to transcriptional regulation PKD1 regulates myocyte contractility by phosphorylating contractile proteins. In further projects, we focus on non-transcriptional functions of PKD1 in acute cardiac stress response.

The effects of cardiomyocyte specific PKD1 elimination (cKO) in angiotensin II (Ang II) induced cardiac remodeling are shown. After Ang II treatment, PKD1 mutant mice (cKO) displayed less cardiac hypertrophy and a reduction in perivascular and interstitial fibrosis (hematoxylin and eosin and Masson's trichrome stainings; top panel). Gen expression of cardiac stress markers (i.e. Atrial natriuretic factor (ANF)), the fetal gene program (i.e. ß-myosin heavy chain (β-MHC)), and fibrosis (i.e. procollagen, type I, α2 (Col1α2)) was reduced in PKD1 mutant mice (bottom panel). Our data show that deletion of PKD1 in cardiomyocytes protects the heart from pathological cardiac remodelling.