Protein kinase Cθ is required for cardiomyocyte survival and cardiac remodeling

Abstract

Protein kinase Cs (PKCs) constitute a family of serine/threonine kinases, which has distinguished and specific roles in regulating cardiac responses, including those associated with heart failure. We found that the PKCθ isoform is expressed at considerable levels in the cardiac muscle in mouse, and that it is rapidly activated after pressure overload. To investigate the role of PKCθ in cardiac remodeling, we used PKCθ−/− mice. In vivo analyses of PKCθ−/− hearts showed that the lack of PKCθ expression leads to left ventricular dilation and reduced function. Histological analyses showed a reduction in the number of cardiomyocytes, combined with hypertrophy of the remaining cardiomyocytes, cardiac fibrosis, myofibroblast hyper-proliferation and matrix deposition. We also observed p38 and JunK activation, known to promote cell death in response to stress, combined with upregulation of the fetal pattern of gene expression, considered to be a feature of the hemodynamically or metabolically stressed heart. In keeping with these observations, cultured PKCθ−/− cardiomyocytes were less viable than wild-type cardiomyocytes, and, unlike wild-type cardiomyocytes, underwent programmed cell death upon stimulation with α1-adrenergic agonists and hypoxia. Taken together, these results show that PKCθ maintains the correct structure and function of the heart by preventing cardiomyocyte cell death in response to work demand and to neuro-hormonal signals, to which heart cells are continuously exposed.

PKC and PKN in heart disease

“…Knockout mice for PKCθ develop dilated cardiomyopathy accompanied by reduced fractional shortening, increased fibrosis, and enhanced levels of cardiomyopathy markers such as ANF, as well as activation of p38 and JNK pathways [71]. In contrast to the dramatic phenotype of PKCθ knockouts, genetic ablation of PKCδ and/or PKCε did not result in a profound postnatal cardiac baseline phenotype [72][73][74][75].…”

Signaling Pathways in Cardiac Myocyte Apoptosis

“…PKC ε may also inhibit apoptosis by phosphorylating Connexin-43 at Ser262 and inhibit interaction between Connexin-43 and Kir6.1, a pore-forming subunit of ATP-sensitive potassium channels [207]. Another PKC isoform, PKC θ , has been shown to be protective based on the observation that global deletion of PKC θ led to p38/JNK activation and ventricular dilation after pressure overload, and PKC θ −/− cardiomyocytes were more susceptible to apoptosis upon stimulation with PE and hypoxia [208]. Treatment with PKC inhibitor chelerythrine or BIM-1 abolished fibroblast growth factor-2 (FGF-2) mediated protection against DOX-induced apoptosis, suggesting that PKC activation is an important prosurvival mechanism downstream of FGF-2 [209].…”

Pharmacological Inhibition of PKCθ Counteracts Muscle Disease in a Mouse Model of Duchenne Muscular Dystrophy

“…In skeletal muscle, we and others showed that PKCθ is mostly involved in mediating signaling pathways regulating fetal and early post-natal growth and maturation ( Madaro et al, 2011 , Madaro et al, 2013 , Marrocco et al, 2014 , Messina et al, 2010 , Zappelli et al, 1996 ). Employing PKCθ −/− mice, we also showed that PKCθ maintains the correct structure and function of the heart by preventing cardiomyocyte cell death in response to work demand and to neuro-hormonal signals, to which heart cells are continuously exposed ( Paoletti et al, 2010 ).…”