Review Article
βIIPKC and εPKC isozymes as potential pharmacological targets in cardiac hypertrophy and heart failure

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Abstract

Cardiac hypertrophy is a complex adaptive response to mechanical and neurohumoral stimuli and under continual stressor, it contributes to maladaptive responses, heart failure and death. Protein kinase C (PKC) and several other kinases play a role in the maladaptative cardiac responses, including cardiomyocyte hypertrophy, myocardial fibrosis and inflammation. Identifying specific therapies that regulate these kinases is a major focus of current research. PKC, a family of serine/threonine kinases, has emerged as potential mediators of hypertrophic stimuli associated with neurohumoral hyperactivity in heart failure. In this review, we describe the role of PKC isozymes that is involved in cardiac hypertrophy and heart failure. This article is part of a special issue entitled “Key Signaling Molecules in Hypertrophy and Heart Failure”.

Research Highlights

► bIIPKC and ePKC are potential intracellular nodes that play critical roles in cardiac hypertrophy and heart failure. ► bIIPKC isozyme is over-activated in human failing heart. ► Selective bIIPKC or ePKC inhibition improves cardiac function and survival in heart failure animal models. ► MAPK, AKT and PKD are PKC downstream targets involved in cardiac hypertrophy and heart failure.

Introduction

Cardiac remodeling is a target organ response to cardiovascular diseases and is an independent risk factor for coronary heart disease, stroke, arrhythmias, heart failure, and cardiovascular morbidity and mortality [1], [2], [3]. The process of cardiac hypertrophy involves multiple progressive alterations of heart geometry mediated by neurohumoral stimulating stress (i.e. epinephrine, norepinephrine, angiotensin II and aldosterone). Various kinases have been described as candidate mediators of the cardiac biochemical stress and trophic response induced by activation of neurohormone receptors [4]. Subcellular changes associated with cardiac hypertrophy and remodeling may be beneficial in the short term, but are often maladaptative and lead to functional decompensation in the long term. Along with this, the potential molecular events underlying the transition from compensated cardiac hypertrophy to failure are still under investigation. Thus a number of studies have focused on identifying intracellular distal strategic nodes where signals converge and/or serve as multi-effector brakes to suppress or reverse hypertrophy inside the cardiac muscle cell, which would become attractive targets for heart failure pharmacological therapy. In this review, we focus on βIIPKC and εPKC isozymes as potential intracellular nodes that play critical roles in cardiac hypertrophy and failure.

Section snippets

PKC isozymes and their distribution in the heart

Identified in 1977 by Nishizuka and coworkers [5], protein kinase C (PKC) is a group of closely related phospholipid-dependent serine-threonine protein kinases, which are activated as a result of receptor-dependent activation of phospholipase C and the hydrolysis of membrane phosphoinositides [6]. The physiological importance of PKC is underscored by the existence of ten different isozymes. These enzymes are classified according to their structure and activation requirements into the following

PKC isozymes in cardiac hypertrophy and heart failure

Prolonged increase of workload triggers cardiac hypertrophy, an adaptative response to normalize wall stress and compensate for the increased neurohormonal stimuli and hemodynamic load. At a cellular level, cardiac myocytes assume a hypertrophic phenotype associated with reactivation of fetal gene programs and quantitative/qualitative changes in the contractile machinery, subcellular organelles, cellular signaling and myocardial metabolism [19], [20]. Several studies have addressed the

PKC targets in cardiac hypertrophy and heart failure

As discussed above, βIIPKC and εPKC isozymes are suited to operate as molecular switches at nodal points in signaling pathways leading to cardiac hypertrophy and heart failure, and downstream mediators of PKC effects have been identified. Pro-hypertrophic stimulation of adult cardiomyocyte cultures with endothelin-1 (ET-1), angiotensin II or phorbol myristate acetate (PMA) resulted in PKC-mediated phosphorylation with further activation of several pro-survival kinases, including mTOR and S6K1

PKC inhibitors

Because specific PKC isozymes contribute to a wide variety of human diseases and sometimes exert even opposing effects in the same disease, the need to produce highly selective pharmacological PKC inhibitors is highlighted. A group of bisindolyl malelmide (BIM) compounds that are based on the scaffold of the nonspecific kinase inhibitor staurosporine have been a focus of active research. These compounds were reported to function as βPKC selective inhibitors and reverse cardiac remodeling and

Summary and perspectives

Taken together, studies using cultured cardiomyocytes, transgenic animals and selective pharmacological tools suggest that both βIIPKC and εPKC are key molecules involved in cardiac hypertrophy and heart failure. Avoiding pathological cardiac remodeling is a goal of heart failure therapy [55]. In this review, we describe a continuum of responses emanating from βIIPKC and εPKC isozymes that contribute to decompensated hypertrophy and heart failure (see Table 1 and Fig. 1). Because specific

Funding

This study was supported by National Institute of Health Grant HL076675 and HL52141 to DMR. JCF holds a post-doctoral fellowship from Fundação de Amparo a Pesquisa do Estado de São Paulo - Brasil (FAPESP 2009/03143-1). PCB holds a scholarship from Conselho Nacional de Pesquisa e Desenvolvimento, Brasil (CNPq BPQ 301519/2008-0).

Disclosures

DM-R is the founder of KAI Pharmaceuticals, Inc, a company that plans to bring PKC regulators to the clinic. However, none of the work described in this study is based on or supported by the company. Other authors have no disclosure.

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