Review Article
Protein kinase Cα as a heart failure therapeutic target

https://doi.org/10.1016/j.yjmcc.2010.10.004Get rights and content

Abstract

Heart failure afflicts ~ 5 million people and causes ~ 300,000 deaths a year in the United States alone. Heart failure is defined as a deficiency in the ability of the heart to pump sufficient blood in response to systemic demands, which results in fatigue, dyspnea, and/or edema. Identifying new therapeutic targets is a major focus of current research in the field. We and others have identified critical roles for protein kinase C (PKC) family members in programming aspects of heart failure pathogenesis. More specifically, mechanistic data have emerged over the past 6–7 years that directly implicate PKCα, a conventional PKC family member, as a nodal regulator of heart failure propensity. Indeed, deletion of the PKCα gene in mice, or its inhibition in rodents with drugs or a dominant negative mutant and/or inhibitory peptide, has shown dramatic protective effects that antagonize the development of heart failure. This review will weigh all the evidence implicating PKCα as a novel therapeutic target to consider for the treatment of heart failure. This article is part of a special issue entitled “Key Signaling Molecules in Hypertrophy and Heart Failure.”

Research Highlights

► Multiple papers have shown that PKCa regulates cardiac contractility. ► Deletion or genetic inhibition of PKCa increases cardiac function and protects from failure. ► Pharmacologic inhibition of PKCa protects from heart failure after injury. ► PKCa inhibitory drugs are promising therapeutics for human heart failure.

Introduction

The protein kinase C (PKC) family of Ca2+ and/or lipid-activated serine/threonine kinases function downstream of many membrane-associated signal transduction pathways [1]. Approximately 10 different isozymes comprise the PKC family, which are broadly classified by their activation characteristics. The conventional PKC isozymes (α, βI, βII, and γ) are Ca2+- and lipid-activated, while the novel isozymes (ε, θ, η, and δ) and atypical isozymes (ζ and λ) are Ca2+-independent but activated by distinct lipids [1]. PKC family members contain N-terminal regulatory and C-terminal catalytic domains separated by a flexible hinge region. In the absence of activating cofactors, the catalytic domain is subject to autoinhibition by the regulatory domain mediated, in part, by a pseudosubstrate sequence motif that resembles the consensus sequence for phosphorylation by PKC [2]. For the classical PKC isozymes, binding of Ca2+ and phosphatidylserine to the C2 domain leads to increased membrane association. Binding of diacylglycerol (DAG) to the zinc finger region of the C1 domain causes a conformational change, further enabling activation of the enzyme [3]. For all PKC isoforms, membrane translocation provides a mechanism to regulate substrate access through docking complexes such as RACKs, although PKC isoforms may also function when unbound and free in the cytosol or nucleus [4]. In addition to changes in phosphorylation and translocation of PKC, alterations in PKC levels can also affect activity and signaling, such as during cardiac development and with pathological events. For example, PKCα, β, ε, and ζ expression are high in fetal and neonatal hearts but decrease in adult hearts [5]. Select PKC isoforms also increase during transition to heart failure in humans, suggesting a reversion back to a neonatal phenotype [3].

With respect to the conventional isoforms, PKCα is the predominant subtype expressed in the mouse, human, and rabbit hearts, while PKCβ and PKCγ are detectable but expressed at substantially lower levels [6], [7], [8]. Numerous reports have also associated PKCα activation or an increase in PKCα expression with hypertrophy, dilated cardiomyopathy, ischemic injury, or mitogen stimulation [1]. For example, hemodynamic pressure overload in rodents promotes translocation and presumed activation of PKCα during the hypertrophic phase or during the later stages of heart failure [9], [10], [11], [12], [13]. Increased expression of PKCα was also observed following myocardial infarction [14], [15]. Human heart failure has also been associated with increased activation of conventional PKC isoforms, including PKCα [15], [16]. Thus, PKCα fits an important criterion as a therapeutic target; its expression and activity are increased during heart disease.

Section snippets

PKCα gene-deleted mice

We and others have shown that PKCα functions as a fundamental regulator of cardiac contractility [17], [18]. PKCα−/− mice showed an increase in cardiac contractile performance in multiple experimental systems. For example, closed-chest invasive hemodynamic assessment showed a 15%–20% increase in maximum dP/dt at baseline, with a corresponding parallel increase in performance after β-adrenergic receptor stimulation. An ex vivo working heart preparation, which shows the intrinsic function of the

Molecular mechanisms of action

A number of independent molecular mechanisms have been associated with the known protection from heart failure by PKCα inhibition, although all of these mechanisms have so far been associated with modulation of cardiac contractility (Fig. 1). The first identified mechanism whereby PKCα inhibition enhances cardiac contractility is through SR Ca2+ loading [17]. Specifically, PKCα phosphorylates inhibitor 1 (I-1) at Ser67, resulting in greater protein phosphatase 1 activity, leading to greater

PKCα inhibitory drugs protect the rodent heart (translational data)

The results in genetically modified animal models and in isolated adult myocytes clearly show a cardioprotective effect with PKCα inhibition. Such results suggested that a nontoxic and tissue available pharmacological inhibitor with selectivity toward PKCα might be of significant therapeutic value. Thus, we and others carefully examined the effects of cPKC inhibitors of the bisindolylmaleimide class, such as ruboxistaurin (LY333531), Ro-32-0432, or Ro-31-8220, in different rodent heart failure

Important future considerations for bringing this to the clinic

Based on genetic experiments and various pharmacological studies discussed above, a more selective PKCα inhibitor would serve as a better therapeutic agent compared with existing cPKC inhibitors. For example, while the non-selective cPKC inhibitor ruboxistaurin also targets PKCβ and γ, inhibiting PKCα clearly predominates in providing protection to the heart [19]. Thus, a PKCα selective inhibitor would greatly reduce potential adverse effects and achieve greater efficacy, especially since PKCβγ

Disclosure Statement

None declared.

Acknowledgments

This work was supported by grants from the National Institutes of Health (NIH), the Fondation Leducq, and the Howard Hughes Medical Institute (J. D. M.). Q. L. was supported by a K99/R00 award from the NIH.

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