Targeting Protein Kinase G to Treat Cardiac Proteotoxicity

Abstract

Impaired or insufficient protein kinase G (PKG) signaling and protein quality control (PQC) are hallmarks of most forms of cardiac disease, including heart failure. Their dysregulation has been shown to contribute to and exacerbate cardiac hypertrophy and remodeling, reduced cell survival and disease pathogenesis. Enhancement of PKG signaling and PQC are associated with improved cardiac function and survival in many pre-clinical models of heart disease. While many clinically used pharmacological approaches exist to stimulate PKG, there are no FDA-approved therapies to safely enhance cardiomyocyte PQC. The latter is predominantly due to our lack of knowledge and identification of proteins regulating cardiomyocyte PQC. Recently, multiple studies have demonstrated that PKG regulates PQC in the heart, both during physiological and pathological states. These studies tested already FDA-approved pharmacological therapies to activate PKG, which enhanced cardiomyocyte PQC and alleviated cardiac disease. This review examines the roles of PKG and PQC during disease pathogenesis and summarizes the experimental and clinical data supporting the utility of stimulating PKG to target cardiac proteotoxicity.

Keywords: PKG; autophagy; heart failure; proteasome; proteostasis; proteotoxicity.

FIGURE 1

Impaired cardiomyocyte proteostasis results in cardiac dysfunction. Cardiac pathologic stress increases production/formation of misfolded proteins that if not removed form large, insoluble protein aggregates. Cardiomyocytes utilize various processes to maintain proteostasis: misfolded proteins will be catalyzed by the ubiquitin proteasome system (UPS) through ubiquitination via a series of enzymatic reactions involving an ubiquitin activating enzyme (E1), ubiquitin conjugating enzyme (E2), and ubiquitin ligase (E3) for degradation by the proteasome (A). Chaperone-mediated autophagy is a process by which the heat shock cognate 70 (HSC70) complex recognizes and binds select protein targets for internalization and degradation to the lysosome through the lysosome-associated membrane protein 2A (LAMP2A) receptor (B). Macroautophagy is the bulk removal of proteins, protein aggregates, and organelles by first forming an autophagosome to surround the cargo followed by merging with the lysosome for degradation (C). The insufficiency or overwhelming of the protein degradation systems during cardiac stress results in an accumulation of aggregated proteins, culminating in reduced cardiac function and lifespan (D).

FIGURE 2

An overview of PKG regulation of cardiomyocyte protein quality control and therapeutic interventions to stimulate PKG activity. PKG is thought to be divided into two primary pools: the membrane and cytosolic pools. Natriuretic peptides binding to the natriuretic peptide receptor activate guanylate cyclase to produce cGMP and ultimately stimulate the membrane pool of PKG. Nitric oxide, produced by nitric oxide synthase, activates guanylate cyclase-1 to produce cGMP, culminating in the activation of the cytosolic PKG pool. Once activated, PKG can increase the activity of the proteasome or phosphorylation of TSC2 to inhibit mTORC1 and enhance autophagic flux. PKG stimulation of the proteasome or autophagy restores cardiomyocyte proteostasis during cardiac stress. AR, adrenoreceptor; GC-1, soluble guanylate cyclase 1; GC-A, guanylyl cyclase-A (receptor); GMP, cyclic guanylyl monophosphate; ER, endoplasmatic reticulum; mTORC1, mammalian target of rapamycin complex 1; NOS, nitric oxide synthase; NP, natriuretic peptide; NPR, NP receptor; PDE, phosphodiesterase; PKG, protein kinase G; PQC, protein quality control; TSC2, tuberin/tuberous sclerosis complex 2.