Proteotoxicity and Cardiac Dysfunction

Abstract

Baseline physiological function of the mammalian heart is under the constant threat of environmental or intrinsic pathological insults. Cardiomyocyte proteins are thus subject to unremitting pressure to function optimally and this depends upon them assuming and maintaining proper conformation. This review explores the multiple defenses a cell may employ for its proteins to assume and maintain correct protein folding and conformation. There are multiple quality control mechanisms to ensure that nascent polypeptides are properly folded and mature proteins maintain their functional conformation. When proteins do misfold, either in the face of normal or pathologic stimuli or because of intrinsic mutations or post-translational modifications, they must either be refolded correctly or recycled. In the absence of these corrective processes, they may become toxic to the cell. Herein, we explore some of the underlying mechanisms that lead to proteotoxicity. The continued presence and chronic accumulation of misfolded or unfolded proteins can be disastrous in cardiomyocytes as these misfolded proteins can lead to aggregation or the formation of soluble peptides that are proteotoxic. This in turn leads to compromised protein quality control and precipitating a downward spiral of the cell's ability to maintain protein homeostasis. Some underlying mechanisms are discussed and the therapeutic potential of interfering with proteotoxicity in the heart is explored.

EHRA/HRS/APHRS/SOLAECE expert consensus on atrial cardiomyopathies: Definition, characterization, and clinical implication

“…77 Amyloidosis represent the deposition of insoluble, fibrillar proteins in a cross b-sheet structure that characteristically binds dyes such as Congo red. The most common form of age-related or senile amyloidosis is limited to the atrium, a condition known as isolated atrial amyloidosis (IAA).…”

Protein Quality Control and Metabolism: Bidirectional Control in the Heart

“…As a post-mitotic cell, cardiomyocytes possess little, if any, replicative capacity in adult life (Bergmann et al, 2009). Thus, maintaining balanced protein quality is fundamental to minimize cellular dysfunction and death (Willis and Patterson, 2013). At the same time, it has been firmly established that metabolic derangements contribute to the pathogenesis of heart disease (Lopaschuk et al, 2010).…”

Association between Heat Shock Protein‐60 and Development of Atrial Fibrillation: Results from the Multi‐Ethnic Study of Atherosclerosis (MESA)

“…Studies in the preclinical setting have shown that the HSPs have a cardioprotective role against cellular stress. Sensing of cellular stress leads to activation of heat shock transcription factor-1 (HSF-1) which upregulates the expression of HSPs [5]. HSP-60 plays an important role in cytoprotection by preventing denaturation and enhancing proper assembly of cellular proteins [23].…”

“…Epidemiological risk factors for AF such as aging, valvular heart disease, hypertension and cardiomyopathy cause atrial stretch and adverse remodeling, which mediate the pathogenesis of AF [3]. Preclinical studies have demonstrated that induction of heat shock proteins (HSPs) has a cytoprotective role against various cardiac diseases [4, 5]. HSPs play an important role in protein-protein interactions such as the establishment of proper protein confirmation and prevention of unwanted aggregation that occurs during cardiac stress [5, 6].…”

“…Preclinical studies have demonstrated that induction of heat shock proteins (HSPs) has a cytoprotective role against various cardiac diseases [4, 5]. HSPs play an important role in protein-protein interactions such as the establishment of proper protein confirmation and prevention of unwanted aggregation that occurs during cardiac stress [5, 6]. In cardiomyocytes, HSPs bind to damaged proteins such as sarcomeric proteins and prevent further adverse structural remodeling and functional loss [6, 7].…”