Abstract
Heart failure is a serious comorbidity and the most common cause of mortality in diabetes patients. Diabetic cardiomyopathy (DCM) features impaired cellular structure and function, culminating in heart failure; however, there is a dearth of specific clinical therapy for treating DCM. Protein homeostasis is pivotal for the maintenance of cellular viability under physiological and pathological conditions, particularly in the irreplaceable cardiomyocytes; therefore, it is tightly regulated by a protein quality control (PQC) system. Three evolutionarily conserved molecular processes, the unfolded protein response (UPR), the ubiquitin-proteasome system (UPS), and autophagy, enhance protein turnover and preserve protein homeostasis by suppressing protein translation, degrading misfolded or unfolded proteins in cytosol or organelles, disposing of damaged and toxic proteins, recycling essential amino acids, and eliminating insoluble protein aggregates. In response to increased cellular protein demand under pathological insults, including the diabetic condition, a coordinated PQC system retains cardiac protein homeostasis and heart performance, on the contrary, inappropriate PQC function exaggerates cardiac proteotoxicity with subsequent heart dysfunction. Further investigation of the PQC mechanisms in diabetes propels a more comprehensive understanding of the molecular pathogenesis of DCM and opens new prospective treatment strategies for heart disease and heart failure in diabetes patients. In this review, the function and regulation of cardiac PQC machinery in diabetes mellitus, and the therapeutic potential for the diabetic heart are discussed.
Highlights
Diabetes mellitus is one of the fastest-growing health issues worldwide, and it is a major threat to cardiovascular health
Accumulating evidence on the molecular pathogenesis of Diabetic cardiomyopathy (DCM) has revealed the essential roles of proper cellular protein quality control in diabetes-associated heart disease
Concerted action of the three cellular systems can tackle proteotoxicity, subsequently improving the cardiac outcome in diabetes; compromised protein quality control (PQC) mechanisms appear to contribute to heart disease as a result of impaired cellular homeostasis
Summary
Diabetes mellitus is one of the fastest-growing health issues worldwide, and it is a major threat to cardiovascular health. The increase in protein disulfide isomerase (PDI) [35], an ER chaperone, and sXBP1 expression [36] in ischemic human hearts suggest UPRER is an adaptive component of the cardiac stress response. The role of over-activated PERK-CHOP and ATF6 ensuing apoptotic signaling via BCL2 associated agonist of cell death (BAD) and contributing to ER-mediated cardiac dysfunction was recapitulated in T2DM rodent hearts [63].
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