Heat Shock Proteins: Potential Modulators and Candidate Biomarkers of Peripartum Cardiomyopathy

Abstract

Peripartum cardiomyopathy (PPCM) is a potentially life-threatening condition in which heart failure and systolic dysfunction occur late in pregnancy or within months following delivery. To date, no reliable biomarkers or therapeutic interventions for the condition exist, thus necessitating an urgent need for identification of novel PPCM drug targets and candidate biomarkers. Leads for novel treatments and biomarkers are therefore being investigated worldwide. Pregnancy is generally accompanied by dramatic hemodynamic changes, including a reduced afterload and a 50% increase in cardiac output. These increased cardiac stresses during pregnancy potentially impair protein folding processes within the cardiac tissue. The accumulation of misfolded proteins results in increased toxicity and cardiac insults that trigger heart failure. Under stress conditions, molecular chaperones such as heat shock proteins (Hsps) play crucial roles in maintaining cellular proteostasis. Here, we critically assess the potential role of Hsps in PPCM. We further predict specific associations between the Hsp types Hsp70, Hsp90 and small Hsps with several proteins implicated in PPCM pathophysiology. Furthermore, we explore the possibility of select Hsps as novel candidate PPCM biomarkers and drug targets. A better understanding of how these Hsps modulate PPCM pathogenesis holds promise in improving treatment, prognosis and management of the condition, and possibly other forms of acute heart failure.

The Role of HSP90 Inhibitors in the Treatment of Cardiovascular Diseases

“…Cardiac fibroblasts are the main cell type of the heart muscle and are responsible for the synthesis and secretion of collagen in response to the hypertrophic response to pressure overload [ 104 ]. Cardiac fibrosis and hypertrophy can make signaling unbalanced leading to the development of the disease, and uncontrolled cardiomyopathy can eventually lead to congestive heart failure (HF) [ 11 , 105 , 106 ].…”

“…As molecular chaperones, their synthesis is related to protein misfolding and denaturation. HSPs can guide the synthesis of new polypeptides through protein folding, avoid protein misfolding and aggregation, and can restore the three-dimensional protein structure after partial deformation to achieve normal physiological functioning [ 4 , 11 ]. HSPs are also involved in controlling the transport of certain regulatory proteins and intracellular proteins.…”

Biomarkers in Peripartum Cardiomyopathy—What We Know and What Is Still to Be Found

“…Figure 4. shows selected endothelial miRs that may be significant for treating PPCM by decreasing angiogenesis via the decreased proliferation of endothelial cells or accelerated senescence of endothelial progenitor cells, increasing endothelial permeability, decreasing TIMPs, and increasing MMP activity that may cause excess inflammation and fibrosis, and additionally by activating macrophages [98][99][100][101][102]. Of particular interest is miR-10a, whose decreased level is associated with the activation of the NF-κβ pathway, known to trigger miR-146a synthesis and release from the endothelium to cardiomyocytes [22,98].…”

Proteotoxic stress response in atherosclerotic cardiovascular disease: Emerging role of heat shock factor 1

“…HSF1 and HSPs confer protection against cardiovascular diseases, including atrial fibrillation, cardiac hypertrophy, and cardiomyopathy ( 35 – 37 ). HSPs have been shown to play crucial roles in atherosclerosis but they can both positively and negatively affect the development of atherosclerosis ( 9 , 38 ).…”