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.

Keywords: biomarkers; cardiomyopathy; drug targets; heat shock protein; pregnancy; stress.

Figure 1

Stress associated with PPCM development. Approximately 10% of PPCM cases present within the third trimester, while 90% of PPCM cases present postpartum. Hemodynamic changes associated with pregnancy begin in the second trimester and persist to approximately 6 months postpartum. Several other stresses, such as hormonal changes are also associated with pregnancy.

Figure 2

Proposed roles of Hsps in PPCM. In cells, Hsp70s perform both housekeeping and stress response related roles. Hsp70s co-operate with various co-chaperones such as Hsp40 and Hsp110 to facilitate the de novo folding of polypeptides from the ribosome to facilitate their folding into their native conformations. Hsp70s also co-operate with Hsp90 and Hop to activate proteins. Hsp70s also form partnerships with Hsp60 to facilitate the translocation of proteins across membranes. Under stress conditions, Hsp70s prevent the formation of aggregates and also facilitate the degradation of misfolded/unfolded proteins.

Figure 3

Interaction of Carboxyl terminus of HSC70-interacting protein (CHIP) with binding partners for protein quality control. Hsp70 functions with co-chaperones CHIP, BAG3 and Hop in maintain cellular proteostasis. (A) The CHIP pathway involves the association of CHIP with Ub, E2, BAG3, Bcl-2-associated athanogene 3 and Hsp70 to facilitate degradation. (B) Formation of sHSPs-BAG3-HSP70 complex to prevent aggregation of proteins thus forming insoluble substrates in the cardiomyocytes. (C) Hsp70-Hsp90 Organising Protein (Hop) adaptor properties to link Heat shock protein 70 (Hsp70) with Heat shock protein 90 for client substrates transfer.

Figure 4

Predicted interactome of several Hsps with PPCM proteins. The heat map shows the interaction of PPCM pathogenesis proteins with Hsp70, Hsp90 and sHsp group members.

Figure 5

Key stages in the PPCM pathophysiology pathway which are modulated by Hsps. Hsps interact with several proteins involved in the PPCM pathophysiological pathway. (A) Several Hsp70 isoforms interact with various proteins involved in PPCM pathogenesis. (B) The stages within the PPCM pathophysiology pathway where Hsp90 and sHsps interact with PPCM proteins are shown. Targeting these stages may be crucial in novel PPCM interventions.

Figure 6

Potential effects of Hsp-directed inhibition in PPCM therapy. Targeting the Hsp types sHsp, Hsp110, Hsp90, and Hsp70 has the potential to disrupt key signalling pathways that are important in PPCM pathophysiology.

Figure 7

Hsps as potential PPCM biomarkers. The Hsps (sHsps, Hsp60, Hsp70, Hsp90) predicted to associate with PPCM pathogenesis proteins may be used as candidate biomarkers.