A novel human S10F‐Hsp20 mutation induces lethal peripartum cardiomyopathy

Abstract

Heat shock protein 20 (Hsp20) has been shown to be a critical regulator of cardiomyocyte survival upon cardiac stress. In this study, we investigated the functional significance of a novel human Hsp20 mutation (S10F) in peripartum cardiomyopathy. Previous findings showed that cardiac‐specific overexpression of this mutant were associated with reduced autophagy, left ventricular dysfunction and early death in male mice. However, this study indicates that females have normal function with no alterations in autophagy but died within a week after 1‐4 pregnancies. Further examination of mutant females revealed left ventricular chamber dilation and hypertrophic remodelling. Echocardiography demonstrated increases in left ventricular end‐systolic volume and left ventricular end‐diastolic volume, while ejection fraction and fractional shortening were depressed following pregnancy. Subsequent studies revealed that cardiomyocyte apoptosis was elevated in mutant female hearts after the third delivery, associated with decreases in the levels of Bcl‐2/Bax and Akt phosphorylation. These results indicate that the human S10F mutant is associated with dysregulation of cell survival signalling, accelerated heart failure and early death post‐partum.

The BAG3-dependent and -independent roles of cardiac small heat shock proteins

“…Compared with non-Tg controls, male HSPB6 S10F -Tg mice developed DCM at 6 months of age, and their survival rate declined rapidly by 11 months (7). Interestingly, cardiac overexpression of HSPB6 S10F induces lethal peripartum cardiomyopathy in female Tg mice (8). The P20L mutation is located 4 amino acids downstream of the PKA/PKG-dependent Ser16 phosphorylation site (6).…”

“…Four sHSP members (HSPB5-8) are highly expressed in the heart (4). Mutations in sHSP-encoding genes have been associated with human cardiac disease (5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18), highlighting the important role of sHSPs in maintaining cardiac function.…”

Probenecid treatment improves outcomes in a novel mouse model of peripartum cardiomyopathy

“…While studying a naturally-occurring polymorphism in the Hsp20 gene (S10F), we recently discovered that this mutation not only diminished the cardioprotective effects of Hsp20 in a transgenic mouse model, but mutant female mice also developed DCM during the course of 2 to 4 pregnancies that resulted in the death of 70% after three pregnancies and 100% after the fourth [14]. It is well known that Hsp20 is a small heat shock protein that exhibits cardioprotective effects via inhibition of several signaling cascades that result in hypertrophy, apoptosis, and myocardial ischemia [15][16][17][18].…”

“…Molecular effects included an increase in atrial naturietic peptide (ANP), beta natriuretic peptide (BNP), and Caspase-3 activity. Thus, it was proposed that the mouse containing the Hsp20 S10F mutation would make a valid and potentially clinically relevant model of PPCM to study various therapeutic options [14].…”

“…As the Hsp20 S10F mutation is also associated with impaired calcium handling and increased apoptosis by impeding Hsp20's interaction with the proapoptotic protein Bax [14], we hypothesized that transient receptor potential vanilloid 2 (TRPV2) stimulation may play a protective role in the development of PPCM in this mouse model. The TRPV2 channel is a stretch and agonist-activated calcium channel [23].…”