BAG3 Expression and Sarcomere Localization in the Human Heart are Linked to HSF-1 and are Differentially Affected by Sex and Disease.

Mutations to the sarcomere-localized co-chaperone protein Bcl2-associated athanogene 3 (BAG3) are associated with dilated cardiomyopathy (DCM) and display greater penetrance in male patients. Decreased protein expression of BAG3 is also associated with non-genetic heart failure, however, the factors regulating cardiac BAG3 expression are unknown. Using left ventricular (LV) tissue from non-failing and DCM human samples we found that whole LV BAG3 expression was not significantly impacted by DCM or sex, however, myofilament localized BAG3 was significantly decreased in males with DCM. DCM females displayed no changes in BAG3 compared with non-failing. This sex-difference appears to be estrogen independent as estrogen treatment in ovariectomized female rats had no impact on BAG3 expression. BAG3 gene expression is primarily regulated by heat shock transcription factor-1 (HSF-1). Thus, we next assessed the relationship between HSF-1 and BAG3 localization/expression. Whole LV HSF-1 expression and nuclear localized/active HSF-1 each displayed a striking positive correlation with whole LV BAG3 expression. We further show that HSF-1 localizes to the sarcomere Z-disc in cardiomyocytes and that this myofilament-associated HSF-1 pool decreases in heart failure. The decrease of HSF-1 was more pronounced in male patients and tightly correlated with myofilament BAG3 expression. Together our findings indicate that cardiac BAG3 expression and myofilament localization are differentially impacted by sex and disease and are linked to HSF-1. Our findings implicate decreased BAG3 expression in DCM pathogenesis for male, but not female patients, and suggest heart failure therapies targeting HSF-1 may be efficacious.