BAG3 expression and sarcomere localization in the human heart are linked to HSF-1 and are differentially affected by sex and disease

Abstract

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.

Genotype-Phenotype Correlation in Familial BAG3 Mutation Dilated Cardiomyopathy

“…[ 13 ]. It was noticed that heat shock transcription factor-1 (HSF-1) expression in the myofilament fraction decreases in male patients with DCM and positively correlates with myofilament BAG3 [ 14 ]. Although one of the main risk factors for poor prognosis in some studies is male gender [ 11 , 13 ], other studies show that dangerous arrhythmias did not occur more frequently in men than in women [ 3 ].…”

Therapeutic targeting of BAG3: considering its complexity in cancer and heart disease

“…The levels of BAG3 in the human heart during HF are not influenced by either age or sex. However, myofilament localization of BAG3 was significantly decreased in cardiac tissue from males with DCM but not in heart tissue from females (121). This difference was independent of estrogen but was closely correlated with changes in LV heat shock transcription factor 1 (HSF1).…”

With or without You: Co-Chaperones Mediate Health and Disease by Modifying Chaperone Function and Protein Triage

“…Interestingly, sex plays a role in the prognosis of DCM patients with BAG3 mutations; females had a better prognosis and developed fewer cardiac events than their male counterparts [158]. Furthermore, reduced expression of BAG3 in myofilaments occurred only in male patients [159].…”

“…One confounding factor in developing anti-BAG3 therapeutics for cancer is that BAG3 plays an essential role in proper heart function, as discussed above. Most recently, Martin et al highlighted the cardiomyocyte toxicity of the cancer therapeutic JG-18 that targets the BAG3-HSP70 interaction [159]. Therefore, much like CHIP, BAG3 inhibitors should be extensively tested for their effects on heart function, as well as localized delivery systems.…”