BAG3: a new player in the heart failure paradigm

Abstract

BAG3 is a cellular protein that is expressed predominantly in skeletal and cardiac muscle but can also be found in the brain and in the peripheral nervous system. BAG3 functions in the cell include: serving as a co-chaperone with members of the heat-shock protein family of proteins to facilitate the removal of misfolded and degraded proteins, inhibiting apoptosis by interacting with Bcl2 and maintaining the structural integrity of the Z-disk in muscle by binding with CapZ. The importance of BAG3 in the homeostasis of myocytes and its role in the development of heart failure was evidenced by the finding that single allelic mutations in BAG3 were associated with familial dilated cardiomyopathy. Furthermore, significant decreases in the level of BAG3 have been found in end-stage failing human heart and in animal models of heart failure including mice with heart failure secondary to trans-aortic banding and in pigs after myocardial infarction. Thus, it becomes relevant to understand the cellular biology and molecular regulation of BAG3 expression in order to design new therapies for the treatment of patients with both hereditary and non-hereditary forms of dilated cardiomyopathy.

Bcl-2–associated athanogene 3 protects the heart from ischemia/reperfusion injury

“…The subjective evaluations of the confocal images were confirmed by counting the number of yellow and red puncta in each group (control, H/R, Ad-siBAG3, and H/R plus Ad-BAG3; Figure 3B). In addition, the average ratio of autolysosomes (red puncta) to auto- 2 and 95% nitrogen at 3 l/min) in the absence of glucose for 14 hours at 37°C followed by reoxygenated for 4 hours with 5% CO 2 and 95% humidified air in medium containing glucose (hypoxia/ reoxygenation [H/R]) or under normoxic conditions. Myocytes were then harvested and cellular lysates were immunoblotted for BAG3, cleaved caspase-3, B cell lymphoma 2 (Bcl-2), and lysosomal-associated protein 2 (LAMP-2).…”

“…First identified by its ability to bind Bcl-2, BAG3 is expressed most abundantly in the heart and skeletal muscle and in many cancers. BAG3 serves as a cochaperone with members of the heat shock family of proteins to regulate protein quality control, interacts with Bcl-2 to inhibit apoptosis, and maintains the structural integrity of the sarcomere by linking filamen with the Z-disc through binding with the actin capping protein β-1 (CapZβ1) (2).…”

BAG3 plays a central role in proteostasis in the heart

“…These results are consistent with the notion that the PQC mechanisms controlled by endogenous BAG3 are involved in protection against myocardial stress. In fact, upregulation of BAG3 improves cardiac function in a mouse model of chronic myocardial infarction and reduces cardiomyocyte death in response to ischemia and reperfusion (8). Thus, interventions to upregulate the level of endogenous BAG3 should be further considered for treating diseases associated with cardiac stress.…”

“…Thus, interventions to upregulate the level of endogenous BAG3 should be further considered for treating diseases associated with cardiac stress. Transcription of BAG3 is regulated by NF-κB and miR-371a-5p and in response to physical exercise (8). Interestingly, although both exercise and overexpression of ATG7 attenuate intracellular protein aggregates by inducing autophagy in desmin-related cardiomyopathy, exercise and ATG7 overexpression have the additive effects of improving cardiac function in another model of proteinopathy (24).…”

“…BCL2-associated athanogene 3 (BAG3) is a co-chaperone protein that regulates the ATPase activity of the HSP70 family and is predominantly expressed in striated muscles (7,8). BAG3 has been studied extensively during the past decade, because, together with small HSPB8, it directs the HSP70 chaperone complex to other proteins involved in major cellular functions, thereby mediating key PQC mechanisms.…”