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.

Fig. 1

BAG3 protein adapted from McCollum et al. [118]

Fig. 2

Role of BAG3 in the cell

Fig. 3

BAG3 levels in failing murine hearts. Wild-type c57BL/6 mice underwent trans-aortic banding (TAC) as has been described previously [119]. Eighteen weeks after TAC, left ventricular contractility was measured using a conductance catheter inserted into the left ventricle through a carotid approach as described previously. Heart weight to body weight ratios were calculated after killing (a). Contractility was measured during intravenous infusion of increasing doses of catecholamine (b). b Sham-operated hatched line = control; solid line = TAC mice. Hearts were then frozen for subsequent measurement of BAG3 levels. Myocardial proteins were extracted as we have described previously separated by gel electrophoresis and probed with a murine BAG3 antibody. As seen in c, there was a significant decrease in BAG3 levels by western blotting in TAC mice when compared with sham-operated controls. A representative western blot is seen in d

Fig. 4

Hemodynamic indices and BAG3 levels in non-infarcted left ventricular myocardium from a pig 4 weeks after balloon occlusion of the left anterior descending coronary artery. a ejection fraction; b fractional shortening; c end diastolic volume; d end systolic volume; e BAG3 levels; f representative western blot