HSPA12B Is A Novel Cardioprotective Heat Shock Protein Against Cardiac Dysfunction And Remodeling Following Chronic Myocardial Infarction

Heat shock proteins (Hsps) have been shown to render cardioprotection from ischemic injury; however, little is known about the role of a newly discovered member of Hsp70 family, HSPA12B, which is predominantly expressed in endothelial cells, in cardioprotection against ischemic injury. We recently reported that overexpression of HSPA12B attenuates endotoxemia-induced cardiac inflammatory response. To investigate whether overexpression of HSPA12B exerts protective effects in cardiac ischemia, we employed a transgenic (Tg) mouse model with overexpression of HSPA12B in the experiments. Tg mice and wild-type littermates were subjected to permanent ligation of left anterior descending coronary artery for 4 weeks. Tg hearts exhibited improved cardiac function and ventricle remodeling. This improvement was accompanied by a significant increase in the formation of capillaries and arterioles, which was associated with increased protein levels of vascular endothelial growth factor (VEGF), angiopoietin-1 in Tg hearts. The extent of apoptotic cell death in Tg hearts was also significantly decreased 24 hrs post-infarction, which was associated with increased protein ratio of Bcl-2/Bax. Additionally, both in vivo and in vitro experiments showed that the expression of HSPA12B was inducible by ischemia or heat shock, an important feature of cytoprotective Hsps. Our data demonstrate that increased HSPA12B expression in endothelial cells protects against chronic cardiac injury, resulting in improved cardiac function and reduced ventricle remodeling. The mechanisms of this action involve promoting angiogenesis and attenuating cardiomyocyte apoptosis. Thus, HSPA12B may constitute a new therapeutic target for chronic ischemic heart diseases.