Treatment with anti-Hsp90 antibody mitigates fibronectin-related cardiac fibrosis induced by pressure overload in mice

Heart failure is a chronic condition with a poor prognosis, and the development of new treatments is an urgent necessity. Extracellular heat shock protein 90 (eHsp90) has been observed to increase in heart failure. However, the pathophysiological role of extracellular Hsp90 (eHsp90) in heart failure development remains unclear. Thus, this study aimed to examine the effects of the anti-Hsp90 antibody 1G6-D7, an eHsp90 inhibitor, on cardiac fibrosis induced by pressure overload. Eight-week-old male C57Bl/6N mice underwent transverse aortic constriction (TAC). Beginning 2 weeks after surgery, the anti-Hsp90 antibody or normal IgG was administered intravenously every 2 weeks. Mice treated with normal IgG developed chronic heart failure with severe myocardial fibrosis 8 weeks after TAC. By contrast, administration of the anti-Hsp90 antibody to the TAC mice partially attenuated myocardial fibrosis and improved cardiac function. The fibronectin level in the myocardial tissue and the interaction between Hsp90 and fibronectin increased in the TAC mice treated with normal IgG. Conversely, these pathophysiological changes were mitigated in the TAC mice treated with the anti-Hsp90 antibody. The results of this study suggest that eHsp90 contributes to cardiac fibrosis by mediating fibronectin in the extracellular space. Furthermore, treatment with the anti-Hsp90 antibody attenuated cardiac fibrosis, which is associated with decreased fibronectin levels. The results of this study indicate eHsp90 as a novel extracellular target molecule for treating heart failure. In addition, our findings also suggested that anti-Hsp90 antibody hold considerable promise as potential pharmaceutical agents for the treatment of heart failure by targeting eHsp90.