Blocking Of Extracellular HSP70Activity Restores Cardiac Function And Attenuates Cardiac Remodeling Induced By Doxorubicin In Mice

Heart failure (HF), which is characterized by progressive ventricular remodeling and functional impairment, is a common terminal phase of heart diseases induced by a variety of injuries. In the progress of HF, cardiac output fails to meet the need of body metabolism because of impairment of myocardial systolic and (or) diastolic function. The incidence rate of HF is gradually increasing. However, the drug therapy only ameliorates symptoms of patient with HF and prognosis of surgery is always poor. The approach in the medical treatment of HF is merely adequate, so the discovery of new drug target is extremely urgent.Numerous evidences show that immune-inflammatory responses play an important role in the pathogenesis of HF. It might be a beneficial strategy to retard the progression of HF by immune modulation. Molecules of damage associated molecular patterns (DAMPs), which can be actively or passively released to the extracellular space, can ignite innate immune response by activating the pattern recognized receptors (for example, Toll like receptor), leading to inflammation response and tissue injury. Our previous research indicated that extracellular HSP70might act as a molecule of DAMP. We wondered if HSP70could induce immune response in the myocardium and participate in the pathogenesis of cardiac remodeling of HF. In this study, we explored the immune-stimulating activity of extracellular HSP70and blocked its activity by a specific anti-HSP70neutralizing antibody (HSP70Ab) to test whether inhibition of extra-HSP70activity could exert therapeutic efficiency against established cardiac remodeling and dysfunction induced by doxorubicin (Dox) and pressure overload. Our studies indicated that administration of Dox enhanced the level of HSP70in the myocardium and serum in mice and the most molecules of HSP70located in the membrane and extracellular space. Therapeutic blocking of extra-HSP70activity markedly attenuated Dox induced cardiac dysfunction and remodeling in acute and chronic HF. The inflammation responses were activated in the Dox-induced acute HF group, evidenced by increasing accumulation of neutrophils and expression of pro-inflammation mediators, including IL-6and IL-17. In contrast, functional blockage of extra-HSP70inhibited the accumulation of neutrophils in the myocardium and inhibited expression of pro-inflammatory mediators, whereas it elevated levels of anti-inflammation and pro-resolution mediators, including specific proteins and lipids. These results indicated that the cardiac protective effects of blocking extra-HSP70were largely attributed to its capability to regulate immune response and promote resolution of inflammation in the heart. Autophagy plays an important role in the immune regulation. Advanced studies indicated that functional blockage of extra-HSP70restored cardiac function and attenuated cardiac remodeling via mitigating oxidative stress, up-regulating autophagy activities and inhibiting cellular senescence in Dox-induced chronic HF in mice. Furthermore, our study indicated that extra-HSP70may act through combining with Toll-like receptor2and then activating its intracellular downstream signals. What’s more, some pro-resolution mediators, such as LXA4, ProD1and RvD1, can significantly inhibit the ligand-stimulated NFκB activity through interfering with NFκB translocation from cytoplast to nucleus. Our study will contribute to understanding the roles of inflammation responses in myocardial injury and remodeling and provide research clues for the development of new anti-HF drugs.