Regulation Of Cardiac Immune Microenvironments Attenuates Doxorubicin-Induced Myocardial Abnormal Remodeling And Dysfunction

Dilated cardiomyopathy (DCM) is a frequently occurring myocardial disease with poor understanding and prognosis. Abnormal cardiac remodeling characterized by cardiomyocyte apoptosis and cardiac fibrosis, is not only the key pathological changes of DCM, but also the most important reason of chronic heart failure. Numerous evidences show that immune responses play an important role in the progressive DCM. It might be a beneficial strategy to retard the progression of DCM by immune modulation. Both exogenous and endogenous pathogens induce to the injures of cardiovascular tissures, and then lots of molecules of damage associated molecular patterns (DAMPs) can be released from injured tissures and activate pattern recognition receptors (PRRs), including Toll-like receptors (TLRs) and non-TLRs, initiates the innate immune responses. Also this effect will modulate the development of adaptive immune response, especially the balance of Thl/Th2 immune responses which supports different immune functions and determine the outcome of tissures injures. In preliminary study we have found that doxorubicin (DOX), a well-known chemotherapeutic agent to cause DCM, stimulated the impairment of cardiomyocyte and maturation of DCs through the activation of TLR4. Thus, we interested if TLRs mediated DOX-induced DCM in vivo. Murine models of DCM were prepared by intraperitoneal injection of DOX. We explored the potential therapeutic effects and associated anti-remodeling mechanisms of TLR2/4 naturalizing antibodies and polysaccharides of mushroom CFX. Our results indicated that TLR4 or TLR2 mediated the different mechanisms in the regulation of cardiac remodeling. We found that pretreatment of mice with a TLR4-neutralizing antibody, but not TLR2-neutralizing antibody, protected from DOX-induced left ventricular dilatation and dysfunction. Moreover, blockage of TLR4 activity not only decreased the animal death but also protected the hearts against DOX-induced cardiomyocyte atrophy, apoptosis, and cardiac fibrosis. These results demonstrated that TLR4 plays a critical role in the acute myocardial inflammatory injury of DOX. However, TLR2-neutralizing antibody, but not TLR4, showed significant efficiency in established cardiac fibrosis and dysfunction induced by acute and chronic administration of DOX. The anti-fibrotic effect of TLR2 antibody related to its reverse role of suppressive immune microenvironment in the hearts. These results suggested that targeting TLR2 has a great potential for prevention and treatment of cardiac fibrosis and chronic heart failure. Our studies also indicated that the cardioprotective actions of targeting TLR2/4 was associated a significant decrease in the expression and extracellular distribution of high mobility group box 1 protein (HMGB1) which was markedly increased in the DOX-injured heart. HMGB1 is a nuclear component that acts as an chromatin-binding factor, but extracellularly it serves as a molecule of DAMPs involved in acute and chronic inflammation. Actually, blocking extracellular activity of HMGB1 by glycyrrhizin, a specific HMGB1 inhibitor, could protect from DOX-induced left ventricular dilatation, dysfunction and cardiac fibrosis. The cardiac protective effects of glycyrrhizin were largely attributed to its capability to block DOX-activated immune response in the heart, which was characterized by increasing the expression of profibrotic factor TGF-P and IL-6. CFX is the fermentative polysaccharides of medical mushroom with potent immune activity. We found that CFX treatment markedly attenuated DOX-induced cardiac dysfunction and fibrosis, which was related to suppress inflammatory responses and attenuate local oxidative stress. In conclusion, the results of this study will not only contribute to understanding the immunopathogenesis of myocardial impairment and fibrosis, but also provide the research clues for the development of new anti-chronic heart failure drugs.