| Congestive or chronic heart failure (HF) is a common terminal phase of heart diseases induced by a variety of injury. Cardiac output of failing hearts fails to meet the need of body metabolism because of impairment of myocardial systolic and (or) diastolic function. Etiologies of HF include coronary heart diseases, hypertension, cardiomyopathy, cardiotoxins, valvular diseases, congenital heart diseases, and so on. As China enters the aging society, the incidence rate of HF is gradually increasing. Though significant progress in therapy of HF including drugs, intervention as well as surgery, these treatments only ameliorate symptoms and signs of patient with HF, improve their quality of life and delay the disease progression. Except for heart transplantation, there is no effective therapy for advanced HF.Cardiac remodeling, including loss of cardiomyocytes, myocardial hypertrophy and fibrosis, is a major pathological characteristic of multiple chronic heat diseases. Accumulating evidence demonstrated that immune-inflammatory responses played vital roles in adverse cardiac remodeling. Endogenous damage associated molecular patterns (DAMPs) released by damaged cells activated pattern recognition receptors (for example, toll like receptor) leading to inflammation and tissue injury, and were involved in the development and progression of HF. Research results showed that TLR2deficiency could mitigate doxorubicin (Dox) induced cardiac dysfunction, inflammation, cardiomyocytes apoptosis as well as improve survival rate, suggesting that TLR2mediated Dox triggered cardiac malfunction. However, we wonder whether inhibition of TLR2activity by anti-TLR2neutralizing antibody (TLR2Ab) would exert therapeutic efficiency against established cardiac remodeling and dysfunction triggered by chronic Dox administration. The findings indicated that therapeutic blocking TLR2activity markedly attenuated Dox induced cardiac dysfunction and remodeling as well as inflammatory responses in the heart. Then through detecting expressions of several important DAMPs strongly related to TLR2, we found Dox significantly upregulated levels of high mobility group box-1(HMGB1), Hsp70, S100A2and S00A8. However, blocking TLR2inhibited the upregulation of HMGB1and Hsp70, with more obvious suppression on HMGB1. Furthermore, TLR2Ab inhibited the interaction of HMGB1and TLR2as assessed by co-immunoprecipitation and confocal microscopy. Therefore, we speculated that Dox resulted in cardiac myocytes death and large mounts of HMGB1were released from these injured cells, and HMGB1participated in the development and progression of HF via engagement of TLR2. To validate the hypothesis, we wonder if administration of glycyrrhizin, functional antagonist of extracellular HMGB1, would exert protective action against injury induced by Dox, as TLR2Ab did. Our results demonstrated that prophylactic usage of glycyrrhizin significantly improved Dox induced myocardial dysfunction and remodeling, as well as repressed the interaction of HMGB1with TLR2. In conclusion, our findings validated that therapeutic blocking TLR2markedly ameliorated HF triggered by doxorubicin by suppressing the of HMGB1expression and the interaction between HMGB1and TLR2.To further confirm the universal role of targeting TLR2in improvement of HF, we utilized myocardial infarction model in mice prepared by surgical occlusion of left coronary artery. Similarly, blockage of TLR2mitigated functional impairment, cardiac inflammation, oxidative stress, cardiac fibrosis and cardiomyocytes apoptosis induced by ischemia, which were associated with activation of AMP-activated protein kinase (AMPK). Collectively, the results of our study not only contribute to understanding the roles of immune system (especially TLR2) in myocardial injury and remodeling, but also provide the research clues and potential targets for the development of new anti-HF and anti-myocardial infarction drugs. |
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