期刊
JOURNAL OF THE AMERICAN HEART ASSOCIATION
卷 8, 期 20, 页码 -出版社
WILEY
DOI: 10.1161/JAHA.119.012338
关键词
cardiac dysfunction; cardiac remodeling; damage-associated molecular patterns; nuclear factor-kappa B; toll-like receptor
资金
- National Key Research and Development Program of China [2017YFA0205400]
- National Science and Technology Major Project of the Ministry of Science and Technology of China [2018ZX09711001-003-009]
- National Natural Science Foundation of China [81530093, 81773781, 81773800]
- Chinese Academy of Medical Sciences (CAMS)
- Innovation Fund for Medical Sciences [2016-I2M-1-007, 2016-I2M-1-010, 2016-I2M-3-008]
- CAMS Central Public-Interest Scientific Institution Basal Research Fund [2018PT35004, 2017PT35001]
Background-Heart failure (HF) is one of the most significant causes of morbidity and mortality for the cardiovascular risk population. We found previously that extracellular HSP70 (heat shock protein) is an important trigger in cardiac hypertrophy and fibrosis, which are associated with the development of heart dysfunction. However, the potential role of HSP70 in response to HF and whether it could be a target for the therapy of HF remain unknown. Methods and Results-An HF mouse model was generated by a single IP injection of doxorubicin at a dose of 15 mg/kg. Ten days later, these mice were treated with an HSP70 neutralizing antibody for 5 times. We observed that doxorubicin treatment increased circulating HSP70 and expression of HSP70 in myocardium and promoted its extracellular release in the heart. Blocking extracellular HSP70 activity by its antibody significantly ameliorated doxorubicin-induced left ventricular dilation and dysfunction, which was accompanied by a significant inhibition of cardiac fibrosis. The cardioprotective effect of the anti-HSP70 antibody was largely attributed to its ability to promote the resolution of myocardial inflammation, as evidenced by its suppression of the toll-like receptor 2-associated signaling cascade and modulation of the intracellular distribution of the p50 and p65 subunits of nuclear factor-kappa B. Conclusions-Extracellular HSP70 serves as a noninfectious inflammatory factor in the development of HF, and blocking extracellular HSP70 activity may provide potential therapeutic benefits for the treatment of HF.
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