1. Academic Validation
  2. Targeting heat shock protein 47 alleviated doxorubicin-induced cardiotoxicity and remodeling in mice through suppression of the NLRP3 inflammasome

Targeting heat shock protein 47 alleviated doxorubicin-induced cardiotoxicity and remodeling in mice through suppression of the NLRP3 inflammasome

  • J Mol Cell Cardiol. 2023 Nov 22:186:81-93. doi: 10.1016/j.yjmcc.2023.11.007.
Wenke Shi 1 Jiaojiao Chen 2 Nan Zhao 1 Yun Xing 1 Shiqiang Liu 1 Mengya Chen 1 Wenxi Fang 1 Tong Zhang 1 Lanlan Li 1 Heng Zhang 1 Min Zhang 3 Xiaofeng Zeng 4 Si Chen 4 Shasha Wang 4 Saiyang Xie 5 Wei Deng 6
Affiliations

Affiliations

  • 1 Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, PR China; Hubei Key Laboratory of Metabolic and Chronic Diseases, Wuhan, PR China.
  • 2 Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, PR China; Department of Pediatrics, Renmin Hospital of Wuhan University, Wuhan 430060, PR China.
  • 3 Department of Endocrinology, The Central Hospital of Enshi Tujia and Miao Autonomous Prefecture, Enshi 445000, PR China.
  • 4 Cardiovascular Research Institute of Wuhan University, Wuhan 430060, PR China.
  • 5 Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, PR China; Hubei Key Laboratory of Metabolic and Chronic Diseases, Wuhan, PR China. Electronic address: yangsai1995@whu.edu.cn.
  • 6 Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, PR China; Hubei Key Laboratory of Metabolic and Chronic Diseases, Wuhan, PR China. Electronic address: vivideng1982@whu.edu.cn.
Abstract

Aim: Doxorubicin-induced cardiotoxicity (DIC) is an increasing problem, occurring in many Cancer patients receiving anthracycline chemotherapy, ultimately leading to heart failure (HF). Unfortunately, DIC remains difficult to manage due to an ignorance regarding pathophysiological mechanisms. Our work aimed to evaluate the role of HSP47 in doxorubicin-induced HF, and to explore the molecular mechanisms.

Methods and results: Mice were exposed to multi-intraperitoneal injection of doxorubicin (DOX, 4mg/kg/week, for 6 weeks continuously) to produce DIC. HSP47 expression was significantly upregulated in serum and in heart tissue in DOX-treated mice and in isolated cardiomyocytes. Mice with cardiac-specific HSP47 overexpression and knockdown were generated using recombinant adeno-associated virus (rAVV9) injection. Importantly, cardiac-specific HSP47 overexpression exacerbated cardiac dysfunction in DIC, while HSP47 knockdown prevented DOX-induced cardiac dysfunction, cardiac atrophy and fibrosis in vivo and in vitro. Mechanistically, we identified that HSP47 directly interacted with IRE1α in cardiomyocytes. Furthermore, we provided powerful evidence that HSP47-IRE1α complex promoted TXNIP/NLRP3 inflammasome and reinforced USP1-mediated NLRP3 ubiquitination. Moreover, NLRP3 deficiency in vivo conspicuously abolished HSP47-mediated cardiac atrophy and fibrogenesis under DOX condition.

Conclusion: HSP47 was highly expressed in serum and cardiac tissue after doxorubicin administration. HSP47 contributed to long-term anthracycline chemotherapy-associated cardiac dysfunction in an NLRP3-dependent manner. HSP47 therefore represents a plausible target for future therapy of doxorubicin-induced HF.

Keywords

Cardiac remodeling; Doxorubicin cardiotoxicity; Heart failure; Heat shock protein 47; NLRP3 inflammasome.

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