2. Academic Validation
  3. Inhibition of MyD88 by a novel inhibitor reverses two-thirds of the infarct area in myocardial ischemia and reperfusion injury

Inhibition of MyD88 by a novel inhibitor reverses two-thirds of the infarct area in myocardial ischemia and reperfusion injury

  • Am J Transl Res. 2020 Sep 15;12(9):5151-5169.
Yan Miao 1 2,  Zuochuan Ding 3,  Zhimiao Zou 1 2,  Yang Yang 1 2,  Min Yang 4,  Xiaoqian Zhang 5,  Zeyang Li 1 2,  Liang Zhou 1 2,  Limin Zhang 1 2,  Xue Zhang 6,  Dunfeng Du 1 2,  Fengchao Jiang 7,  Ping Zhou 1 2
Affiliations

Affiliations

  • 1 Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology Wuhan, China.
  • 2 Key Laboratory of Organ Transplantation, Ministry of Education, NHC Key Laboratory of Organ Transplantation, Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences Wuhan, China.
  • 3 Department of General Surgery, The First Affiliated Hospital of Nanchang University Nanchang, China.
  • 4 Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology Wuhan, China.
  • 5 Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology Wuhan, China.
  • 6 Department of Breast Surgery, Renmin Hospital of Wuhan University, Wuhan University Wuhan, China.
  • 7 Academy of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology Wuhan, China.
PMID: 33042411
Abstract

Cardiomyocytes, macrophages, and fibroblasts play important roles in inflammation and repair during myocardial ischemia/reperfusion injury (MIRI). Myeloid differentiation primary response 88 (MyD88) is upregulated in immunocytes, cardiomyocytes, and fibroblasts during MIRI. MyD88 induces the secretion of proinflammatory cytokines, including interleukin (IL)-1β, IL-6, and tumor necrosis factor alpha (TNF-α), while fibroblasts are recruited and activated to mediate cardiac remodeling. The aim of this study was to assess the anti-MIRI effect and mode of action of the novel MyD88 Inhibitor TJ-M2010-5. We synthesized TJ-M2010-5 and identified its target by co-immunoprecipitation, after which we established a murine MIRI model and tested the protective effect of TJ-M2010-5 by immunohistochemistry, flow cytometry, Real-Time PCR, and western blotting. Neonatal rat cardiomyocytes subjected to anoxia/reoxygenation were also isolated and their supernatants used to stimulate cardiac macrophagocytes and fibroblasts in vitro. MyD88 was found upregulated during the early and late phases after MIRI. The MyD88 Inhibitor considerably improved cardiac function, reduced cardiomyocyte Apoptosis, reduced IL-1β, IL-6, and TNF-α secretion, and inhibited CD80+CD86+MHCII+ macrophage and fibroblast migration. Moreover, TJ-M2010-5 markedly inhibited Toll-like Receptor/MyD88 signaling in vivo and in vitro. Thus, our findings highlight TJ-M2010-5 as a potential therapeutic agent for MIRI treatment.

Keywords

Anoxia/reoxygenation; TJ-M2010-5; myeloid differentiation factor 88; myocardial ischemia and reperfusion injury; remodeling.

Figures
Products