Sacubitril/valsartan attenuates myocardial ischemia/reperfusion injury via inhibition of the GSK3β/NF-κB pathway in cardiomyocytes

  • Arch Biochem Biophys. 2022 Sep 27;730:109415. doi: 10.1016/j.abb.2022.109415.
Fangping Xiao  1 ,  Lei Wang  2 ,  Meng Liu  1 ,  Mingyue Chen  1 ,  Hao He  1 ,  Zhiqiang Jia  1 ,  Lai Zhang  3 ,  Yaqing Yang  3 ,  Qianfan Hu  3 ,  Mei Hong  4 ,  Hanwen Zhang  5
Affiliations
  • 1. Department of Cardiology, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, China.
  • 2. Department of Pathology, The Affiliated BenQ Hospital of Nanjing Medical University, Nanjing, China.
  • 3. Key Laboratory of Targeted Intervention of Cardiovascular Disease, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Nanjing Medical University, Nanjing, China.
  • 4. Department of Cardiology, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, China. Electronic address: [email protected].
  • 5. Key Laboratory of Targeted Intervention of Cardiovascular Disease, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Nanjing Medical University, Nanjing, China. Electronic address: [email protected].
PMID: 36179911 DOI: 10.1016/j.abb.2022.109415
Abstract

In ischemia/reperfusion (I/R) injury, both inflammation and Apoptosis play a vital role, and the inhibition of excessive inflammation and Apoptosis show substantial clinical potential in the treatment of I/R disease. The role of sacubitril/valsartan (SAC/VAL)-a first-in-class angiotensin receptor-neprilysin inhibitor (ARNI)-in inflammation regulation and Apoptosis in the context of I/R injury needs to be further explored. In this study, we investigate the short- and long-term effects of SAC/VAL administration in treating adult murine I/R injury both in vivo and in vitro. Our results verified that the application of SAC/VAL could reduce infarct size and suppress Apoptosis and the inflammatory response in the acute phase post I/R. Long-term application of SAC/VAL for four weeks significantly improved ventricular function and reversed pathological ventricular remodeling. Mechanistically, SAC/VAL treatment induces the inhibition of the GSK3β-mediated NF-κB pathway through synergistically blocking angiotensin 1 receptor (AT1R) and activating natriuretic peptide receptor (NPR). In summary, we reported the therapeutic role of SAC/VAL in regulating the GSK3β/NF-κB signaling pathway to suppress the inflammatory response and Apoptosis, thereby reducing cardiac dysfunction and remodeling post I/R.

Keywords
Glycogen synthase kinase 3β; Hypoxia/reoxygenation; Inflammation; Myocardial ischemia/reperfusion injury; Nuclear factor kappa-B; Sacubitril/valsartan.
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