2. Academic Validation
  3. GSK2795039 prevents RIP1-RIP3-MLKL-mediated cardiomyocyte necroptosis in doxorubicin-induced heart failure through inhibition of NADPH oxidase-derived oxidative stress

GSK2795039 prevents RIP1-RIP3-MLKL-mediated cardiomyocyte necroptosis in doxorubicin-induced heart failure through inhibition of NADPH oxidase-derived oxidative stress

  • Toxicol Appl Pharmacol. 2023 Feb 8;116412. doi: 10.1016/j.taap.2023.116412.
Xiao-Juan Zhang 1,  Lu Li 2,  Ai-Ling Wang 3,  Hong-Xia Guo 3,  Hui-Ping Zhao 3,  Rui-Fang Chi 3,  Hui-Yu Xu 4,  Li-Guo Yang 3,  Bao Li 5,  Fu-Zhong Qin 5,  Jia-Pu Wang 6
Affiliations

Affiliations

  • 1 The Second Hospital of Shanxi Medical University, Taiyuan 030001, Shanxi, PR China; Shanxi Medical University, Taiyuan 030001, Shanxi, PR China; Shanxi Province Cardiovascular Hospital, Taiyuan 030024, Shanxi, PR China.
  • 2 Shanxi Medical University, Taiyuan 030001, Shanxi, PR China.
  • 3 The Second Hospital of Shanxi Medical University, Taiyuan 030001, Shanxi, PR China; Shanxi Medical University, Taiyuan 030001, Shanxi, PR China.
  • 4 Shanxi Medical University, Taiyuan 030001, Shanxi, PR China; Shanxi Province Cardiovascular Hospital, Taiyuan 030024, Shanxi, PR China.
  • 5 The Second Hospital of Shanxi Medical University, Taiyuan 030001, Shanxi, PR China; Shanxi Medical University, Taiyuan 030001, Shanxi, PR China. Electronic address: [email protected].
  • 6 Shanxi Province Cardiovascular Hospital, Taiyuan 030024, Shanxi, PR China.
PMID: 36764612 DOI: 10.1016/j.taap.2023.116412
Abstract

Doxorubicin (DOX), which is widely used for the treatment of Cancer, induces cardiomyopathy associated with NADPH oxidase-derived Reactive Oxygen Species. GSK2795039 is a novel small molecular NADPH Oxidase 2 (Nox2) inhibitor. In this study, we investigated whether GSK2795039 prevents receptor-interacting protein kinase 1 (RIP1)-RIP3-mixed lineage kinase domain-like protein (MLKL)-mediated cardiomyocyte Necroptosis in DOX-induced heart failure through NADPH Oxidase inhibition. Eight-week old mice were randomly divided into 4 groups: control, GSK2795039, DOX and DOX plus GSK2795039. H9C2 cardiomyocytes were treated with DOX and GSK2795039. In DOX-treated mice, the survival rate was reduced, left ventricular (LV) end-systolic dimension was increased and LV fractional shortening was decreased, and these alterations were attenuated by the GSK2795039 treatment. GSK2795039 inhibited not only myocardial NADPH Oxidase subunit gp91phox (Nox2) protein, but also p22phox, p47phox and p67phox proteins and prevented oxidative stress 8-hydroxy-2'-deoxyguanosine levels in DOX-treated mice. RIP3 protein and phosphorylated RIP1 (p-RIP1), p-RIP3 and p-MLKL proteins, reflective of their respective kinase activities, markers of Necroptosis, were markedly increased in DOX-treated mice, and the increases were prevented by GSK2795039. GSK2795039 prevented the increases in serum Lactate Dehydrogenase and myocardial fibrosis in DOX-treated mice. Similarly, in DOX-treated cardiomyocytes, GSK2795039 improved cell viability, attenuated Apoptosis and necrosis and prevented the increases in p-RIP1, p-RIP3 and p-MLKL expression. In conclusion, GSK2795039 prevents RIP1-RIP3-MLKL-mediated cardiomyocyte Necroptosis through inhibition of NADPH oxidase-derived oxidative stress, leading to the improvement of myocardial remodeling and function in DOX-induced heart failure. These findings suggest that GSK2795039 may have implications for the treatment of DOX-induced cardiomyopathy.

Keywords

Doxorubicin; GSK2795039; Heart failure; NADPH oxidase; Necroptosis; Oxidative stress.

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