2. Academic Validation
  3. NADPH oxidase 2 inhibitor GSK2795039 prevents against cardiac remodeling after MI through reducing oxidative stress and mitochondrial dysfunction

NADPH oxidase 2 inhibitor GSK2795039 prevents against cardiac remodeling after MI through reducing oxidative stress and mitochondrial dysfunction

  • Eur J Pharmacol. 2025 Mar 6:997:177483. doi: 10.1016/j.ejphar.2025.177483.
Yun Liu 1,  Zhiming Wu 2,  Xiaoping Jin 2,  Meili Ji 3,  Tianyi Huang 2,  Peina Meng 2,  Tian Xu 2,  Yifei Wang 2,  Qiang Lin 4,  Yanfang Zhao 1,  Wei You 5,  Fei Ye 6,  Xiangqi Wu 7
Affiliations

Affiliations

  • 1 Department of Cardiology, The Eighty-first Hospital of PLA Affiliated with Anhui Medical University, Nanjing, China.
  • 2 Department of Cardiology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China.
  • 3 Department of Geriatric, Nanjing First Hospital, Nanjing Medical University, Nanjing, China.
  • 4 Department of Rehabilitation Medicine, Nanjing First Hospital, Nanjing Medical University, Nanjing, China.
  • 5 Department of Cardiology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China. Electronic address: youwei@njmu.edu.cn.
  • 6 Department of Cardiology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China. Electronic address: yefei@njmu.edu.cn.
  • 7 Department of Cardiology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China. Electronic address: wuxiangqi@njmu.edu.cn.
PMID: 40057160 DOI: 10.1016/j.ejphar.2025.177483
Abstract

Myocardial infarction (MI) is the leading cause of mortality in cardiovascular diseases and continues to pose a substantial challenge in clinical management, despite the availability of guideline-directed medical therapy. The present study aimed to investigate the potential protective effects of the NADPH Oxidase Inhibitor (NI) GSK2795039 on cardiac remodeling following MI, and to elucidate the underlying mechanisms involved. We established the MI model by ligating the left anterior descending artery in mice. Additionally, we replicated this model in vitro by stimulating H9C2 cells with levarterenol (LN). The assessment of cardiac function, cardiomyocyte size, Apoptosis, infarct size, and mitochondrial structure was conducted utilizing echocardiography, WGA staining, TUNEL assay, Masson's staining, and electron microscopy, respectively. The investigation of this mechanism utilized colorimetry, Western blotting, flow cytometry, and RT-PCR techniques. Compared to mice with MI or H9C2 cells stimulated by LN, NI treatment significantly improved cardiac dysfunction and hypertrophy. It also resulted in a reduction of cardiomyocyte size and Apoptosis, decreased infarct size, alleviated mitochondrial structural damage, lowered levels of malondialdehyde and NOX2, diminished ROS production while inhibiting NOX activity, and enhanced the activities of T-SOD, GSH-PX, as well as mitochondrial complexes I-V. Additionally, it led to an increase in mitochondrial OCR, ATP levels and MMP. These findings indicate that GSK2795039 can mitigate oxidative stress and mitochondrial dysfunction through the inhibition of NOX2, thereby providing a cardioprotective effect against cardiac remodeling induced by MI. This suggests that GSK2795039 may possess therapeutic potential for patients following MI.

Keywords

GSK2795039; Mitochondrial dysfunction; Myocardial infarction; NADPH oxidase; Oxidative stress.

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