2. Academic Validation
  3. Hydralazine protects the heart against acute ischaemia/reperfusion injury by inhibiting Drp1-mediated mitochondrial fission

Hydralazine protects the heart against acute ischaemia/reperfusion injury by inhibiting Drp1-mediated mitochondrial fission

  • Cardiovasc Res. 2022 Jan 7;118(1):282-294. doi: 10.1093/cvr/cvaa343.
Siavash Beikoghli Kalkhoran 1 2 3,  Janos Kriston-Vizi 4,  Sauri Hernandez-Resendiz 2 3,  Gustavo E Crespo-Avilan 2 3 5,  Ayeshah A Rosdah 6 7 8,  Jarmon G Lees 6 8,  Joana Rodrigues Simoes Da Costa 4,  Naomi X Y Ling 9,  Jessica K Holien 8 10 11,  Parisa Samangouei 1 3,  Kroekkiat Chinda 12,  En Ping Yap 2 3,  Jaime A Riquelme 1 13,  Robin Ketteler 4,  Derek M Yellon 1,  Shiang Y Lim 6 8,  Derek J Hausenloy 1 2 3 14 15
Affiliations

Affiliations

  • 1 The Hatter Cardiovascular Institute, Institute of Cardiovascular Science, University College, 67 Chenies Mews, WC1E 6HX London, UK.
  • 2 Cardiovascular and Metabolic Disorder Programme, Duke-NUS Medical School, 8 College Road, 169857, Singapore.
  • 3 National Heart Research Institute Singapore, National Heart Centre, 5 Hospital Drive, 169609, Singapore.
  • 4 MRC Laboratory for Molecular Cell Biology, University College, Gower St, Kings Cross, WC1E 6BT London, UK.
  • 5 Department of Biochemistry, Medical Faculty, Justus Liebig-University, Ludwigstraße 23, 35390 Giessen, Germany.
  • 6 O'Brien Institute Department, St Vincent's Institute of Medical Research, 9 Princes Street Fitzroy Victoria, 3065, Australia.
  • 7 Faculty of Medicine, Universitas Sriwijaya, Palembang, Bukit Lama, Kec. Ilir Bar. I, Kota Palembang, 30139 Sumatera Selatan, Indonesia.
  • 8 Department of Surgery and Medicine, University of Melbourne, Medical Building, Cnr Grattan Street & Royal Parade, 3010 Victoria, Australia.
  • 9 Metabolic Signalling Laboratory, St Vincent's Institute of Medical Research, School of Medicine, University of Melbourne, Melbourne, Victoria, Australia.
  • 10 St Vincent's Institute of Medical Research, 9 Princes Street, Fitzroy Victoria, 3065, Australia.
  • 11 ACRF Rational Drug Discovery Centre, St Vincent's Institute of Medical Research, 9 Princes Street Fitzroy Victoria, 3065, Australia.
  • 12 Department of Physiology, Faculty of Medical Science, Naresuan University, Tha Pho, Mueang Phitsanulok, 65000, Thailand.
  • 13 Advanced Center for Chronic Disease (ACCDiS), Facultad de Ciencias Químicas y Farmacéuticas & Facultad de Medicina, Universidad de Chile, Sergio Livingstone 1007, Independencia, Santiago, Chile.
  • 14 Yong Loo Lin School of Medicine, National University Singapore, 1E Kent Ridge Road, 119228, Singapore.
  • 15 Cardiovascular Research Center, College of Medical and Health Sciences, Asia University, Lioufeng Rd., Wufeng, 41354 Taichung, Taiwan.
PMID: 33386841 DOI: 10.1093/cvr/cvaa343
Abstract

Aims: Genetic and pharmacological inhibition of mitochondrial fission induced by acute myocardial ischaemia/reperfusion injury (IRI) has been shown to reduce myocardial infarct size. The clinically used anti-hypertensive and heart failure medication, hydralazine, is known to have anti-oxidant and anti-apoptotic effects. Here, we investigated whether hydralazine confers acute cardioprotection by inhibiting Drp1-mediated mitochondrial fission.

Methods and results: Pre-treatment with hydralazine was shown to inhibit both mitochondrial fission and mitochondrial membrane depolarisation induced by oxidative stress in HeLa cells. In mouse embryonic fibroblasts (MEFs), pre-treatment with hydralazine attenuated mitochondrial fission and cell death induced by oxidative stress, but this effect was absent in MEFs deficient in the mitochondrial fission protein, Drp1. Molecular docking and surface plasmon resonance studies demonstrated binding of hydralazine to the GTPase domain of the mitochondrial fission protein, Drp1 (KD 8.6±1.0 µM), and inhibition of Drp1 GTPase activity in a dose-dependent manner. In isolated adult murine cardiomyocytes subjected to simulated IRI, hydralazine inhibited mitochondrial fission, preserved mitochondrial fusion events, and reduced cardiomyocyte death (hydralazine 24.7±2.5% vs. control 34.1±1.5%, P=0.0012). In ex vivo perfused murine hearts subjected to acute IRI, pre-treatment with hydralazine reduced myocardial infarct size (as % left ventricle: hydralazine 29.6±6.5% vs. vehicle control 54.1±4.9%, P=0.0083), and in the murine heart subjected to in vivo IRI, the administration of hydralazine at reperfusion, decreased myocardial infarct size (as % area-at-risk: hydralazine 28.9±3.0% vs. vehicle control 58.2±3.8%, P<0.001).

Conclusion: We show that, in addition to its antioxidant and anti-apoptotic effects, hydralazine, confers acute cardioprotection by inhibiting IRI-induced mitochondrial fission, raising the possibility of repurposing hydralazine as a novel cardioprotective therapy for improving post-infarction outcomes.

Keywords

Acute myocardial ischaemia/reperfusion injury; Cardioprotection; Hydralazine; Mitochondrial fission.

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