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

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.

Mitochondrial Quality Control in Cardiac-Conditioning Strategies against Ischemia-Reperfusion Injury

“…On the other hand, treatment with Mdivi-1 before myocardial ischemia results in the lengthening of interfibrillary mitochondria and a reduction in the size of the infarct, which confirms that by preventing mitochondrial fission, the induction of mitochondrial fusion is favored, benefiting the survival of cardiomyocytes [107,127]. On the other hand, the administration of hydralazine, an agent used in the treatment of hypertension and chronic heart failure, not only protects the heart from acute I/R through its antioxidants and anti-apoptotic effects, but if administered at the time of reperfusion, it decreases the size of the infarct by inhibiting mitochondrial fission [128].…”

The histone demthylase KDM3A protects the myocardium from ischemia/reperfusion injury via promotion of ETS1 expression

“…Once oxidative stress disrupts the balance between antioxidant defence and ROS in favour of the latter, it constitutes a crucial aetiological component of MIRI 10 . Excessive ROS elicits an imbalanced redox status, particularly as reflected by the inactivation of the antioxidant enzyme SOD and increased MDA levels 11 , 14 , 33 . Furthermore, inflammation has been proposed to aggravate MIRI 5 .…”

“…Since achieving success in reperfusion to dampen ischemia, the focus of current experimental and clinical efforts has shifted towards the limitations of myocardial I/R injury (MIRI) to optimize the benefits of revascularization 3 – 5 , 7 – 10 . Although not completely clear, current investigations indicate that MIRI aetiologies consist of diverse cellular events with respect to apoptosis, reactive oxygen species (ROS), and inflammation 11 – 13 . Intriguingly, accumulating studies have illustrated that the dynamic regulation of epigenetic processes, such as histone methylation and acetylation, might be closely involved in these pathophysiologic progressions in response to MIRI 4 , 8 , 9 , 14 .…”

Repurposing drugs to treat cardiovascular disease in the era of precision medicine

“…For example, hydralazine has antioxidant effects and reduces apoptosis, in addition to antihypertensive and afterload-reducing effects. Understanding that these processes have important roles in reperfusion injury after myocardial infarction led to the evaluation of hydralazine for the treatment of myocardial injury after infarction, with promising results in in vivo models 18 . Other cardiovascular drugs that have been studied as therapies for other diseases include diuretics as antiparasitic agents (tested in vitro) 19 , statins as adjuvant therapy for cancers (reviewed previously 20 ) and antihypertensive agents for bipolar disorder 21 .…”