Mdivi-1 attenuates oxidative stress and exerts vascular protection in ischemic/hypoxic injury by a mechanism independent of Drp1 GTPase activity

Abstract

Vascular dysfunctions such as vascular hyporeactivity following ischemic/hypoxic injury are a major cause of death in injured patients. In this study, we showed that treatment with mitochondrial division inhibitor 1 (Mdivi-1), a selective inhibitor of dynamin-related protein 1 (Drp1), significantly improved vascular reactivity in ischemic rats by attenuating oxidative stress. The antioxidative effects of Mdivi-1 were relatively Drp1-independent, and possibly due to an increase in the levels of the antioxidant enzymes, SOD1 and catalase, as well as to enhanced Nrf2 expression. In addition, we found that while Mdivi-1 had little effect on Drp1 GTPase activity in vascular smooth muscle cells, it inhibited hypoxia-induced Drp1 phosphorylation at Ser-616, reducing excessive mitochondrial fission and slightly enhancing mitochondrial fusion. These effects possibly contributed to vascular protection at an early stage of ischemic/hypoxic injury. Finally, Mdivi-1 stabilized hemodynamics, increased vital organ perfusion, and improved rat survival after ischemic/hypoxic injury, proving a promising therapeutic agent for ischemic/hypoxic injury.

Mitochondrial Drp1 recognizes and induces excessive mPTP opening after hypoxia through BAX-PiC and LRRK2-HK2

“…Vascular smooth muscle cells (VSMCs) were obtained from the superior mesenteric arteries (SMAs) of SD rats using an explant technique, as previously described [ 10 ]. VSMCs were cultured in Dulbecco-modified Eagle medium (DMEM)-F12 (Gibco, NY, USA) supplemented with 10% FBS (Hyclone, Logan, UT, USA) and 1% antibiotics.…”

Autophagy Is Involved in Stellate Ganglion Block Reversing Posthemorrhagic Shock Mesenteric Lymph-Mediated Vascular Hyporeactivity

“…It should be pointed out that vascular contractility following hemorrhagic shock was studied by various methods, such as pressor response to NE in vivo (Zhao et al, 2012 ; Li et al, 2014 ), a reduced percentage of vascular diameter after NE administration in vivo (Li et al, 2014 ), and isolated vascular contractile response to gradient concentrations of NE in vitro (Duan et al, 2020 ; Yue et al, 2021 ). While all these methods clarified that hemorrhagic shock induced vascular hyporeactivity in various ways.…”

“…After stabilizing for 5 min, NE with gradient concentration was added to the bath and the final concentration of NE in the bath was increased gradually to 0.1, 0.3, 1, 3, 10, 30, and 100 μM. The vascular constriction response of the artery rings to each concentration of NE was recorded using PowerLab System through a force transducer (Duan et al, 2020 ). The difference in tension between maximal value and baseline following stimulation with each concentration of NE was used as the value of vascular reactivity at this concentration.…”

Mitochondrial Fission-Mediated Lung Development in Newborn Rats With Hyperoxia-Induced Bronchopulmonary Dysplasia With Pulmonary Hypertension

“…Combined with our findings, we speculated that lung injury caused by hyperoxia in newborn rats would increase mitochondrial fission, namely the expression of Drp1, due to oxidative stress. In addition, experiments have confirmed the relationship between hypoxia and Drp1, studies were not only involved in animal models about Lung Ischemia-reperfusion Injury (30) and lung vascular ischemic/hypoxic injury (31), but also in others like hepatocellular carcinoma cells in hypoxia (32), and Hypoxia-Reoxygenation Injury of Cardiomyocytes (33). Although hypoxia or hyperoxia can trigger similar pathological responses, such as oxidative stress and inflammation, these underlying mechanisms need to be further studied at the cellular level.…”