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

Duan, Chenyang; Wang, Li; Zhang, Jie; Xiang, Xinming; Wu, Yuzhang; Zhang, Zisen; Li, Qinghui; Tian, Kui; Xue, Mingying; Liu, Liangming; Li, Tao

doi:10.1016/j.redox.2020.101706

Cited by 58 publications

(74 citation statements)

References 38 publications

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“…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.…”

Section: Methodsmentioning

confidence: 99%

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

et al. 2021

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Mitochondrial mass imbalance is one of the key causes of cardiovascular dysfunction after hypoxia. The activation of dynamin-related protein 1 (Drp1), as well as its mitochondrial translocation, play important roles in the changes of both mitochondrial morphology and mitochondrial functions after hypoxia. However, in addition to mediating mitochondrial fission, whether Drp1 has other regulatory roles in mitochondrial homeostasis after mitochondrial translocation is unknown. In this study, we performed a series of interaction and colocalization assays and found that, after mitochondrial translocation, Drp1 may promote the excessive opening of the mitochondrial permeability transition pore (mPTP) after hypoxia. Firstly, mitochondrial Drp1 maximumly recognizes mPTP channels by binding Bcl-2-associated X protein (BAX) and a phosphate carrier protein (PiC) in the mPTP. Then, leucine-rich repeat serine/threonine-protein kinase 2 (LRRK2) is recruited, whose kinase activity is inhibited by direct binding with mitochondrial Drp1 after hypoxia. Subsequently, the mPTP-related protein hexokinase 2 (HK2) is inactivated at Thr-473 and dissociates from the mitochondrial membrane, ultimately causing structural disruption and overopening of mPTP, which aggravates mitochondrial and cellular dysfunction after hypoxia. Thus, our study interprets the dual direct regulation of mitochondrial Drp1 on mitochondrial morphology and functions after hypoxia and proposes a new mitochondrial fission-independent mechanism for the role of Drp1 after its translocation in hypoxic injury.

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Section: Methodsmentioning

confidence: 99%

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

et al. 2021

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“…Fresh heart tissues were prepared according to the protocol described previously ( Duan, et al, 2020 ). The samples were observed with a transmission electron microscope (H-7500, Hitachi Company, Japan).…”

Section: Methodsmentioning

confidence: 99%

Protective Effects of Inhibition of Mitochondrial Fission on Organ Function After Sepsis

Zhu

Kuang

et al. 2021

Front. Pharmacol.

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Sepsis-associated organ dysfunction plays a critical role in its high mortality, mainly in connection with mitochondrial dysfunction. Whether the inhibition of mitochondrial fission is beneficial to sepsis-related organ dysfunction and underlying mechanisms are unknown. Cecal ligation and puncture induced sepsis in rats and dynamic related protein 1 knockout mice, lipopolysaccharide-treated vascular smooth muscle cells and cardiomyocytes, were used to explore the effects of inhibition of mitochondrial fission and specific mechanisms. Our study showed that mitochondrial fission inhibitor Mdivi-1 could antagonize sepsis-induced organ dysfunction including heart, vascular smooth muscle, liver, kidney, and intestinal functions, and prolonged animal survival. The further study showed that mitochondrial functions such as mitochondrial membrane potential, adenosine-triphosphate contents, reactive oxygen species, superoxide dismutase and malonaldehyde were recovered after Mdivi-1 administration via improving mitochondrial morphology. And sepsis-induced inflammation and apoptosis in heart and vascular smooth muscle were alleviated through inhibition of mitochondrial fission and mitochondrial function improvement. The parameter trends in lipopolysaccharide-stimulated cardiomyocytes and vascular smooth muscle cells were similar in vivo. Dynamic related protein 1 knockout preserved sepsis-induced organ dysfunction, and the animal survival was prolonged. Taken together, this finding provides a novel effective candidate therapy for severe sepsis/septic shock and other critical clinical diseases.

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“…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.…”

Section: Discussionmentioning

confidence: 99%

“…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.…”

Section: Methodsmentioning

confidence: 99%

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

Wang

Zhao

et al. 2021

Front. Physiol.

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Objective: The aim of this study was to clarify the role of autophagy in stellate ganglion block (SGB) reversing posthemorrhagic shock mesenteric lymph (PHSML)-mediated vascular hyporeactivity.Methods: Hemorrhagic shock model in conscious rats was employed to observe the effects of SGB (0.2 ml of 0.25% ropivacaine hydrochloride hydrate) and autophagy inhibitor 3-methyladenine (3-MA; 30 mg/kg) on the vascular reactivity of second-order rat mesenteric arteries in vitro, while the effects of PHSML (1 ml/kg) and autophagy agonist rapamycin (Rapa, 10 mg/kg) on the beneficial effect of SGB were investigated. The cellular viability, contractility, and autophagy-related protein expressions in vascular smooth muscle cells (VSMCs) were detected following treatments of PHSML, PHSML obtained from the rats that underwent hemorrhagic shock plus SGB (PHSML-SGB), and PHSML plus 3-MA (5 mM), respectively.Results: Hemorrhagic shock significantly decreased the vascular reactivity to gradient norepinephrine (NE), which is reversed by the SGB treatment and 3-MA administration. On the contrary, PHSML intravenous infusion and Rapa administration inhibited the vascular contractile responses in rats that underwent hemorrhagic shock plus SGB treatment. PHSML treatment significantly inhibited the cellular viability and contractility in VSMCs, increased the expressions of LC3-II and Beclin 1, and decreased the expression of p62, along with opposite appearances in these indices following PHSML-SGB treatment. In addition, 3-MA counteracted the adverse roles of PHSML in these indices in VSMCs.Conclusion: SGB inhibits PHSML-mediated vascular hyporeactivity by reducing the excessive autophagy in VSMCs.

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

Cited by 58 publications

References 38 publications

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

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

Protective Effects of Inhibition of Mitochondrial Fission on Organ Function After Sepsis

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

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