MARCH5 restores endothelial cell function against ischaemic/hypoxia injury via Akt/eNOS pathway

Abstract

MARCH5 is a critical regulator of mitochondrial dynamics, apoptosis and mitophagy. However, its role in cardiovascular system remains poorly understood. This study aimed to investigate the role of MARCH5 in endothelial cell (ECs) injury and the involvement of the Akt/eNOS signalling pathway in this process. Rat models of myocardial infarction (MI) and human cardiac microvascular endothelial cells (HCMECs) exposed to hypoxia (1% O2) were used in this study. MARCH5 expression was significantly reduced in ECs of MI hearts and ECs exposed to hypoxia. Hypoxia inhibited the proliferation, migration and tube formation of ECs, and these effects were aggravated by knockdown of MARCH5 but antagonized by overexpressed MARCH5. Overexpression of MARCH5 increased nitric oxide (NO) content, p‐eNOS and p‐Akt, while MARCH5 knockdown exerted the opposite effects. The protective effects mediated by MARCH5 overexpression on ECs could be inhibited by eNOS inhibitor L‐NAME and Akt inhibitor LY294002. In conclusion, these results indicated that MARCH5 acts as a protective factor in ischaemia/hypoxia‐induced ECs injury partially through Akt/eNOS pathway.

RETRACTED: Molecular Perspectives of Mitophagy in Myocardial Stress: Pathophysiology and Therapeutic Targets

“…Moderate mitophagy promotes mitochondrial turnover and therefore protects the heart against acute injuries ( Cao et al, 2020 ; Li et al, 2020 ). The E3 ubiquitin ligase membrane-associated ring finger 5 (MARCH5), a newly identified mitophagy receptor, was found to be downregulated in the hearts of myocardial infarction model rats ( Lei et al, 2021 ). On the other hand, overexpression of MARCH5 activated mitophagy and improved the microcirculatory perfusion of the infarcted heart by increasing nitric oxide expression, enhancing the migratory response and reducing apoptosis in endothelial cells ( Li et al, 2020 ; Lugassy et al, 2020 ; Lei et al, 2021 ).…”

Lessons from Comparison of Hypoxia Signaling in Plants and Mammals

“…This beneficial effect stems from a range of NO-mediated effects, including the induction of enzymes such as ADH1 and PDC [ 140 , 141 , 142 ], as well as the regulation of genes necessary to shift ATP generation to oxygen-independent mechanisms and reduce oxidative stress in response to low oxygen [ 142 , 143 ]. In mammals, NO also contributes to the regulation of oxygen sensing mechanisms (see below) while also facilitating vasodilation, anti-thrombotic effects, and angiogenesis to increase oxygenated blood getting to hypoxic tissues [ 144 , 145 , 146 ]. The latter effect is similar to the role of NO in plants in facilitating the transport of oxygen to hypoxic tissues through the formation of aerenchyma, which facilitates gas exchange in waterlogged plants [ 147 ].…”

“…While all three mammalian NOS isoforms have important physiological roles in both homeostasis as well as stress conditions, of particular importance in mammalian tolerance to hypoxia is the constitutively expressed eNOS. NO production by eNOS (especially in vascular endothelial cells) during hypoxia and anoxia allows vasodilation, angiogenesis, and wound repair [ 144 , 146 , 149 ]. It has also been shown clinically that eNOS has protective effects in ischaemic brain injury and stroke [ 150 ].…”

“…Similarly, in mammals, ubiquitination is important in regulating eNOS in hypoxic conditions ( Figure 2 ). The E3 ubiquitin ligase Membrane Associated Ring-CH-type finger 5 (MARCH5) has a protective role against the effects of hypoxia in endothelial cells [ 146 ]. Specifically, MARCH5 increases eNOS expression at the transcriptional and translational levels.…”

“…This, together with the use of Akt inhibitors, has suggested that Akt may be the kinase that is responsible for phosphorylating and activating eNOS. Hence, MARCH5 induces its protective effect on endothelial cells in hypoxia by inducing NO production through Akt-dependent eNOS phosphorylation [ 146 ].…”