Mst1 deletion reduces hyperglycemia‐mediated vascular dysfunction via attenuating mitochondrial fission and modulating the JNK signaling pathway

Abstract

Diabetes is a leading cause of microvascular complications, such as nephropathy and retinopathy. Recent studies have proposed that hyperglycemia-induced endothelial cell dysfunction is modulated by mitochondrial stress. Therefore, our experiment was to detect the upstream mediator of mitochondrial stress in hyperglycemia-treated endothelial cells with a focus on macrophage-stimulating 1 (Mst1) and mitochondrial fission. Our data illuminated that hyperglycemia incubation reduced cell viability, as well as increased apoptosis ratio in endothelial cell, and this alteration seemed to be associated with Mst1 upregulation. Inhibition of Mst1 via transfection of Mst1 siRNA into an endothelial cell could sustain cell viability and maintain mitochondrial function. At the molecular levels, endothelial cell death was accompanied with the activation of mitochondrial oxidative stress, mitochondrial apoptosis, and mitochondrial fission. Genetic ablation of Mst1 could reduce mitochondrial oxidative injury, block mitochondrial apoptosis, and repress mitochondrial fission. Besides, we also found Mst1 triggered mitochondrial dysfunction as well as endothelial cell damage through augmenting JNK pathway. Suppression of JNK largely ameliorated the protective actions of Mst1 silencing on hyperglycemia-treated endothelial cells and sustain mitochondrial function. The present study identifies Mst1 as a primary key mediator for hyperglycemia-induced mitochondrial damage and endothelial cell dysfunction. Increased Mst1 impairs mitochondrial function and activates endothelial cell death via opening mitochondrial death pathway through JNK. K E Y W O R D S endothelial cells, hyperglycemia, JNK pathway, mitochondria, Mst1

RAGE Regulating Vascular Remodeling in Diabetes by Regulating Mitochondrial Dynamics with JAK2/STAT3 Pathway

“…Our results corroborate the findings of previous researchers who showed that mitochondrial dysfunction is a key player in obesity and hypertension [22]. e mitigation of mitochondrial fission by Mst1 knockout in hyperglycemia-mediated vascular damage was also reported [23] and corroborated our present work. Another researcher has also conveyed that the antidiabetic drug metformin exerts its therapeutic effect by inhibition of mitochondrial fission [24].…”

Mst1 silencing alleviates hypertensive myocardial injury associated with the augmentation of microvascular endothelial cell autophagy

“…The present study also found that Mst1 knockout significantly improved myocardial microvascular endothelial integrity in HP mice, suggesting a role for Mst1 in endothelial cell function, consistent with the findings of a previous study (39). One factor that contributes to HP is the apoptosis of microvascular endothelial cells, as this directly leads to microcirculation reduction and peripheral resistance increase, both of which result in elevated blood pressure (10,40).…”

Influence of Optimal Management of Hyperglycemia and Intensive Nursing on Blood Glucose Control Level and Complications in Patients with Postoperative Cerebral Hemorrhage

“…The time of blood glucose reaching the standard and the time of insulin pump were shorter than those who received ordinary care intervention, the insulin dosage was less than those who received ordinary care intervention, and the incidence of hypoglycemia was lower than those who received ordinary care intervention. The above results suggest that intensive care for optimal management of hyperglycemia can effectively control the blood glucose level, 3 Computational and Mathematical Methods in Medicine [21][22][23]. When insulin was injected intravenously, physiological insulin secretion mode was simulated as much as possible, and timely adjustment of enteral nutrition was helpful to control blood glucose fluctuation, effectively reduce blood glucose variability, and maintain blood glucose stability [24][25][26].…”

“…The above results suggest that intensive care for optimal management of hyperglycemia can effectively control the blood glucose level, reduce insulin dosage, and decrease hypoglycemia in patients after cerebral hemorrhage. This is due to high blood sugar optimization management intensive nursing intervention through regular monitoring of blood sugar, timely upload data to neurology and nutrition doctors, and jointly develop reasonable blood sugar control objectives, intervention of individualized insulin therapy, and nutritional intervention [ 21 – 23 ]. When insulin was injected intravenously, physiological insulin secretion mode was simulated as much as possible, and timely adjustment of enteral nutrition was helpful to control blood glucose fluctuation, effectively reduce blood glucose variability, and maintain blood glucose stability [ 24 – 26 ].…”