Empagliflozin rescues diabetic myocardial microvascular injury via AMPK-mediated inhibition of mitochondrial fission

Abstract

Impaired cardiac microvascular function contributes to diabetic cardiovascular complications although effective therapy remains elusive. Empagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor recently approved for treatment of type 2 diabetes, promotes glycosuria excretion and offers cardioprotective actions beyond its glucose-lowering effects. This study was designed to evaluate the effect of empagliflozin on cardiac microvascular injury in diabetes and the underlying mechanism involved with a focus on mitochondria. Our data revealed that empagliflozin improved diabetic myocardial structure and function, preserved cardiac microvascular barrier function and integrity, sustained eNOS phosphorylation and endothelium-dependent relaxation, as well as improved microvessel density and perfusion. Further study suggested that empagliflozin exerted its effects through inhibition of mitochondrial fission in an adenosine monophosphate (AMP)-activated protein kinase (AMPK)-dependent manner. Empagliflozin restored AMP-to-ATP ratio to trigger AMPK activation, suppressed Drp1S616 phosphorylation, and increased Drp1S637 phosphorylation, ultimately leading to inhibition of mitochondrial fission. The empagliflozin-induced inhibition of mitochondrial fission preserved cardiac microvascular endothelial cell (CMEC) barrier function through suppressed mitochondrial reactive oxygen species (mtROS) production and subsequently oxidative stress to impede CMEC senescence. Empagliflozin-induced fission loss also favored angiogenesis by promoting CMEC migration through amelioration of F-actin depolymerization. Taken together, these results indicated the therapeutic promises of empagliflozin in the treatment of pathological microvascular changes in diabetes.

Effect of Mst1 on Endometriosis Apoptosis and Migration: Role of Drp1-Related Mitochondrial Fission and Parkin-Required Mitophagy

“…Ample evidence identifies miR-181c as the transcriptional repressor of Mst1 [45]. Moreover, numerous studies have profiled the role of miR-181c in mitochondrial protection [60][61][62]. Furthermore, a high expression of miR-181c is considered a predictive marker of the recurrence in colorectal cancer, suggesting an inhibitory effect of miR-181c on cell survival and proliferation.…”

Hyperglycaemia Stress-Induced Renal Injury is Caused by Extensive Mitochondrial Fragmentation, Attenuated MKP1 Signalling, and Activated JNK-CaMKII-Fis1 Biological Axis

“…Moreover, mitochondrial oxidative stress, mitochondrial calcium imbalance, mitochondrial antioxidant system malfunction, and oxidative phosphorylation cessation [10,11] are the inter-related risk factors for mitochondrial aetiology in diabetic renal disorders. Recently, mitochondrial fragmentation, which primarily results from increased mitochondrial mitotic fission and/or decreased mitochondrial fusion, is found to be correlated with a fall in myocardial function in the setting of hyperglycaemia stress [12]. At the molecular level, mitochondrial fragmentation is the defensive reaction of mitochondria upon hyperglycaemia exposure.…”

“…However, uncontrolled mitochondrial division, as evidenced by extensively fragmented mitochondria, represses the ability of mitochondria to produce sufficient ATP and finally contribute to the opening of the mitochondrial apoptotic pathway [14,15]. Although mitochondrial fragmentation is observed in hyperglycaemia-challenged cardiomyocytes [12], the role of mitochondrial fragmentation is not defined in diabetic renal damage.…”

Mammalian STE20-Like Kinase 1 Deletion Alleviates Renal Ischaemia-Reperfusion Injury via Modulating Mitophagy and the AMPK-YAP Signalling Pathway

“…Moderate mitophagy has been acknowledged as a protective mechanism, accounting for cell metabolism, proliferation and survival [17]. Mitophagy activation is accompanied by a decline in the mass of poorly structured mitochondria and is also reported to be involved in mitochondrial biosynthesis [18]. The functional role of mitophagy has been explored in acute cardiac I/R injury [19] and chronic liver fatty disease [20].…”