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

H Zhou, S Wang, P Zhu, S Hu, Y Chen, J Ren - Redox biology, 2018 - Elsevier
H Zhou, S Wang, P Zhu, S Hu, Y Chen, J Ren
Redox biology, 2018Elsevier
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 …
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.
Elsevier