Fig. 8.

Scheme depicting proposed mechanisms involved in empagliflozin-offered protection against microvasculature damage in diabetes. Empagliflozin activates AMPK pathways through regulation of the AMP/ATP ratio. Activated AMPK pathways regulates Drp1 posttranscriptional phosphorylation modifications at Ser616 and Ser637, leading to the inability of Drp1 to translocate onto mitochondria and mitochondrial fission impairment. The loss of mitochondrial fission retards cellular senescence and preserves endothelial barrier/permeability by suppressing superfluous ROS. In consequence, endothelial migration and vascularization are improved by balanced F-actin degradation. Moreover, empagliflozin reduces CMEC apoptosis, increases cardiac microvessel density, promotes eNOS phosphorylation and alleviates vascular collagen deposition, leading to improved endothelial function and preserved vascular remodeling, ultimately lower levels of inflammatory cell penetration and better vascular relaxation. Through these aforementioned mechanisms, empagliflozin eventually facilitates diabetic myocardial perfusion and protects the heart against hyperglycemic injury.