Induction of KLF2 by exercise activates eNOS to improve vasodilatation in diabetic mice

Diabetic endothelial dysfunction associated with diminished endothelial nitric oxide synthase (eNOS) activity accelerates the development of atherosclerosis and cardiomyopathy. However, the approaches to restore eNOS activity and endothelial function in diabetes remain limited. The present study shows that enhanced expression of KLF2, a shear stress-inducible transcription factor, effectively improves endothelial function through increasing NO bioavailability. KLF2 expression is suppressed in diabetic mouse aortic endothelium. Running exercise and simvastatin treatment induce endothelial KLF2 expression in db/db mice. Adenovirus-mediated endothelium-specific KLF2 overexpression enhances both endothelium-dependent relaxation and flow-mediated dilatation while it attenuates oxidative stress in diabetic mouse arteries. KLF2 overexpression increases the phosphorylation of eNOS at serine 1177 and eNOS dimerization. RNA-sequencing analysis reveals that KLF2 transcriptionally upregulates genes that are enriched in the cGMP-PKG signaling pathway, cAMP signaling pathway, and insulin signaling pathway, all of which are the upstream regulators of eNOS activity. Activation of the PI3K-Akt pathway and Hsp90 contributes to KLF2-induced increase of eNOS activity. The present results suggest that approaches inducing KLF2 activation such as physical exercise are effective to restore eNOS activity against diabetic endothelial dysfunction.