MicroRNA-375 repression of Kruppel-like factor 5 improves angiogenesis in diabetic critical limb ischemia

Peripheral artery disease (PAD) is an occlusive disease of limb arteries. Critical limb ischemia (CLI) is an advanced form of PAD that is prognostically worse in subjects with diabetes and can result in limb loss, gangrene, and death, although the underlying signaling mechanisms that contribute to its development remain poorly understood. By comparing plasma samples from diabetic humans with PAD and mouse models of PAD, we identified miR-375 to be significantly downregulated in humans and mice during progression to CLI. Overexpression of miR-375 was pro-angiogenic in endothelial cells in vitro and induced endothelial migration, proliferation, sprouting, and vascular network formation, whereas miR-375 inhibition conferred anti-angiogenic effects. Intramuscular delivery of miR-375 improved blood flow recovery to diabetic mouse hindlimbs following femoral artery ligation (FAL) and improved neovessel growth and arteriogenesis in muscle tissues. Using RNA-sequencing and prediction algorithms, Kruppel-like factor 5 (KLF5) was identified as a direct target of miR-375 and siRNA knockdown of KLF5 phenocopied the effects of miR-375 overexpression in vitro and in vivo through regulatory changes in NF-kB signaling. Together, a miR-375-KLF5-NF-kB signaling axis figures prominently as a potential therapeutic pathway in the development CLI in diabetes.

Automated summary

Peripheral artery disease (PAD) is a serious condition that can lead to limb loss and death, especially in subjects with diabetes. In this study, researchers identified miR-375 as a potential therapeutic target for critical limb ischemia (CLI), an advanced form of PAD. They found that miR-375, when overexpressed, promotes angiogenesis and arteriogenesis, improving blood flow recovery in diabetic mice. Further investigation revealed that miR-375 regulates the NF-kB signaling pathway by targeting Kruppel-like factor 5 (KLF5). These findings suggest that targeting the miR-375-KLF5-NF-kB signaling axis may be an effective strategy for treating CLI in diabetes.