SIRT5 Promotes Vascular Regeneration in Peripheral Muscle Ischemia by Regulating Malonylation and Glycolysis

Peripheral artery disease (PAD) is a prominent contributor to the global prevalence and mortality of cardiovascular diseases, yet the therapeutic strategies remain limited and urgently to explore the new methods of promoting vascular regeneration. Metabolism involves numerous aspects of angiogenesis, including the energetics, proliferation, signal transduction and gene expression of endothelial cells (ECs). Sirtuin (SIRT) family play an important role in regulating numerous metabolic processes due to its protein modification activity. Herein, the effect of SIRTs on regulating muscle vascular regeneration of PAD patients was demonstrated. We reanalyzed the SIRTs family by using the reported data of single-nuclei atlas of human PAD limb muscle and found that SIRT5 expression in ECs was significantly downregulated. Then the dynamic changes of SIRTs in ischemic hindlimb of mice and hypoxia-induced HUVECs were observed, among which, SIRT5 showed the most sensitive and significant change in responding to ischemia. Deletion of SIRT5 inhibited the blood flow perfusion recovery and consequently aggravated ischemic hindlimb injury in mice. SIRT5 knock down in vitro inhibited the proliferation, migration and angiogenesis of HUVECs both under normoxia and hypoxia. The mechanism was involved in significantly decreased expression of glycolytic enzymes and increased malonylation of proteins, especially GAPDH, in HUVECs with SIRT5 knock down. In conclusion, SIRT5 controlled the vascular regeneration capacity of lower limb muscles by regulating glycolysis and malonylation modification. Regulating SIRT5 activity might be novel therapeutic target for PAD patients.