Hindlimb ischemia (HLI), in which blood perfusion to the hindlimb is obstructed, is one of the major complications of diabetes. Skeletal muscle cells are crucial for revascularization as they can secrete various angiogenic factors; however, hyperglycemia impairs their viability and subsequently their angiogenic potential. Salidroside can promote skeletal muscle cell viability under hyperglycemia; however, the molecular mechanism is still poorly understood. Here we revealed that salidroside could suppress hyperglycemia-induced ferroptosis in skeletal muscle cells by promoting GPX4 expression, thereby restoring their viability and paracrine functions.

These in turn promoted the proliferation and migration potentials of blood vessel-forming cells. Furthermore, we showed that salidroside/GPX4-mediated ferroptosis inhibition is crucial for promoting angiogenesis and blood perfusion recovery in diabetic HLI mice. Together, we reveal a novel molecular mechanism of salidroside in enhancing skeletal muscle cells-mediated revascularization and blood perfusion recovery in diabetic HLI mice, further highlighting it as a potential compound for treating diabetic HLI.Diabetes, a chronic metabolic disease characterized by hyperglycemia, has remained the fifth leading cause of death worldwide, and directly resulted in 1.6 million deaths in 2014. In chronic conditions, diabetes can lead to long-term damage, dysfunction, and failure of various organs, especially the eyes, kidneys, nerves, heart, and blood vessels. Vascular complication, especially hindlimb ischemia (HLI), is the major cause of diabetes-related morbidity and mortality.

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Mishita
Jornal co-ordinator
Journal of Heart and Cardiovascular Research