We have demonstrated that stromal cell-derived factor 1(SDF-1) protects against palmitate-induced cardiac cell death via CXCR7-mediated activation of AMPK signaling (Diabetes 62:2545-2558, 2013). Whether SDF-1 prevents diabetic cardiomyopathy (DCM) and what the underlying mechanism has not been addressed. Here we evaluated the prevention of SDF-1 from DCM in a high fat diet plus streptozotocin (HFD/STZ)-induced type 2 diabetic model in C57BL/6J mice. After 1 month on HFD, the HFD-fed mice were injected with one low dose STZ (100mg/kg body weight, ip). Five days after STZ injection, mice with blood glucose levels ≥250 mg/dl were defined as diabetic. In parallel, the age-matched normal diet-fed mice injected with a same volume of vehicle were used as control. After onset of diabetes, the mice were maintained on HFD or normal diet for another 4 months with or without SDF-1 treatment. Then cardiac function was assayed again, and the mice were sacrificed and cardiac tissue collected for cardiomyopathic index assay. We found that 1 month HFD feeding induced a significant insulin resistance without effect on cardiac function, but continued HFD feeding after STZ injection significantly increased insulin resistance and blood glucose, as well as blood insulin, triglyceride and cholesterol levels. Furthermore, HFD/STZT significantly impaired cardiac function, which were accompanied by increased cardiac inflammation, oxidative stress and fibrotic remodeling. Treatment with SDF-1 dose-dependently prevented diabetes-induced cardiac dysfunction, inflammation and remodeling, but without significant effects on the above mentioned other pathophysiological changes. Mechanistic study demonstrated that diabetes significantly inhibited the function of AMPK and Nrf2, and the expression of CXCR7, but not CXCR4; while treatment with SDF-1 significantly preserved AMPK and Nrf2 function and CXCR7 expression. Knockout CXCR4 did not affect SDF-1 preservation of AMPK and Nrf2 function, but SiRNA knockdown of AMPK resulted in blockade of SDF-1 preservation of Nrf2 function. These results indicate that SDF-1 prevents from DCM via CXCR7/AMPK-mediated Nrf2 activation in type 2 diabetic mice.
Reducing effect of insulin resistance on alpha-synuclein gene expression in skeletal muscle
