miR‐34a/SIRT1/HIF‐1α axis is involved in cardiac angiogenesis of type 2 diabetic rats: The protective effect of sodium butyrate combined with treadmill exercise

Abstract Type 2 diabetes mellitus (T2DM) is one of the most common metabolic disorders worldwide. Recent research has indicated that sodium butyrate (NaB) affects glucose metabolism and exercise has an anti‐hyperglycemic effect in diabetes. This study aimed to evaluate the effects of NaB and treadmill exercise on heart angiogenesis through the miR‐34a/SIRT1/FOXO1‐HIF‐1α pathway. Diabetic animals received NaB (400 mg/kg daily, orally) and treadmill exercise for 6 weeks. The effect of NaB and treadmill exercise, alone or combined, on miR‐34a expression, SIRT1, FOXO1, HIF‐1α levels, and angiogenesis in diabetic heart tissue was measured. Diabetes caused increased miR‐34a ( p < 0.01) and FOXO1 ( p < 0.001) expression levels. Also, SIRT1 ( p < 0.001) and HIF‐1α (not significant) expression levels were reduced in diabetic rats. NaB and treadmill exercise decreased miR‐34a (respectively p < 0.05 and not significant) and FOXO1 (both p < 0.001) expression levels and improved SIRT1 (both not significant) and HIF‐1α (respectively p < 0.01 and p < 0.001) levels. Also, NaB combined with treadmill exercise decreased miR‐34a ( p < 0.001) and FOXO1 ( p < 0.001) expression levels, and elevated SIRT1 ( p < 0.05) and HIF‐1α ( p < 0.001) levels in comparison with the diabetic group. NaB and treadmill exercises modulate the expression of miR‐34a and the levels of SIRT1, FOXO1, and HIF‐1α proteins, thus increasing angiogenesis in the heart tissue of diabetic rats. It can be concluded that NaB and treadmill exercise, alone or combined, may be useful in the treatment of diabetes through the miR‐34a/SIRT1/FOXO1‐HIF‐1α pathway.