Alpha-lipoic acid treatment improves adverse cardiac remodelling in the diabetic heart - The role of cardiac hydrogen sulfide-synthesizing enzymes.

INTRODUCTION

Alpha-lipoic acid (ALA) is a licensed drug for the treatment of diabetic neuropathy. We recently reported that it also improves diabetic cardiomyopathy (DCM) in type 2 diabetes mellitus (T2DM). In this study, we present evidence supporting our hypothesis that the cardioprotective effect of ALA is via upregulation of cardiac hydrogen sulfide (HS)-synthesizing enzymes.

METHODS

Following 12 h of overnight fasting, T2DM was induced in 23 out of 30 male Sprague-Dawley rats by intraperitoneal administration of nicotinamide (110 mg/kg) followed by streptozotocin (55 mg/kg) while the rest served as healthy control (HC). T2DM rats then received either oral administration of ALA (60 mg/kg/day; n = 7) or 40 mg/kg/day DL-propargylglycine (PAG, an endogenous HS inhibitor; n = 7) intraperitoneally for 6 weeks after which all rats were sacrificed and samples collected for analysis. Untreated T2DM rats served as diabetic control (DCM; n = 9).

RESULTS

T2DM resulted in weight loss, islet destruction, reduced pancreatic β-cell function and hyperglycemia. Histologically, DCM rats showed significant myocardial damage evidenced by myocardial degeneration, cardiomyocyte vacuolation and apoptosis, cardiac fibrosis and inflammation, which positively correlated with elevated levels of cardiac damage markers compared to HC rats (p < 0.001). These pathological alterations worsened significantly in PAG-treated rats (p < 0.05). However, ALA treatment restored normoinsulemia, normoglycemia, prevented DCM, and improved lipid and antioxidant status. Mechanistically, ALA significantly upregulated the expression of cardiac HS-synthesizing enzymes and increased plasma HS concentration compared to DCM rats (p < 0.001).

CONCLUSION

ALA preserves myocardial integrity in T2DM likely by maintaining the expression of cardiac HS-synthezing enzymes and increasing plasma HS level.