Alpha-lipoic acid treatment improves adverse cardiac remodelling in the diabetic heart – The role of cardiac hydrogen sulfide-synthesizing enzymes
Date
2022
Journal Title
Journal ISSN
Volume Title
Publisher
Biochemical Pharmacology
Abstract
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 (H2S)-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 H2S 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, car diomyocyte 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, nor moglycemia, prevented DCM, and improved lipid and antioxidant status. Mechanistically, ALA significantly
upregulated the expression of cardiac H2S-synthesizing enzymes and increased plasma H2S concentration
compared to DCM rats (p < 0.001).
Conclusion: ALA preserves myocardial integrity in T2DM likely by maintaining the expression of cardiac H2S synthezing enzymes and increasing plasma H2S level.
Description
Research Article
Keywords
Alpha-lipoic acid (ALA), Type 2 diabetes mellitus (T2DM), Diabetic cardiomyopathy (DCM), hydrogen sulfide (H2S), H2S-synthesizing enzymes