Combination Therapy of Alpha-Lipoic Acid, Gliclazide and Ramipril Protects Against Development of Diabetic Cardiomyopathy via Inhibition of TGF-β/Smad Pathway

Abstract

Background: Diabetic cardiomyopathy (DCM) is a major long-term complication of diabetes mellitus, accounting for over 20% of annual mortality rate of diabetic patients globally. Although several existing anti-diabetic drugs have improved glycemic status in diabetic patients, prevalence of DCM is still high. This study investigates cardiac effect of alpha-lipoic acid (ALA) supplementation of anti-diabetic therapy in experimental DCM.Methods: Following 12 h of overnight fasting, 44 male Sprague Dawley rats were randomly assigned to two groups of healthy control (n = 7) and diabetic (n = 37) groups, and fasting blood glucose was measured. Type 2 diabetes mellitus (T2DM) was induced in diabetic group by intraperitoneal (i.p.) administration of nicotinamide (110 mg/kg) and streptozotocin (55 mg/kg). After confirmation of T2DM on day 3, diabetic rats received monotherapies with ALA (60 mg/kg; n = 7), gliclazide (15 mg/kg; n = 7), ramipril (10 mg/kg; n = 7) or combination of the three drugs (n = 7) for 6 weeks while untreated diabetic rats received distilled water and were used as diabetic control (n = 9). Rats were then sacrificed, and blood, pancreas and heart tissues were harvested for analyses using standard methods.Results: T2DM induction caused pancreatic islet destruction, hyperglycemia, weight loss, high relative heart weight, and development of DCM, which was characterized by myocardial degeneration and vacuolation, cardiac fibrosis, elevated cardiac damage markers (plasma and cardiac creatine kinase-myocardial band, brain natriuretic peptide and cardiac troponin I). Triple combination therapy of ALA, gliclazide and ramipril preserved islet structure, maintained body weight and blood glucose level, and prevented DCM development compared to diabetic control (p < 0.001). In addition, the combination therapy markedly reduced plasma levels of inflammatory markers (IL-1β, IL-6 and TNF-α), plasma and cardiac tissue malondialdehyde, triglycerides and total cholesterol while significantly increasing cardiac glutathione and superoxide dismutase activity and high-density lipoprotein-cholesterol compared to diabetic control (p < 0.001). Mechanistically, induction of T2DM upregulated cardiac expression of TGF-β1, phosphorylated Smad2 and Smad3 proteins, which were downregulated following triple combination therapy (p < 0.001).Conclusion: Triple combination therapy of ALA, gliclazide and ramipril prevented DCM development by inhibiting TGF-β1/Smad pathway. Our findings can be extrapolated to the human heart, which would provide effective additional pharmacological therapy against DCM in T2DM patients.

Inflammation in diabetes complications: molecular mechanisms and therapeutic interventions

“…75 The decreased content of TGF-β1, Smad2, and Smad3 protein improved heart function and prevented DCM devolopment. 77 Smad3 deficiency had been reported to inhibit myocardial fibrosis and cardiac inflammation in db/db mice. 78 In DN, TGF-β1 contributed to the repair process of renal injury and was a key regulator of renal inflammation.…”

“…In DCM, TGF‐β1 could promote myocardial fibrosis as well as induce DCM progress through TGF‐β1/Smads pathway 75 . The decreased content of TGF‐β1, Smad2, and Smad3 protein improved heart function and prevented DCM devolopment 77 . Smad3 deficiency had been reported to inhibit myocardial fibrosis and cardiac inflammation in db/db mice 78 .…”

Vanillin and pentoxifylline ameliorate isoproterenol-induced myocardial injury in rats via the Akt/HIF-1α/VEGF signaling pathway

“…73,74 The anti-inflammatory effects of Ram were previously reported in rat diabetic cardiomyopathy and in hypertensive patients. 75,76 Angiotensin II induces inflammation through several pathways including NF-κB activation. Therefore, the anti-inflammatory effects of Ram could be attributed to reduced angiotensin II levels.…”

Linking MDA Levels and Blood Glucose in Streptozotocin-Induced Rat Diabetes: Implications for Diabetic Complications and Therapeutic Strategies

“…Pharmacological agents with antioxidative properties, such as alpha-lipoic acid and angiotensinconverting enzyme (ACE) inhibitors, are commonly used to counteract oxidative damage and mitigate the harmful effects of reactive oxygen species (ROS) on cellular structures (Dugbartey et al, 2022). Simultaneously, lifestyle modifications, including quitting smoking, adopting a nutrient-rich diet with antioxidant properties, and integrating regular exercise, have shown significant effectiveness in reducing oxidative stress and lowering the risk of diabetic complications.…”