Management of cardiac fibrosis in diabetic rats; The role of peroxisome proliferator activated receptor gamma (PPAR-gamma) and calcium channel blockers (CCBs)

Abstract

Background: Diabetes mellitus (DM) and hypertension (HTN) are accused of being responsible for the development of the cardiac fibrosis due to severe cardiomyopathy.

Methods: Blood glucose (BG) test was carried out, lipid concentrations, tumor necrosis factor alpha (TNF-α), transforming growth factor beta (TGF-β), matrix metalloproteinase (MMP-2), collagen-I and collagen-III were measured in male Albino rats weighing 179-219 g. The rats were divided into five groups, kept on either control diet or high fat diet (HFD), and simultaneously treated with rosiglitazone (PPAR-gamma) only for one group with 3 mg/kg/day via oral route for 30 days, and with rosiglitazone and felodipine combination for another group with 3 mg/kg/day and 5 mg/kg/day, respectively via oral route for 30 days.

Results: Diabetic hypertensive (DH) rats which fed on a HFD, injected with streptozotocin (STZ) (i.p.) and obstruction for its right kidney was occurred develop hyperglycemia, hypertension, cardiac fibrosis, hypertriglyceridemia, hypercholesterolemia, increased TNF-α, increased TGF-β, decreased MMP-2, increased collagen-I and increased collagen-III, when compared to rats fed on control diet. Treating the DH rats with rosiglitazone only causes a significant decrease for BG levels by 52.79%, triglycerides (TGs) by 24.05%, total cholesterol (T-Chol) by 30.23%, low density lipoprotein cholesterol (LDL-C) by 40.53%, TNF-α by 20.81%, TGF-β by 46.54%, collagen-I by 48.11% and collagen-III by 53.85% but causes a significant increase for MMP-2 by 272.73%. Moreover, Treating the DH rats with rosiglitazone and felodipine combination causes a significant decrease for BG levels by 61.08%, blood pressure (BP) by 16.78%, TGs by 23.80%, T-Chol by 33.27%, LDL-C by 45.18%, TNF-α by 22.82%, TGF-β by 49.31%, collagen-I by 64.15% and collagen-III by 53.85% but causes a significant increase for MMP-2 by 290.91%. Rosiglitazone alone failed to decrease the BP in DH rats in the current dosage and duration.

Conclusion: Our results indicate that the co-existence of diabetes and hypertension could induce cardiomyopathy which could further result in cardiac fibrosis, and that combination treatment with rosiglitazone and felodipine has a great protective role against the metabolic abnormalities, meanwhile, the treatment with rosiglitazone alone has a protective role with a minimal effect against these abnormalities and has no effect on decreasing BP in these cases which may lead to coronary artery diseases (CADs) in future.