Synergism in hyperhomocysteinemia and diabetes: role of PPAR gamma and tempol

Paras K Mishra,Irving G Joshua,Neetu Tyagi,Utpal Sen,Suresh C Tyagi

doi:10.1186/1475-2840-9-49

Abstract

BackgroundHyperhomocysteinemia (HHcy) and hyperglycemia cause diabetic cardiomyopathy by inducing oxidative stress and attenuating peroxisome proliferator- activated receptor (PPAR) gamma. However, their synergistic contribution is not clear.MethodsDiabetic Akita (Ins2+/-) and hyperhomocysteinemic cystathionine beta synthase mutant (CBS+/-) were used for M-mode echocardiography at the age of four and twenty four weeks. The cardiac rings from WT, Akita and hybrid (Ins2+/-/CBS+/-) of Akita and CBS+/- were treated with different doses of acetylcholine (an endothelial dependent vasodilator). High performance liquid chromatography (HPLC) was performed for determining plasma homocysteine (Hcy) level in the above groups. Akita was treated with ciglitazone (CZ) - a PPAR gamma agonist and tempol-an anti-oxidant, separately and their effects on cardiac remodeling were assessed.ResultsAt twenty four week, Akita mice were hyperglycemic and HHcy. They have increased end diastolic diameter (EDD). In their heart PPAR gamma, tissue inhibitor of metalloproteinase-4 (TIMP-4) and anti-oxidant thioredoxin were attenuated whereas matrix metalloproteinase (MMP)-9, TIMP-3 and NADPH oxidase 4 (NOX4) were induced. Interestingly, they showed synergism between HHcy and hyperglycemia for endothelial-myocyte (E-M) uncoupling. Additionally, treatment with CZ alleviated MMP-9 activity and fibrosis, and improved EDD. On the other hand, treatment with tempol reversed cardiac remodeling in part by restoring the expressions of TIMP-3,-4, thioredoxin and MMP-9.ConclusionsEndogenous homocysteine exacerbates diabetic cardiomyopathy by attenuating PPAR gamma and inducing E-M uncoupling leading to diastolic dysfunction. PPAR gamma agonist and tempol mitigates oxidative stress and ameliorates diastolic dysfunction in diabetes.

Highlights

Hyperhomocysteinemia (HHcy) and hyperglycemia cause diabetic cardiomyopathy by inducing oxidative stress and attenuating peroxisome proliferator- activated receptor (PPAR) gamma
To determine whether elevation of glucose and Hcy level had effect on the cardiac function, M-mode echocardiography was performed, which showed increase in end diastolic diameter (EDD) in twenty four week Akita (Figure 1C). Since both glucose and Hcy level was enhanced in Akita (Figure 1A, B), the independent and/ or synergistic effect of Hcy and glucose on cardiac dysfunction was determined by using double knock out (Ins2+/-/Cystathionine beta synthase (CBS)+/-)
The genotypes of the mutants were confirmed by PCR using Insulin 2 (Ins2) and CBS specific primers (Figure 2)

Summary

Introduction

Hyperhomocysteinemia (HHcy) and hyperglycemia cause diabetic cardiomyopathy by inducing oxidative stress and attenuating peroxisome proliferator- activated receptor (PPAR) gamma. Plasma homocysteine level is elevated [3,4]. Both hyperglycemia and HHcy lead to diabetic cardiomyopathy, which is a leading cause of morbidity and mortality [5,6,7,8,9]. Hcy mediated generation of oxidative radicals induce matrix metalloproteinases (MMPs) and inhibit their tissue inhibitors (TIMPs) that result into extracellular matrix (ECM) remodeling [18,19]. Synergism between Hcy and hyperglycemia in diabetic cardiomyopathy is unclear

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Results

Conclusion