Synergism in hyperhomocysteinemia and diabetes: role of PPAR gamma and tempol.
BACKGROUND
Hyperhomocysteinemia (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.


METHODS
Diabetic 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.


RESULTS
At 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.


CONCLUSIONS
Endogenous 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.
Mishra
Paras K
PK
Department of Physiology & Biophysics, School of Medicine, University of Louisville, Louisville, Kentucky 40202, USA.
Tyagi
Neetu
N
Sen
Utpal
U
Joshua
Irving G
IG
Tyagi
Suresh C
SC
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D009202:Cardiomyopathies / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism; D003497:Cyclic N-Oxides / Q000494:pharmacology*; D048909:Diabetes Complications / Q000188:drug therapy / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000150:complications / Q000188:drug therapy / Q000378:metabolism; D004357:Drug Synergism; D006943:Hyperglycemia / Q000188:drug therapy / Q000378:metabolism; D020138:Hyperhomocysteinemia / Q000150:complications / Q000188:drug therapy / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000494:pharmacology; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D047495:PPAR gamma / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D013113:Spin Labels; D045162:Thiazolidinediones / Q000494:pharmacology*; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000378:metabolism; D019714:Tissue Inhibitor of Metalloproteinases / Q000378:metabolism; D000097792:Tissue Inhibitor of Metalloproteinase-4
D000975:Antioxidants; D003497:Cyclic N-Oxides; D007004:Hypoglycemic Agents; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; D047495:PPAR gamma; D013113:Spin Labels; D045162:Thiazolidinediones; D019717:Tissue Inhibitor of Metalloproteinase-3; D019714:Tissue Inhibitor of Metalloproteinases; D000097792:Tissue Inhibitor of Metalloproteinase-4; C422943:Nox4 protein, mouse; C001803:tempol; C039671:ciglitazone