The agonists of peroxisome proliferators activated receptor gamma (PPAR) ameliorate cardiovascular complications associated with diabetes mellitus. We tested the hypothesis that recovery from ailing to failing myocardium in diabetes by PPAR agonist is in part due to decreased matrix metalloproteinase-9 (MMP-9) activation, and left ventricular (LV) tissue levels of homocysteine (Hcy). C57BL/6J mice were made diabetic (D) by feeding them a high fat-calorie diet. PPAR was activated by adding pioglitazone (Pi) to the diet. After 6 wks, mice were grouped into: Normal calorie diet (N), D, N+Pi and D+Pi (n=6 in each group). LV variables were measured by echocardiography, endothelial-myocyte (E-M) coupling was measured in cardiac rings, and MMP-9 activation was measured by zymography. Blood glucose levels were 2-fold higher in D mice as compared to N mice. Pi decreased the levels of glucose in D group to the levels in N mice. LV Hcy levels were 3.5±0.5 µM in N groups as compared to 12.4±0.6 µM in D groups. Treatment with Pi normalized the LV levels of Hcy, but had no effect on plasma levels of Hcy. In the D group, LV contraction was reduced as compared to N group and was ameliorated by treatment with Pi. LV wall thickness was reduced to 0.25±0.02 mm in D as compared to 0.42±0.01 mm in N group. LV diastolic diameter was 3.05±0.01 mm in D as compared to 2.20±0.02 mm in N group. LV systolic diameter was 1.19±0.02 in D and 0.59±0.01 in N group. Pi normalized the LV variables in D mice. The responses to acetylcholine and nitroprusside were attenuated in diabetic hearts, suggesting that there was E-M uncoupling in the D group as compared to the N group, which was ameliorated by Pi. Plasma and LV levels of MMP-2 and -9 activities were higher in the D group than N group but normalized after Pi treatment. These results suggest that E-M uncoupling in the myocardium, in part, is due to increased MMP activities secondary to suppressing PPAR activity in high fat-calorie induced type 2 diabetes mellitus.