The agonists of peroxisome proliferator-activated receptor-gamma (PPARgamma) ameliorate cardiovascular complications associated with diabetes mellitus. We tested the hypothesis that recovery from ailing to failing myocardium in diabetes by PPARgamma 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. PPARgamma was activated by adding pioglitazone (Pi) to the diet. After 6 wk, 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 twofold higher in D mice compared with N mice. Pi decreased the levels of glucose in D mice to the levels in N mice. LV Hcy levels were 3.5 +/- 0.5 microM in N groups compared with 12.4 +/- 0.6 microM 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 compared with that of the N group and was ameliorated by treatment with Pi. LV wall thickness was reduced to 0.25 +/- 0.02 mm in the D group compared with 0.42 +/- 0.01 mm in the N group. LV diastolic diameter was 3.05 +/- 0.01 mm in the D group compared with 2.20 +/- 0.02 mm in the N group. LV systolic diameter was 1.19 +/- 0.02 mm in the D group and 0.59 +/- 0.01 mm in the N group. Pi normalized the LV variables in D mice. The responses to ACh and nitroprusside were attenuated in diabetic hearts, suggesting that there was E-M uncoupling in the D group compared with 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 in the 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 PPARgamma activity in high-fat, calorie-induced Type 2 diabetes mellitus.
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【Pioglitazone prevents cardiac remodeling in high-fat, high-calorie-induced Type 2 diabetes mellitus.].
【吡格列酮可预防高脂，高热量诱导的2型糖尿病的心脏重塑。】
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DOI：10.1152/ajpheart.01331.2005文章类型：杂志文章
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过氧化物酶体增殖物激活受体 γ (PPARgamma) 的激动剂可改善与糖尿病相关的心血管并发症。我们检验了以下假设: PPARgamma激动剂从糖尿病的病痛恢复到衰竭的心肌部分是由于基质metalloproteinase-9 (MMP-9) 激活降低和同型半胱氨酸 (Hcy) 的左心室 (LV) 组织水平降低。通过给C57BL/6J小鼠喂食高脂肪卡路里饮食，使它们成为糖尿病 (D)。通过在饮食中添加吡格列酮 (Pi) 来激活PPARgamma。6周后，将小鼠分为: 正常卡路里饮食 (N)，D，N Pi和D Pi (每组n = 6)。通过超声心动图测量LV变量，在心脏环中测量内皮-肌细胞 (E-M) 偶联，并通过酶谱测量MMP-9活化。D小鼠的血糖水平比N小鼠高两倍。Pi将D小鼠的葡萄糖水平降低至N小鼠的水平。N组LV Hcy水平为3.5 +/- 0.5 microM，D组为12.4 +/- 0.6 microM。Pi治疗使LV的Hcy水平正常化，但对血浆Hcy水平没有影响。在D组中，与N组相比，LV收缩减少，并通过Pi治疗得到改善。与N组的0.42 +/-0.01毫米相比，D组的LV壁厚减小至0.25 +/-0.02毫米。D组左室舒张直径为3.05 +/-0.01毫米，N组为2.20 +/-0.02毫米。左室收缩直径D组为1.19 +/-0.02毫米，N组为0.59 +/-0.01毫米。Pi对D小鼠的左室变量进行标准化。在糖尿病心脏中，对ACh和硝普钠的反应减弱，表明与N组相比，D组存在E-M解偶联，Pi对此有所改善。D组的血浆和LV MMP-2和-9活性水平高于N组，但在Pi处理后恢复正常。这些结果表明，心肌中的E-M解偶联部分是由于在高脂肪，卡路里诱导的2型糖尿病中抑制PPARgamma活性继发于MMP活性的增加。
