Left-ventricular diastolic dysfunction may be prevented by chronic treatment with PPAR-α or -γ agonists in a type 2 diabetic animal model
Left-ventricular diastolic dysfunction may be prevented by chronic treatment with PPAR-α or -γ agonists in a type 2 diabetic animal model
复制标题
DOI：
10.1002/dmrr.410
复制
发表时间：
2003-11-01
影响因子：
8
通讯作者：
Cha, BS
中科院分区：
文献类型：
--
作者：
Kim, SK;Zhao, ZS;Cha, BS
目的本研究的目的是确定过氧化物酶体增殖物激活受体（PPAR）配体是否可以预防晚期糖尿病大鼠的左心室舒张功能障碍（LVDD）。此外，本研究还检测了丙二酰辅酶A脱羧酶（MCD）的活性是否因糖尿病状态本身或用PPAR配体治疗而改变，所述MCD是一种已知调节脂肪酸代谢的与丙二酰辅酶A降解相关的酶。未处理、吡格列酮处理（10 mg/kg/d）和非诺贝特处理（150 mg/kg/d）组。大鼠治疗10周。雄性Long-Evans德岛大冢（LETO）大鼠用作非糖尿病对照。多普勒超声心动图和测量的MCD活动在心肌performed.Results的年龄在38周，OLETF大鼠治疗与（p）ioglitazone或非诺贝特显示出改善血糖水平后，葡萄糖负荷以及改善空腹血浆胰岛素，甘油三酯和FFA水平相比，未经处理的OLETF大鼠。未治疗的OLETF大鼠显示E波减速时间（DTE）延长（74.3 +/- 3.7 vs LETO，56.3 +/- 3.8 ms，P < 0.05）和舒张早期峰值速度波与舒张晚期峰值速度波比值（E/A比值）降低（1.25 +/- 0.06 vs LETO 1.54 +/- 0.08，P < 0.05）。与未治疗的OLETF大鼠相比，吡格列酮治疗可改善DTE（51.6 ± 1.7 ms，P < 0.05），非诺贝特治疗也可改善DTE（61.4 ± 4.3 ms，P < 0.05）和E/A比值（1.57 ± 0.05，P < 0.05）。与收缩功能相关的参数在治疗前和治疗后均未发生变化。OLETF大鼠心肌MCD活性显著低于LETO大鼠（3.26 ± 0.38 vs 7.76 ± 0.84 nmol/min/mg蛋白，P < 0.05）。吡格列酮和非诺贝特治疗导致MCD活性增加，与未治疗的大鼠相比（分别为7.20 ± 0.74和8.33 ± 0.83 nmol/min/mg蛋白，P < 0.05）。结论PPAR-alpha或-gamma激动剂可预防晚期糖尿病大鼠心脏的LVDD，可能通过改善心肌中的脂肪酸代谢或纠正高血糖症和/或高脂血症。版权所有（C）2003约翰威利父子有限公司。
Objectives The aim of this study was to determine whether the peroxisome proliferator-activated receptor (PPAR) ligands could prevent left-ventricular diastolic dysfunction (LVDD) in rats with advanced diabetes. in addition, this study examined whether the activity of malonyl-CoA decarboxylase (MCD), which is an enzyme related to the degradation of malonyl-CoA that is known to regulate the fatty acid metabolism, is changed by the diabetic state itself or by treatment with the PPAR ligands.Methods Male Otsuka Long-Evans Tokushima Fatty (OLETF) rats, a model of type 2 diabetes, aged 28 weeks, were divided into 3 groups: the untreated, pioglitazone-treated (10 mg/kg/d), and fenofibrate-treated (150 mg/kg/d) groups. The rats were treated for 10 weeks. Male Long-Evans Tokushima Otsuka (LETO) rats were used as nondiabetic control. Doppler echocardiography and measurements of the MCD activity at the myocardium were performed.Results At the age of 38 weeks, the OLETF rats treated with either (p)ioglitazone or fenofibrate showed an improvement in the plasma glucose levels after glucose loading as well as an improvement in the fasting plasma insulin, triglyceride, and FFA levels compared to the untreated OLETF rats. The untreated OLETF rats showed a prolonged deceleration time of the E-wave (DTE) (74.3 +/- 3.7 vs LETO, 56.3 +/- 3.8 ms, P < 0.05) and a reduced ratio of the peak early diastolic velocity wave to the late diastolic wave (E/A ratio) (1.25 +/- 0.06 vs LETO 1.54 +/- 0.08, P < 0.05). Pioglitazone treatment in the OLETF rats improved the DTE (51.6 +/- 1.7 ms, P < 0.05), and the fenofibrate treatment also improved the DTE (61.4 +/- 4.3 ms, P < 0.05) and E/A ratio (1.57 +/- 0.05, P < 0.05) compared to the untreated OLETF rats. The parameters related to the systolic function did not change among the groups at both pre- and post-treatments. The MCD activity of the myocardium was remarkably lower in the OLETF rats compared to the LETO rats (3.26 +/- 0.38 vs 7.76 +/- 0.84 nmol/min/mg protein, P < 0.05). The pioglitazone and fenofibrate treatments resulted in an increase in the MCD activity compared to that in the untreated rats (7.20 +/- 0.74 and 8.33 +/- 0.83 nmol/min/mg protein, P < 0.05, respectively).Conclusions The PPAR-alpha or -gamma agonists prevented LVDD in the advanced diabetic rat hearts, possibly through an improvement in the fatty acid metabolism in the myocardium or a correction of the hyperglycemia and/or hyperlipidemia. Copyright (C) 2003 John Wiley Sons, Ltd.