Peroxisome proliferator-activated receptor α-independent actions of Fenofibrate exacerbates left ventricular dilation and fibrosis in chronic pressure overload
Peroxisome proliferator-activated receptor α-independent actions of Fenofibrate exacerbates left ventricular dilation and fibrosis in chronic pressure overload
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DOI：
10.1161/hypertensionaha.107.086926
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发表时间：
2007-05-01
期刊：
影响因子：
8.3
通讯作者：
Sam, Flora
中科院分区：
文献类型：
--
作者：
Duhaney, Toni-Ann S.;Cui, Lei;Sam, Flora
进行性心脏重构的特征是随后的腔室肥大、扩大和泵功能障碍。它还与心脏纤维化和基质周转增加有关。有趣的是，过氧化物酶体增殖物激活受体（PPAR）α激活剂可减少心脏肥大、炎症和纤维化。关于非诺贝特在慢性压力超负荷（PO）介导非依赖于PPAR α的效应中的作用知之甚少。对野生型和PPARalpha缺陷小鼠进行由升主动脉缩窄引起的慢性PO，以测试非诺贝特在通过PPARalpha非依赖性机制的慢性进行性心脏重塑中的作用。在升主动脉缩窄前1周和后8周，将小鼠随机分配至常规食物或含有非诺贝特的食物（每天100 mg/kg体重）。在存在PPAR α的情况下，用非诺贝特治疗的野生型慢性PO小鼠具有改善的心脏重塑。然而，用非诺贝特治疗的PO PPAR α缺陷小鼠的死亡率增加，左心室舒张末期（3.4 +/- 0.1对4.2 +/- 0.1 mm）和收缩末期（1.5 +/-0.2对2.5 +/- 0.2 mm）尺寸显著不良，缩短分数（57 +/- 3%对40 +/- 3%）。非诺贝特还增加PO PPAR α缺陷小鼠的心肌肥大、心肌纤维化和基质金属蛋白酶-2/基质金属蛋白酶组织抑制剂-2的比率。非诺贝特在体外抑制基质金属蛋白酶活性和醛固酮诱导的细胞外信号调节激酶磷酸化的增加。因此，非诺贝特改善慢性PO小鼠的心脏重塑。然而，在PPAR α缺陷小鼠中，这种慢性PO加重，并与心肌纤维化增加和基质重塑改变相关。在不存在PPAR α的情况下，非诺贝特发挥有害的多效性心肌作用。这是一个重要的观察结果，因为认为PPAR α激动剂是重塑心脏中心脏重塑的可能抑制性调节剂。
Progressive cardiac remodeling is characterized by subsequent chamber hypertrophy, enlargement, and pump dysfunction. It is also associated with increased cardiac fibrosis and matrix turnover. Interestingly, peroxisome proliferator-activated receptor ( PPAR) alpha activators reduce cardiac hypertrophy, inflammation, and fibrosis. Little is known about the role of fenofibrates in mediating PPAR alpha-independent effects in response to chronic pressure overload ( PO). Wild-type and PPAR alpha-deficient mice were subjected to chronic PO caused by ascending aortic constriction to test the role of fenofibrates in chronic, progressive cardiac remodeling by a PPAR alpha-independent mechanism. Mice were randomized to regular chow or chow-containing fenofibrate ( 100 mg/kg of body weight per day) for 1 week before and 8 weeks after ascending aortic constriction. In the presence of PPAR alpha, wild-type chronic PO mice, treated with fenofibrate, had improved cardiac remodeling. However, PO PPAR alpha-deficient mice treated with fenofibrate had increased mortality, significantly adverse left ventricular end diastolic (3.4 +/- 0.1 versus 4.2 +/- 0.1 mm) and end systolic ( 1.5 +/- 0.2 versus 2.5 +/- 0.2 mm) dimensions, and fractional shortening ( 57 +/- 3% versus 40 +/- 3%). Fenofibrate also increased myocardial hypertrophy, cardiac fibrosis, and the ratio of matrix metalloproteinase- 2/tissue inhibitor of matrix metalloproteinase- 2 in PO PPAR alpha-deficient mice. Fenofibrate inhibited matrix metalloproteinase activity in vitro and aldosterone-induced increases in extracellular signal-regulated kinase phosphorylation. Thus, fenofibrate improved cardiac remodeling in chronic PO mice. However, in PPAR alpha-deficient mice, this chronic PO was exacerbated and associated with increased myocardial fibrosis and altered matrix remodeling. In the absence of PPAR alpha, fenofibrates exerts deleterious, pleiotropic myocardial actions. This is an important observation, because PPAR alpha agonists are considered possible inhibitory regulators of cardiac remodeling in the remodeled heart.