Peroxisome Proliferator-Activated Receptor-γ Mutations Responsible for Lipodystrophy With Severe Hypertension Activate the Cellular Renin-Angiotensin System
Peroxisome Proliferator-Activated Receptor-γ Mutations Responsible for Lipodystrophy With Severe Hypertension Activate the Cellular Renin-Angiotensin System
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DOI：
10.1161/atvbaha.112.300962
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发表时间：
2013-04-01
影响因子：
8.7
通讯作者：
Caron-Debarle, Martine
中科院分区：
文献类型：
--
作者：
Auclair, Martine;Vigouroux, Corinne;Caron-Debarle, Martine
过氧化物酶体增殖物激活受体-γ（PPAR-gamma）基因突变导致家族性部分脂肪代谢障碍（FPLD 3）综合征，与早发性严重高血压相关PPAR-gamma可抑制血管肾素-血管紧张素系统（RAS）和血管紧张素II受体1的表达。我们使用FPLD 3患者的细胞和表达突变型或野生型PPARgamma的人血管平滑肌细胞评估了PPARgamma失活和细胞RAS之间的关系。方法和结果-我们鉴定了2种新的PPARG突变，R165 T和L339 X，位于PPARDNA和配体结合域。2个FPLD 3家系的4例患者。在培养的皮肤成纤维细胞和外周血单核细胞从4例患者和健康对照组，我们比较了RAS激活，氧化应激和炎症的标志物，并测试了PPAR γ和血管紧张素II受体1的调节剂的效果。我们研究了这2个突变对转染的人血管平滑肌细胞中PPAR γ转录活性和血管RAS的影响。患者的全身RAS没有改变。然而，RAS标志物在患者的成纤维细胞和外周血单核细胞中过表达，如在表达突变型PPAR γ的血管细胞中。血管紧张素II介导的丝裂原活化蛋白激酶活性在患者的成纤维细胞中增加，与RAS组成性激活一致。患者的细胞也表现出氧化应激和炎症。PPARgamma激活和血管紧张素II受体1 mRNA沉默逆转RAS过度激活，氧化应激和炎症，主张血管紧张素II受体1在这些processing. Conclusions的作用，两个新的FPLD 3连接PPARG突变与一个缺陷transrepression细胞RAS导致细胞功能障碍，这可能有助于特定的FPLD 3连接的严重高血压。（动脉硬化血栓血管生物学。2013; 33：829-838。）
Objective-Inactivating peroxisome proliferator-activated receptor-gamma (PPAR gamma) mutations lead to a syndrome of familial partial lipodystrophy (FPLD3) associated with early-onset severe hypertension. PPAR gamma can repress the vascular reninangiotensin system (RAS) and angiotensin II receptor 1 expression. We evaluated the relationships between PPAR gamma inactivation and cellular RAS using FPLD3 patients' cells and human vascular smooth muscle cells expressing mutant or wild-type PPAR gamma.Approach and Results-We identified 2 novel PPARG mutations, R165T and L339X, located in the DNA and ligand-binding domains of PPAR., respectively in 4 patients from 2 FPLD3 families. In cultured skin fibroblasts and peripheral blood mononuclear cells from the 4 patients and healthy controls, we compared markers of RAS activation, oxidative stress, and inflammation, and tested the effect of modulators of PPAR gamma and angiotensin II receptor 1. We studied the impact of the 2 mutations on the transcriptional activity of PPAR gamma and on the vascular RAS in transfected human vascular smooth muscle cells. Systemic RAS was not altered in patients. However, RAS markers were overexpressed in patients' fibroblasts and peripheral blood mononuclear cells, as in vascular cells expressing mutant PPAR gamma. Angiotensin II-mediated mitogen-activated protein kinase activity increased in patients' fibroblasts, consistent with RAS constitutive activation. Patients' cells also displayed oxidative stress and inflammation. PPAR gamma activation and angiotensin II receptor 1 mRNA silencing reversed RAS overactivation, oxidative stress, and inflammation, arguing for a role of angiotensin II receptor 1 in these processes.Conclusions-Two novel FPLD3-linked PPARG mutations are associated with a defective transrepression of cellular RAS leading to cellular dysfunction, which might contribute to the specific FPLD3-linked severe hypertension. (Arterioscler Thromb Vasc Biol. 2013; 33: 829-838.)