Vascular smooth muscle cell-selective peroxisome proliferator-activated receptor-gamma deletion leads to hypotension.
Vascular smooth muscle cell-selective peroxisome proliferator-activated receptor-gamma deletion leads to hypotension.
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DOI：
10.1161/circulationaha.108.815803
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发表时间：
2009-04-28
期刊：
影响因子：
37.8
通讯作者：
Chen YE
中科院分区：
文献类型：
--
作者：
Chang L;Villacorta L;Zhang J;Garcia-Barrio MT;Yang K;Hamblin M;Whitesall SE;D'Alecy LG;Chen YE
过氧化物酶体增殖物激活受体-γ(PPARγ)激动剂通常用于糖尿病的治疗，尽管其PPARγ依赖的作用超越了它们作为胰岛素增敏剂的作用。噻唑烷二酮类药物可降低糖尿病患者的血压，而传统的/组织特异性的PPARγ实验模型的结果表明，PPARγ在控制血压方面具有重要的多效性作用。几乎没有证据表明血管平滑肌细胞特异性PPARγ在基础血管张力中的作用的分子机制。我们发现，血管平滑肌细胞选择性缺失PPARγ(SMPG KO)会损害血管活性，总体上会降低血压。β肾上腺素能受体(β-adr)激动剂可降低去甲肾上腺素(NE)引起的主动脉收缩，增强血管松弛。类似地，SMPG KO小鼠表现出对去甲肾上腺素的双相血压反应，给予β-adr阻滞剂可逆转，而使用β-adr激动剂可增强血压下降。与增强的β-2-adr反应性一致，我们发现血管平滑肌细胞中缺乏pPARγ增加了β-2-adr的表达，可能导致静止期的低血压表型。这些数据揭示了β-2-adr是PPARγ转录抑制的新靶点，表明γ对β2-肾上腺素能信号的调控在BP的调控中起重要作用。
Peroxisome proliferator-activated receptor-γ (PPARγ) agonists are commonly used for the treatment of diabetes although their PPARγ-dependent effects transcend their role as insulin sensitizers. Thiazolidinediones lower blood pressure (BP) in diabetic patients while results from conventional/tissue-specific PPARγ experimental models suggest an important pleiotropic role for PPARγ in BP control. Little evidence is available on the molecular mechanisms underlying the role of vascular smooth muscle cells (VSMC)-specific PPARγ in basal vascular tone. We show that VSMC-selective deletion of PPARγ (SMPG KO) impairs vasoactivity with an overall reduction in BP. Aortic contraction in response to norepinephrine (NE) is reduced and vasorelaxation is enhanced in response to β-adrenergic receptor (β-AdR) agonists in vitro. Similarly, SMPG KO mice display a biphasic response to NE in BP, reversible upon administration of β-AdR blocker and enhanced BP reduction upon treatment with β-AdR agonists. Consistent with enhanced β2-AdR responsiveness, we found that absence of PPARγ in VSMC increased β2-AdR expression possibly leading to the hypotensive phenotype during the rest phase. These data uncovered the β2-AdR as a novel target of PPARγ transcriptional repression in VSMC and indicate that PPARγ regulation of β2-adrenergic signaling is important in modulation of BP.