Rosiglitazone attenuates hypoxia-induced pulmonary arterial remodeling
Rosiglitazone attenuates hypoxia-induced pulmonary arterial remodeling
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DOI：
10.1152/ajplung.00258.2006
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发表时间：
2007-04-01
影响因子：
4.9
通讯作者：
Klemm, Dwight J.
中科院分区：
文献类型：
--
作者：
Crossno, Joseph T.;Garat, Chrystelle V.;Klemm, Dwight J.
噻唑烷二酮类（TZD）是胰岛素增敏剂，也可降低全身血压，减轻动脉粥样硬化病变的形成，并阻断受损动脉壁的重塑。最近，TZDs被证明可以防止用野百合碱治疗的大鼠的肺动脉（PA）重塑。目前，我们报告的研究测试TZD罗格列酮（ROSI）的能力，以减轻病理性肺动脉重塑和预防肺动脉高压（PH）的发展，在大鼠慢性缺氧。与仅暴露于缺氧的动物相比，暴露于缺氧的ROSI处理的动物的PA重塑减少。ROSI治疗阻断了远端肺小动脉的肌化，逆转了先前暴露于慢性缺氧的动物肺中的重塑和新肌化。在ROSI治疗的动物中，PA重塑减少与PA壁中平滑肌细胞增殖减少、胶原和弹性蛋白沉积减少以及基质金属蛋白酶-2活性增加相关。表达c-Kit细胞表面标志物的细胞在暴露于缺氧的未处理动物的PA外膜中观察到，但在ROSI处理的缺氧大鼠中未观察到。在ROSI处理的缺氧动物中，右心室肥大和心肌细胞肥大也被钝化。有趣的是，平均PA压力在未治疗组和ROSI治疗组中同样升高，表明ROSI对PH的发展没有影响。然而，法舒地尔（一种抑制RhoA/Rho激酶介导的血管收缩的药物）使两组缺氧暴露动物的平均PA压力急性正常化。我们的结论是，ROSI可以减弱和逆转PA重塑和新生肌与缺氧PH。然而，这种药物未能阻止PH的发展，显然是因为它无法抑制持续的Rho激酶介导的动脉血管收缩。
Thiazolidinediones (TZDs) are insulin-sensitizing agents that also decrease systemic blood pressure, attenuate the formation of atherosclerotic lesions, and block remodeling of injured arterial walls. Recently, TZDs were shown to prevent pulmonary arterial (PA) remodeling in rats treated with monocrotaline. Presently we report studies testing the ability of the TZD rosiglitazone (ROSI) to attenuate pathological arterial remodeling in the lung and prevent the development of pulmonary hypertension (PH) in rats subjected to chronic hypoxia. PA remodeling was reduced in ROSI-treated animals exposed to hypoxia compared with animals exposed to hypoxia alone. ROSI treatment blocked muscularization of distal pulmonary arterioles and reversed remodeling and neomuscularization in lungs of animals previously exposed to chronic hypoxia. Decreased PA remodeling in ROSI-treated animals was associated with decreased smooth muscle cell proliferation, decreased collagen and elastin deposition, and increased matrix metalloproteinase-2 activity in the PA wall. Cells expressing the c-Kit cell surface marker were observed in the PA adventitia of untreated animals exposed to hypoxia but not in ROSI-treated hypoxic rats. Right ventricular hypertrophy and cardiomyocyte hypertrophy were also blunted in ROSI-treated hypoxic animals. Interestingly, mean PA pressures were elevated equally in the untreated and ROSI-treated groups, indicating that ROSI had no effect on the development of PH. However, mean PA pressure was normalized acutely in both groups of hypoxia-exposed animals by Fasudil, an agent that inhibits RhoA/Rho kinase-mediated vasoconstriction. We conclude that ROSI can attenuate and reverse PA remodeling and neomuscularization associated with hypoxic PH. However, this agent fails to block the development of PH, apparently because of its inability to repress sustained Rho kinase-mediated arterial vasoconstriction.