Takeda K, Ichiki T, Tokunou T, Funakoshi Y, Iino N, Hirano K, Kanaide H, Takeshita A
Department of Cardiovascular Medicine, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.
Circulation. 2000 Oct 10;102(15):1834-9. doi: 10.1161/01.cir.102.15.1834.
Peroxisome proliferator-activated receptor gamma (PPARgamma) activators, such as troglitazone (Tro), not only improve insulin resistance but also suppress the neointimal formation after balloon injury. However, the precise mechanisms have not been determined. Angiotensin II (Ang II) plays crucial roles in the pathogenesis of atherosclerosis, hypertension, and neointimal formation after angioplasty. We examined the effect of PPARgamma activators on the expression of Ang II type 1 receptor (AT(1)-R) in cultured vascular smooth muscle cells (VSMCs).
AT(1)-R mRNA and AT(1)-R protein levels were determined by Northern blot analysis and radioligand binding assay, respectively. Natural PPARgamma ligand 15-deoxy-Delta(12,14)-prostaglandin J(2), as well as Tro, reduced the AT(1)-R mRNA expression and the AT(1)-R protein level. The PPARgamma activators also reduced the calcium response of VSMCs to Ang II. PPARgamma activators suppressed the AT(1)-R promoter activity measured by luciferase assay but did not affect the AT(1)-R mRNA stability, suggesting that the suppression occurs at the transcriptional level.
PPARgamma activators reduced the AT(1)-R expression and calcium response to Ang II in VSMCs. Downregulation of AT(1)-R may contribute to the inhibition of neointimal formation by PPARgamma activators.
过氧化物酶体增殖物激活受体γ（PPARγ）激动剂，如曲格列酮（Tro），不仅能改善胰岛素抵抗，还能抑制球囊损伤后的内膜增生。然而，确切机制尚未明确。血管紧张素II（Ang II）在动脉粥样硬化、高血压及血管成形术后内膜增生的发病机制中起关键作用。我们研究了PPARγ激动剂对培养的血管平滑肌细胞（VSMCs）中血管紧张素II 1型受体（AT(1)-R）表达的影响。
分别通过Northern印迹分析和放射性配体结合试验测定AT(1)-R mRNA和AT(1)-R蛋白水平。天然PPARγ配体15-脱氧-Δ(12,14)-前列腺素J(2)以及Tro均降低了AT(1)-R mRNA表达和AT(1)-R蛋白水平。PPARγ激动剂还降低了VSMCs对Ang II的钙反应。PPARγ激动剂通过荧光素酶试验抑制了AT(1)-R启动子活性，但不影响AT(1)-R mRNA稳定性，提示这种抑制发生在转录水平。
PPARγ激动剂降低了VSMCs中AT(1)-R表达及对Ang II的钙反应。AT(1)-R的下调可能有助于PPARγ激动剂抑制内膜增生。
