Matsuda Yasushi, Hoshikawa Yasushi, Ameshima Shingo, Suzuki Satoshi, Okada Yoshinori, Tabata Toshiharu, Sugawara Takafumi, Matsumura Yuuji, Kondo Takashi
Department of Thoracic Surgery, Institute of Development, Aging and Cancer, Tohoku University.
Nihon Kokyuki Gakkai Zasshi. 2005 May;43(5):283-8.
Peroxisome proliferator-activated receptor gamma (PPARgamma) is a member of the nuclear hormone receptor superfamily, which regulates transcription of target genes in a ligand-dependent manner. Ligands for PPARgamma have been shown to attenuate proliferation of vascular smooth muscle cells, and to induce apoptosis in several cell lines in vitro. Since monocrotaline (MCT)-induced pulmonary hypertension in rats is characterized by proliferation of pulmonary vascular smooth muscle cells, we hypothesized that PPARgamma ligands may reduce MCT-induced pulmonary hypertension. To test this hypothesis, we treated MCT-injected rats with pioglitazone and troglitazone, synthetic ligands for PPARgamma, for three weeks and measured pulmonary artery pressure and pulmonary vessel wall thickness. TdT-mediated dUTP-biotin nick end labeling (TUNEL) and immunostaining for proliferating cell nuclear antigen (PCNA) were utilized to assess apoptosis and cell proliferation in the pulmonary arterial walls of pioglitazone-treated rats. MCT with pioglitazone or troglitazone treatment significantly reduced pulmonary hypertension and wall thickening of the pulmonary arteries. TUNEL-positive apoptotic cells were not seen in the pulmonary arterial walls of either MCT-injected or control rats with or without pioglitazone. PCNA-positive cells were only seen in the thickened pulmonary arterial walls of MCT rats, but not in the pulmonary arterial walls of controls and of pioglitazone-treated MCT rats. We conclude that PPARgamma ligands reduce MCT-induced pulmonary hypertension and pulmonary vascular wall thickening in rats. Inhibition of MCT-induced cell proliferation in the pulmonary arterial walls may account for this effect
过氧化物酶体增殖物激活受体γ（PPARγ）是核激素受体超家族的成员，它以配体依赖的方式调节靶基因的转录。已表明PPARγ的配体可减弱血管平滑肌细胞的增殖，并在体外诱导多种细胞系凋亡。由于大鼠中野百合碱（MCT）诱导的肺动脉高压以肺血管平滑肌细胞增殖为特征，我们推测PPARγ配体可能减轻MCT诱导的肺动脉高压。为了验证这一假设，我们用PPARγ的合成配体吡格列酮和曲格列酮治疗注射了MCT的大鼠三周，并测量肺动脉压和肺血管壁厚度。利用TdT介导的dUTP生物素缺口末端标记（TUNEL）和增殖细胞核抗原（PCNA）免疫染色来评估吡格列酮治疗大鼠肺动脉壁的细胞凋亡和细胞增殖。MCT联合吡格列酮或曲格列酮治疗显著降低了肺动脉高压和肺动脉壁增厚。在注射MCT的大鼠或接受或未接受吡格列酮治疗的对照大鼠的肺动脉壁中均未见到TUNEL阳性凋亡细胞。PCNA阳性细胞仅在MCT大鼠增厚的肺动脉壁中可见，而在对照大鼠和吡格列酮治疗的MCT大鼠的肺动脉壁中未见。我们得出结论，PPARγ配体可减轻大鼠中MCT诱导的肺动脉高压和肺血管壁增厚。抑制MCT诱导的肺动脉壁细胞增殖可能是造成这种效应的原因。
