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TIGAR reduces smooth muscle cell autophagy to prevent pulmonary hypertension.
Yamanaka, Ryoetsu; Hoshino, Atsushi; Fukai, Kuniyoshi; Urata, Ryota; Minami, Yoshito; Honda, Sakiko; Fushimura, Yohei; Hato, Daichi; Iwai-Kanai, Eri; Matoba, Satoaki.
Afiliação
  • Yamanaka R; Department of Cardiovascular Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kyoto, Japan.
  • Hoshino A; Department of Cardiovascular Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kyoto, Japan.
  • Fukai K; Department of Cardiovascular Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kyoto, Japan.
  • Urata R; Department of Cardiovascular Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kyoto, Japan.
  • Minami Y; Department of Cardiovascular Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kyoto, Japan.
  • Honda S; Department of Cardiovascular Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kyoto, Japan.
  • Fushimura Y; Department of Cardiovascular Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kyoto, Japan.
  • Hato D; Department of Cardiovascular Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kyoto, Japan.
  • Iwai-Kanai E; Faculty of Health Care, Tenri Health Care University, Tenri, Nara, Japan.
  • Matoba S; Department of Cardiovascular Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kyoto, Japan.
Am J Physiol Heart Circ Physiol ; 319(5): H1087-H1096, 2020 11 01.
Article em En | MEDLINE | ID: mdl-32946259
Yamanaka R, Hoshino A, Fukai K, Urata R, Minami Y, Honda S, Fushimura Y, Hato D, Iwai-Kanai E, Matoba S. TIGAR reduces smooth muscle cell autophagy to prevent pulmonary hypertension. Am J Physiol Heart Circ Physiol 319: H1087-H1096, 2020. First published September 18, 2020; doi:10.1152/ajpheart.00314.2020.-Pulmonary arterial hypertension (PAH) is a refractory disease. Its prognosis remains poor; hence, establishment of novel therapeutic targets is urgent. TP53-induced glycolysis and apoptosis regulator (TIGAR) is a downstream target of p53 and exhibits functions inhibiting autophagy and reactive oxygen species (ROS). Recently, p53 was shown to suppress PAH progression. Because inhibition of autophagy and ROS is known to improve PAH, we examined the effect of TIGAR on PAH progression. We compared pulmonary hypertension (PH) development between TIGAR-deficient knockout (KO) and wild-type (WT) mice using a hypoxia-induced PH model. Human pulmonary artery smooth muscle cells (PASMCs) were used for in vitro experiments with small interfering RNA (siRNA) to investigate the possible molecular mechanisms. From the analysis of right ventricular pressure, right ventricular weight, and mortality rate, we concluded that the hypoxia-induced PH development was remarkably higher in TIGAR KO than in WT mice. Pathological investigation revealed that medial thickening of the pulmonary arterioles and cell proliferation were increased in TIGAR KO mice. Autophagy and ROS activity were also increased in TIGAR KO mice. TIGAR knockdown by siRNA increased cell proliferation and migration, exacerbated autophagy, and increased ROS generation during hypoxia. Autophagy inhibition by chloroquine and ROS inhibition by N-acetylcysteine attenuated the proliferation and migration of PASMCs caused by TIGAR knockdown and hypoxia exposure. TIGAR suppressed the proliferation and migration of PASMCs via inhibiting autophagy and ROS and, therefore, improved hypoxia-induced PH. Thus, TIGAR might be a promising therapeutic target for PAH.NEW & NOTEWORTHY Pulmonary arterial hypertension is a refractory disease. TP53-induced glycolysis and apoptosis regulator (TIGAR) is a downstream target of p53 and exhibits functions inhibiting autophagy and reactive oxygen species (ROS). By using TIGAR-deficient knockout mice and human pulmonary artery smooth muscle cells, we found that TIGAR suppressed the proliferation and migration of PASMCs via inhibiting autophagy and ROS and, therefore, improved hypoxia-induced PH. TIGAR will be a promising therapeutic target for PAH.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Autofagia / Monoéster Fosfórico Hidrolases / Miócitos de Músculo Liso / Proteínas Reguladoras de Apoptose / Hipertensão Pulmonar Tipo de estudo: Prognostic_studies Limite: Animals / Humans / Male Idioma: En Revista: Am J Physiol Heart Circ Physiol Assunto da revista: CARDIOLOGIA / FISIOLOGIA Ano de publicação: 2020 Tipo de documento: Article País de afiliação: Japão

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Autofagia / Monoéster Fosfórico Hidrolases / Miócitos de Músculo Liso / Proteínas Reguladoras de Apoptose / Hipertensão Pulmonar Tipo de estudo: Prognostic_studies Limite: Animals / Humans / Male Idioma: En Revista: Am J Physiol Heart Circ Physiol Assunto da revista: CARDIOLOGIA / FISIOLOGIA Ano de publicação: 2020 Tipo de documento: Article País de afiliação: Japão