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Basic Sciences

Crucial Role of ROCK2 in Vascular Smooth Muscle Cells for Hypoxia-Induced Pulmonary Hypertension in MiceSignificance

Toru Shimizu, Yoshihiro Fukumoto, Shin-ichi Tanaka, Kimio Satoh, Shohei Ikeda, Hiroaki Shimokawa
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https://doi.org/10.1161/ATVBAHA.113.301357
Arteriosclerosis, Thrombosis, and Vascular Biology. 2013;33:2780-2791
Originally published November 13, 2013
Toru Shimizu
From the Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan.
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Yoshihiro Fukumoto
From the Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan.
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Shin-ichi Tanaka
From the Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan.
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Kimio Satoh
From the Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan.
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Shohei Ikeda
From the Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan.
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Hiroaki Shimokawa
From the Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan.
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Abstract

Objective—Rho/Rho-kinase (ROCK) pathway in vascular smooth muscle cells (VSMCs) plays an important role in the pathogenesis of cardiovascular diseases, including pulmonary arterial hypertension (PAH). Rho-kinase has 2 isoforms, ROCK1 and ROCK2, with different functions in different cells; ROCK1 for circulating inflammatory cells and ROCK2 for the vasculature. In the present study, we aimed to examine whether ROCK2 in VSMC is involved in the pathogenesis of PAH.

Approach and Results—In patients with PAH, the expression of ROCK2 was increased in pulmonary arterial media and primary pulmonary arterial smooth muscle cells when compared with controls. To investigate the role of ROCK2 in VSMC, we generated VSMC-specific heterozygous ROCK2-deficient (ROCK2+/−) mice and VSMC-specific ROCK2-overexpressing transgenic (ROCK2-Tg) mice. The extent of hypoxia-induced pulmonary hypertension was reduced in ROCK2+/− mice and was enhanced in ROCK2-Tg mice compared with respective littermates. The protein expression of ROCK activity and phosphorylated extracellular signal–regulated kinase and the number of Ki67-positive proliferating cells in the lung were reduced in ROCK2+/− mice and were increased in ROCK2-Tg mice compared with respective littermates. In cultured mouse aortic VSMC, migration and proliferation activities were reduced in ROCK2+/− mice, and migration activity was increased in ROCK2-Tg mice compared with respective littermates. In addition, in primary pulmonary arterial smooth muscle cells from a patient with PAH, ROCK2 was required for migration and proliferation through ROCK and extracellular signal–regulated kinase activation.

Conclusions—ROCK2 in VSMC contributes to the pathogenesis of PAH.

  • hypertension, pulmonary
  • muscle, smooth, vascular
  • rho-associated kinase
  • Received February 13, 2013.
  • Accepted September 30, 2013.
  • © 2013 American Heart Association, Inc.

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December 2013, Volume 33, Issue 12
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    Crucial Role of ROCK2 in Vascular Smooth Muscle Cells for Hypoxia-Induced Pulmonary Hypertension in MiceSignificance
    Toru Shimizu, Yoshihiro Fukumoto, Shin-ichi Tanaka, Kimio Satoh, Shohei Ikeda and Hiroaki Shimokawa
    Arteriosclerosis, Thrombosis, and Vascular Biology. 2013;33:2780-2791, originally published November 13, 2013
    https://doi.org/10.1161/ATVBAHA.113.301357

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    Crucial Role of ROCK2 in Vascular Smooth Muscle Cells for Hypoxia-Induced Pulmonary Hypertension in MiceSignificance
    Toru Shimizu, Yoshihiro Fukumoto, Shin-ichi Tanaka, Kimio Satoh, Shohei Ikeda and Hiroaki Shimokawa
    Arteriosclerosis, Thrombosis, and Vascular Biology. 2013;33:2780-2791, originally published November 13, 2013
    https://doi.org/10.1161/ATVBAHA.113.301357
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    • Smooth Muscle Proliferation and Differentiation
  • Cardiology
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        • Pulmonary Hypertension
        • Hypertension

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