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(Circulation Research. 2007;101:734.)
© 2007 American Heart Association, Inc.

Integrative Physiology

Interleukin-10 Expression Mediated by an Adeno-Associated Virus Vector Prevents Monocrotaline-Induced Pulmonary Arterial Hypertension in Rats

Takayuki Ito, Takashi Okada, Hiroshi Miyashita, Tatsuya Nomoto, Mutsuko Nonaka-Sarukawa, Ryosuke Uchibori, Yoshikazu Maeda, Masashi Urabe, Hiroaki Mizukami, Akihiro Kume, Masafumi Takahashi, Uichi Ikeda, Kazuyuki Shimada, Keiya Ozawa

From the Division of Genetic Therapeutics (T.I., T.N., M.N.-S., M.U., H.M., A.K., K.O., R.U.), the Division of Cardiovascular Medicine (T.I., H.M., M.N.-S., K.S., Y.M.), Jichi Medical University, Japan; the Department of Molecular Therapy (T.O.), National Institute of Neuroscience, National Center of Neurology and Psychiatry, Japan; and the Department of Organ Regeneration (M.T., U.I.), Shinshu University Graduate School of Medicine, Japan.

Correspondence to Takayuki Ito, MD, PhD, Division of Genetic Therapeutics, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke, Tochigi 329-0498, Japan. E-mail titou{at}jichi.ac.jp

Pulmonary arterial hypertension (PAH) is a fatal disease associated with inflammation and pathological remodeling of the pulmonary artery (PA). Interleukin (IL)-10 is a pleiotropic antiinflammatory cytokine with vasculoprotective properties. Here, we report the preventive effects of IL-10 on monocrotaline-induced PAH. Three-week-old Wistar rats were intramuscularly injected with an adeno-associated virus serotype 1 vector expressing IL-10, followed by monocrotaline injection at 7 weeks old. IL-10 transduction significantly improved survival rates of the PAH rats 8 weeks after monocrotaline administration compared with control gene transduction (75% versus 0%, P<0.01). IL-10 also significantly reduced mean PA pressure (22.8±1.5 versus 29.7±2.8 mm Hg, P<0.05), a weight ratio of right ventricle to left ventricle plus septum (0.35±0.04 versus 0.42±0.05, P<0.05), and percent medial thickness of the PA (12.9±0.3% versus 21.4±0.4%, P<0.01) compared with controls. IL-10 significantly reduced macrophage infiltration and vascular cell proliferation in the remodeled PA in vivo. It also significantly decreased the lung levels of transforming growth factor-ß₁ and IL-6, which are indicative of PA remodeling. In addition, IL-10 increased the lung level of heme oxygenase-1, which strongly prevents PA remodeling. In vitro analysis revealed that IL-10 significantly inhibited excessive proliferation of cultured human PA smooth muscle cells treated with transforming growth factor-ß₁ or the heme oxygenase inhibitor tin protoporphyrin IX. Thus, IL-10 prevented the development of monocrotaline-induced PAH, and these results provide new insights into the molecular mechanisms of human PAH.

Key Words: pulmonary hypertension • interleukins • gene therapy • inflammation • vascular smooth muscle cell proliferation

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