Published online before print August 2, 2007, doi: 10.1161/CIRCRESAHA.107.153023
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Submitted on March 28, 2007
Revised on July 12, 2007
Accepted on July 23, 2007
Interleukin-10 Expression Mediated by an Adeno-Associated Virus Vector Prevents Monocrotaline-Induced Pulmonary Arterial Hypertension in Rats
Takayuki Ito *;
From the Division of Genetic Therapeutics (T.I., T.N., M.N.-S., M.U., H.M., A.K., K.O.), the Division of Cardiovascular Medicine (T.I., H.M., M.N.-S., K.S.), 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.
* To whom correspondence should be addressed. 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-
1 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-1 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
This article has been cited by other articles:
 |
|
 |
|
  Y. Wang and Z. Sun Klotho Gene Delivery Prevents the Progression of Spontaneous Hypertension and Renal Damage Hypertension, October 1, 2009; 54(4): 810 - 817. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. L. Burke, M. G. Frid, C. L. Kunrath, V. Karoor, A. Anwar, B. D. Wagner, D. Strassheim, and K. R. Stenmark Sustained hypoxia promotes the development of a pulmonary artery-specific chronic inflammatory microenvironment Am J Physiol Lung Cell Mol Physiol, August 1, 2009; 297(2): L238 - L250. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. K. Idriss, A. D. Blann, and G. Y.H. Lip Hemoxygenase-1 in Cardiovascular Disease J. Am. Coll. Cardiol., September 16, 2008; 52(12): 971 - 978. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. G. Abraham and A. Kappas Pharmacological and Clinical Aspects of Heme Oxygenase Pharmacol. Rev., March 1, 2008; 60(1): 79 - 127. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Daley, C. Emson, C. Guignabert, R. de Waal Malefyt, J. Louten, V. P. Kurup, C. Hogaboam, L. Taraseviciene-Stewart, N. F. Voelkel, M. Rabinovitch, et al. Pulmonary arterial remodeling induced by a Th2 immune response J. Exp. Med., February 18, 2008; 205(2): 361 - 372. [Abstract] [Full Text] [PDF]
|
|