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This Article Full Text Full Text (PDF) All Versions of this Article: 292/4/L885    most recent 00258.2006v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (7) Citing Articles via Google Scholar Google Scholar Articles by Crossno, J. T. Articles by Klemm, D. J. Search for Related Content PubMed PubMed Citation Articles by Crossno, J. T., Jr. Articles by Klemm, D. J.

Rosiglitazone attenuates hypoxia-induced pulmonary arterial remodeling

¹Research, ²Endocrine, and ³Pulmonary and Critical Care Services, Veterans Affairs Medical Center, Denver; and ⁴Cardiovascular Pulmonary Research Laboratory, Divisions of ⁵Endocrinology and ⁶Pulmonary Science and Critical Care Medicine, Department of Medicine, and ⁷Developmental Lung Biology, Department of Pediatrics, University of Colorado Health Sciences Center, Denver, Colorado

Submitted 11 July 2006 ; accepted in final form 18 December 2006

Thiazolidinediones (TZDs) are insulin-sensitizing agents that also decrease systemic blood pressure, attenuate the formation of atherosclerotic lesions, and block remodeling of injured arterial walls. Recently, TZDs were shown to prevent pulmonary arterial (PA) remodeling in rats treated with monocrotaline. Presently we report studies testing the ability of the TZD rosiglitazone (ROSI) to attenuate pathological arterial remodeling in the lung and prevent the development of pulmonary hypertension (PH) in rats subjected to chronic hypoxia. PA remodeling was reduced in ROSI-treated animals exposed to hypoxia compared with animals exposed to hypoxia alone. ROSI treatment blocked muscularization of distal pulmonary arterioles and reversed remodeling and neomuscularization in lungs of animals previously exposed to chronic hypoxia. Decreased PA remodeling in ROSI-treated animals was associated with decreased smooth muscle cell proliferation, decreased collagen and elastin deposition, and increased matrix metalloproteinase-2 activity in the PA wall. Cells expressing the c-Kit cell surface marker were observed in the PA adventitia of untreated animals exposed to hypoxia but not in ROSI-treated hypoxic rats. Right ventricular hypertrophy and cardiomyocyte hypertrophy were also blunted in ROSI-treated hypoxic animals. Interestingly, mean PA pressures were elevated equally in the untreated and ROSI-treated groups, indicating that ROSI had no effect on the development of PH. However, mean PA pressure was normalized acutely in both groups of hypoxia-exposed animals by Fasudil, an agent that inhibits RhoA/Rho kinase-mediated vasoconstriction. We conclude that ROSI can attenuate and reverse PA remodeling and neomuscularization associated with hypoxic PH. However, this agent fails to block the development of PH, apparently because of its inability to repress sustained Rho kinase-mediated arterial vasoconstriction.

thiazolidinedione; pulmonary hypertension; metalloproteinase; right ventricular hypertrophy; peroxisome proliferator-activated receptor

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