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1 Univ Colo Hlth Sci Ctr, Denver, Colorado, United States
2 Univ Colo Hlth Sci Ctr, Denver, Colorado, United States; Univ Colo Hlth Sci Ctr
3 Denver,, Colorado, United States; Univ Colo Hlth Sci Ctr, Denver, Colorado, United States
4 CVP Lab/B-133, University of Colorado, Denver, Colorado, United States
5 Department of Medicine, University of Colorado Health Science Center, Denver, Colorado, United States
6 Developmental Lung Biology, University of Colorado, Health Science Center, Denver, United States
7 Cardiovascular Pulmonary Research/Pulmonary Critical Care, University of Colorado Health Sciences Center, Denver,, Colorado, United States
* To whom correspondence should be addressed. E-mail: dwight.klemm{at}uchsc.edu.
Thiazolidinediones (TZDs) are insulin-sensitizing agents that decrease systemic blood pressure, and block remodeling of injured arteries. Recently, TZDs were shown to prevent pulmonary arterial (PA) remodeling in rats treated with monocrotaline. Here we report studies testing the ability of the TZD, rosiglitazone (ROSI) to attenuate arterial remodeling in the lung and prevent the development of PH in rats subjected to chronic hypoxia. PA remodeling was reduced in ROSI-treated animals exposed to hypoxia compared to 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 (SMC) proliferation, decreased collagen and elastin deposition, and increased matrix metalloproteinase-2 (MMP-2) in the PA wall. Cells expressing the c-Kit surface marker were observed in the PA adventitia of untreated animals exposed to hypoxia, but not in ROSI-treated hypoxic rats. Right ventricular (RV) 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, PA pressure was normalized in both groups of hypoxia-exposed animals by Fasudil, an agent that inhibits RhoA/Rho kinase-mediated vasoconstriction. We conclude that ROSI attenuates and reverses PA remodeling and neomuscularization associated with hypoxic PH. However, this agent fails to block the development of PH due to its inability to repress sustained Rho kinase-mediated arterial vasoconstriction.
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