Published online before print September 29, 2005, doi: 10.1161/01.RES.0000188211.83193.1a
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Submitted on February 7, 2005
Revised on June 7, 2005
Accepted on September 15, 2005
Cyclin-Dependent Kinase Inhibitor p27Kip1, but not p21WAF1/Cip1, Is Required for Inhibition of Hypoxia-Induced Pulmonary Hypertension and Remodeling by Heparin in Mice
Lunyin Yu ;
From the Department of Medicine, Pulmonary and Critical Care Unit, Massachusetts General Hospital, Harvard Medical School, Boston, Mass.
* To whom correspondence should be addressed. E-mail: chales{at}partners.org.
Heparin has growth inhibitory effects on pulmonary artery smooth muscle cell (PASMC) in vitro and in vivo. However, the mechanism has not been fully defined. In this study, we investigated the role of cyclin-dependent kinase inhibitors, p21 and p27, in the inhibitory effect of heparin on PASMC proliferation in vitro and on hypoxia-induced pulmonary hypertension in vivo using p21WAF1/cip1 (p21) and p27Kip1 (p27)-null mice. In vitro, loss of the p27 gene negated the inhibitory effect of heparin on PASMC proliferation, but p21 was not critical for this inhibition. In vivo, heparin significantly inhibited the development of hypoxia-induced pulmonary hypertension and remodeling, as evidenced by decreased right ventricular systolic pressure, ratio of right ventricular weight to left ventricle plus septum weight, and percent wall thickness of pulmonary artery, in p21+/+, p21-/-, p27+/+, and p27+/-, but not in p27-/- mice. We also observed that hypoxia decreased p27 expression significantly in mouse lung, which was restored by heparin. Heparin inhibited Ki67 proliferative index in terminal bronchial vessel walls in p27+/+ and p27+/-, but not in p27-/- mice exposed to hypoxia. Therefore, we conclude that the cyclin-dependent kinase inhibitor p27, but not p21, is required for the inhibition of hypoxic pulmonary vascular remodeling by heparin.
Key words: p27Kip1 • p21WAF1/cip1 • heparin • pulmonary hypertension • hypoxia • mouse
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