Chronic hypoxia produces pulmonary hypertension which is due to a combination of pulmonary vasoconstriction, polycythemia and structural alterations in the lung blood vessels. This pulmonary hypertension can become a major factor limiting the quality of life and survival in diseases that are characterized by chronic alveolar hypoxia such as chronic obstructive lung disease, cystic fibrosis, kyphoscoliosis, and alveolar hypoventilation syndromes. Heparin can block smooth muscle cell (SMC) proliferation in vitro and in vivo and can inhibit the pulmonary hypertension (PH), right ventricular hypertrophy (RVH) and pulmonary vascular SMC increase following chronic hypoxia in mice and rats. The objective of this proposal is to determine if the mechanism of action of heparin in preventing hypoxic pulmonary hypertension and the increase in pulmonary SMC is via its anticoagulant activity or some other feature such as its direct antiproliferative effect. To address this objective we have developed a guinea pig model which has chronically implanted pulmonary and carotid catheters so that serial pressures and cardiac outputs can be measured during chronic hypoxia (10% O2). Quantitative morphometry on the lung vessels is performed at the end of each experiment. Pilot data shows that low dose heparin in the guinea pig does not affect acute hypoxic vasoconstriction but substantially decreases the PH and SMC increase of chronic hypoxia. In this proposal, we will address whether heparin works via interfering with coagulation by using coumadin and several different heparin fragments with vary from whole heparin and each other in their anticoagulant effect, antithrombotic effect, antiproliferative effect and charge. We will also explore whether heparin or heparin fragments can reverse established hypoxic PH and finally whether practical approaches such as use of commercially available low molecular weight heparin will do equally well in preventing chronic hypoxic PH and SMC proliferation. This proposal thus should extend our knowledge about the role of coagulation in chronic pulmonary hypertension, our understanding about how heparin impedes pulmonary hypertension and a practical basis for considering human trials of heparin in cor pulmonale.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
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Respiratory and Applied Physiology Study Section (RAP)
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Massachusetts General Hospital
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Zhao, Gaofeng; Seng, Jingjing; Beagle, John et al. (2015) Heparin reduces overcirculation-induced pulmonary artery remodeling through p38 MAPK in piglet. Ann Thorac Surg 99:1677-84
Yu, Lunyin; Hales, Charles A (2011) Effect of chemokine receptor CXCR4 on hypoxia-induced pulmonary hypertension and vascular remodeling in rats. Respir Res 12:21
Yu, Lunyin; Hales, Charles A (2011) Silencing of sodium-hydrogen exchanger 1 attenuates the proliferation, hypertrophy, and migration of pulmonary artery smooth muscle cells via E2F1. Am J Respir Cell Mol Biol 45:923-30
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