In patients with advanced cystic fibrosis or chronic obstructive pulmonary disease, chronic hypoxia produces pulmonary arterial hypertension (PA HTN) that reduces both quality of life and survival. Hypoxia causes PA HTN through vasoconstriction and structural alterations of lung blood vessels that when severe are poorly reversible with oxygen. We have shown that heparin impairs the development of hypoxic PA HTN in the mouse and the guinea pig not by impairing vasoconstriction but by reducing the amount of vascular smooth muscle that accumulates in the media of hypoxic pulmonary arteries. We have also shown that hypoxic PA HTN stabilizes and that established PA HTN can be partially reversed by 89) and non-anticoagulant heparin fragments are not effective suggesting a nonanticoagulant action of heparin, possibly an antiproliferative effect on vascular smooth muscle cells (SMC). Other investigators have shown variable effects of heparin in hypoxic PA HTN in the rat and calf and no effect in monocrotaline-induced PA HTN in the rat suggesting that heparin's effect may not be generalizable. However, because commercial heparins vary considerably in composition and in antiproliferative activity, some of these negative studies may be explained by the lot of heparin used. Our pilot studies support this conclusion and show that lots of heparin with the greatest antiproliferative activity in vitro are the most effective in vivo. In this proposal we will select antiproliferative commercial heparins by using PA SMC cultures and will test active heparins in both monocrataline and hypoxic PA HTN in the rat and on hypoxic PA HTN in the Yucatan minipig as steps toward clinical trials. We will also fractionate commercial heparins and examine the structural and biochemical aspects of the heparin fraction necessary to inhibit PA SMC growth, and we will test these fractions in guinea pigs. Finally, we will see if heparin inhibits hypoxic vascular remodeling by inhibiting SMC hyperplasia through inhibition of the SMC Na+/H+ exchanger. Growth factor-induced activation of the exchanger may be a key permissive event for SMC growth. We will complete our preliminary studies that suggest heparin inhibits the Na+/H+ exchanger in cultured PA SMC. The effect of endothelial cell derived heparan (1000 times more antiproliferative than heparin) and nonantiproliferative heparin fractions or chondroitan sulfate on Na+/H+ exchange will examine the specificity of heparin's effect in vitro. Experiments with PA rings will examine the Na+/H+ exchange in PA chronically exposed to hypoxia or heparin in situ. These studies will be an important step toward understanding the nature of heparin's effect on experimental PA HTN and will hopefully lead to ) therapeutic trials of this promising approach to the treatment of a common clinical problem.
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