| Pulmonary Arterial Hypertension (PAH) is a disease that causes obliterative remodeling of the pulmonary arteries, leading to symptoms, right heart failure and death. There are few effective therapies and mortality is high. Traditionally, therapies for PAH have involved vasodilation of the pulmonary vascular bed, either by providing exogenous vasodilating substances such as calcium channel blockers, nitric oxide or prostacyclin and its derivatives, or by blocking vasoconstricting substances such as endothelin with endothelin receptor blockers. It is increasingly recognized that PAH involves remodeling of the pulmonary vasculature in addition to vasoconstriction, and that effective therapies for PAH must target this remodeling. We demonstrate that inhibition and reversal of the proliferative remodeling that leads to PAH is possible in a rat model by both drug therapy, with a metabolic modulator drug called dichloroacetate, and gene therapy, with a dominant negative survivin protein that promotes pulmonary artery smooth muscle cell apoptosis. Not all "anti-growth" or "pro-apoptosic" strategies are successful, and we demonstrate that drug therapy with combined sirolimus and atorvastatin, as well as gene therapy with human BMPR2, both fail to improve rat PAH Therapies that target the proliferative remodeling of PAH, such as dichloroacetate or survivin inhibitors, may be beneficial in human PAH. |
