Multidisciplinary approaches to gene therapy of pulmonary hypertension

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To develop novel therapeutic methods for intractable pulmonary hypertension, multidisciplinary researches were conducted and the following findings were obtained.1.On known genes related to PH. a)Suppression of vascular remodeling : Apoptosis of vascular cells closely related to the vascular remodeling. Different statines worked via distinctively different pathways to induce apoptosis in vascular smooth muscles. Mechanisms of endothelin-1 and angiotensin II on myocardial cells were elucidated. Polymorphism of prostacyclin synthase gene resulted in varied production of 6-keto PG. b)Regeneration of vasculature : In vitro colony forming ability of vascular endothelial cell progenitors were investigated to find that the ability was significantly decreased in patients with pulmonary emphysema and stable coronary insufficiency. It was significantly increased, however, in patients with aortic aneurism. This findings suggested critical roles of the progenitor cells in repairing vascular endothelial damage.2.On gene introduction methods. a)Development of vector. An AAV vector carrying foreign VEGF gene was successful in recovering organ ischemia in an animal model, b)Establishment of an animal model which enabled gene delivciy specific to the lung : By transfecting a foreign gene to a syngeneic tibroblasts and injecting them to the lung via intra-venous or intra-tracheal routs, the gene expression specific to lung parenchyma was achieved in high levels.3.Screening of unknown genes related to vascular functions. Cultured human pulmonary arterial endothelial cells and smooth muscle cells were treated by prostacyclin or bosentan, and the gene expressions were exhaustively investigated. Several genes common to both agents responded to the treatment, and were validated by real-time PCR analysis. These findings together would contribute to new strategies for treating intractable pulmonary hypertension.