The goal of this proposal is to develop a better understanding of the regulation of arginase in both a cell culture and a murine model of hypoxia-induced pulmonary hypertension. The long-term objectives are to apply these discoveries and enable the translation of these findings into clinical practice. Pulmonary hypertension, which can be associated with hypoxia, is a life-threatening disease characterized by vascular remodeling and smooth muscle cell proliferation that results in decreased luminal diameter, increased pulmonary vascular resistance, increased right ventricular pressures, progressive right heart failure and premature death. Arginase has been shown to be vital for proliferation in many cell types including vascular smooth muscle cells. The arginase II isoform has been shown to be involved in the hypoxia-induced proliferation of human pulmonary artery smooth muscle cells (hPASMC) and preliminary studies indicate that cAMP prevented arginase II expression and cell proliferation. Therefore, in this proposal, the mechanisms mediating the vascular remodeling and smooth muscle cell proliferation crucial to the pathogenesis of pulmonary hypertension will be elucidated, as it relates to arginase II expression.
The specific aims for this proposal are 1) to test the hypotheses that hypoxia induces arginase II expression in hPASMC through a MAP kinase-dependent signaling pathway by using small molecule inhibitors of the MAP kinase subfamilies and assessing for arginase II expression and proliferation, 2) to test the hypothesis that PKA activity is required for inhibition of arginase II induction by cAMP in hypoxic hPASMC by using small molecule inhibitors and siRNA-mediated PKA knockdown and examining arginase expression and cell proliferation, and 3) to test the hypothesis that knockout of Pde3a and/or Pde3b attenuates arginase induction in mouse lungs and alleviates pulmonary hypertension during chronic hypoxia. Right ventricular pressures, vessel wall thickness, and right ventricle/(left ventricle+septum) ratios will also be measured to assess vascular remodeling and the degree of pulmonary hypertension. Thus, the question of whether the deficiency of PDE3 will attenuate or prevent pulmonary hypertension will definitively be answered using isoform-specific Pde3-deficient mice. These studies will provide the rationale for the design of novel therapeutic targets involved in the pathogenesis of pulmonary hypertension, for the eventual testing of these therapies in animal models, and finally for the translation of these findings, as a long-term goal, to discover more effective therapies in the prevention and/or treatment of pulmonary hypertension in humans.
Pulmonary hypertension is a life-threatening disease characterized by thickening and changes in the blood vessel wall resulting in high blood pressure in the lungs. This high blood pressure leads to an increase in pressures on the right side of the heart, progressive right heart failure, and premature death. With no cure for pulmonary hypertension, this proposal addresses the underlying causes of the blood vessel wall changes seen in this disease in order to find new options for the prevention and treatment of pulmonary hypertension.
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