The goal of this proposal is to develop a better understanding of the role of the specific isoform arginase 2 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 endothelial 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 endothelial and smooth muscle cells. The arginase 2 isoform has been shown to be involved in the hypoxia-induced proliferation of human pulmonary microvascular endothelial cells (hPMVEC) and pulmonary artery smooth muscle cells (hPASMC). Furthermore, pharmacologic nonspecific arginase inhibition has been shown to attenuate animal models of pulmonary hypertension. Given the lack of available arginase 2-specific inhibitors, in this proposal, the role of arginase 2 will be evaluated by utilizing mice with a targeted genetic mutation of the arginase 2 gene in a murine model of pulmonary hypertension.
The specific aims for this proposal are 1) to test the hypotheses that a targeted genetic mutation of arginase II will attenuate chronic hypoxia-induced pulmonary hypertension in a murine model, and 2) to test the hypothesis that cell proliferation will be attenuated in PASMCs and PMVECs isolated from arginase 2 knockout mice. We will evaluate right ventricular pressures, right ventricle/(left ventricle+septum) ratios, and assess distal pulmonary arterial muscularization as evidence for pulmonary vascular remodeling and the degree of pulmonary hypertension. The effect of arginase 2 knockout on the nitric oxide pathway will also be examined, given that both arginase and nitric oxide synthase share the common substrate L-arginine. Arginase 1 is the critical isoform in urea cycle metabolism, while arginase 2 is the hypoxia-induced isoform necessary for cell proliferation in the pulmonary vasculature. Thus, the question of whether deficiency of arginase 2 will attenuate or prevent pulmonary hypertension will definitively be answered using isoform-specific arginase 2-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.
