Pulmonary arterial hypertension (PAH) is a lethal disease caused by elevated vascular resistance due to lumen obliterating processes in small pulmonary arteries. Recent studies including ours have implicated a key role for interleukin-13 (IL-13), a T helper type 2-cell (Th2) effector cytokine, in the pathogenesis of PAH. Our recently published findings in rodent models have corroborated these findings: 1) we found that IL-13 transgenic mice (IL-13 tg mice) develop significant pulmonary vascular remodeling and pulmonary hypertension (PH); 2) this was at least in part due to increased proliferation of pulmonary artery smooth muscle cells (PASMCs); and 3) we identified IL-13 receptor α2 (IL-13Rα2) and Arginase2 (Arg2), the mitochondrial isozyme that breaks down L-Arginine, as key modulators of the IL-13 effect on pulmonary vascular remodeling. Recently, increased fatty acid beta-oxidation that might lead to decreased glucose oxidation via the mutually inhibitory balance between two metabolic pathways (the Randle cycle), has been implicated to play a key role in the generation of proliferative phenotype in PH cells. In our preliminary studies, we observed that inhibition of fatty acid beta-oxidation by giving Ranolazine Dihydrochloride via drinking water (30mg/250ml) for one month significantly attenuated not only lung inflammation but also the PH phenotype of right ventricle (RV) of IL-13 tg mice (N=3 in each group). Based on these findings, we hypothesize that the development of tissue and cellular inflammatory responses by IL-13, including IL-13-induced pulmonary vascular phenotype, requires fatty acid beta-oxidation. To address this, we will do the following. First, we will do the same animal experiments using a large group of animals. Then remodeling assessment of pulmonary arteries and right ventricle (RV) as well as measurement of RV systolic pressure by performing right heart catheterization will be done. Second, we will determine the roles of fatty acid metabolism in the regulation of IL-13-specific effects on PASMCs, cardiac myocytes and inflammatory cells. Lastly, we will investigate the roles of the IL-13Rα2 – Arg2 axis in the regulation of fatty acid metabolism by IL-13 using Arg2 and IL-13Rα2 null mutant mice as well as PASMCs and cardiac myocytes transfected with the specific siRNA of Arg2 or IL-13Rα2.