The majority of patients with elevated pulmonary vascular resistance die from right ventricular (RV) failure, yet very little is known about this process. We believe that one potential mechanism of action involves signaling via cyclic guanosine monophosphate (cGMP) and nitric oxide (NO). Manipulation of this pathway to increase the concentration of cGMP or NO may prove beneficial to patients with RV failure. We and others have suggested that the NO/cGMP pathway is limited greatly by the unregulation of arginase in cardiopulmonary disease. Arginase, a metalloenzyme that may inhibit endogenous cGMP/NO signaling by directly competing with nitric oxide synthase, thus promoting RV dysfunction. We hypothesize that, in pulmonary hypertension patients, arginase promotes both the development of RV hypertrophy and the progression to failure due to its interaction with the cGMP/NO signaling pathway. We will therefore use a pulmonary artery banding (PAB) model of pulmonary hypertension to determine the role of arginase in RV hypertrophy and failure (Specific Aim 1). We anticipate that arginase inhibition will lead to measurable changes in NO synthase activity as well as ventricular fibrosis and function. Further experiments will aim to elucidate the mechanism of arginase effects in RV hypertrophy and failure signaling through analysis of downstream targets using transgenic mice small interfering RNA and arginase inhibitors (Specific Aim 2). Likely candidates were identified in previous studies and include nicotinamide adenine dinucleotide phosphate (NADPH), reactive oxygen species and Rho-GTPases.