Our laboratory’s principle research focus is to find ways to improve the lives of people with pulmonary hypertension (PH). PH is defined as mean pulmonary artery pressure in excess of 25 mmHg. According to the Center for Disease Control, in 2002 pulmonary hypertension resulted in 260,000 hospital visits and 15,668 deaths. It is clear that we still do not understand the critical underlying mechanisms responsible for PH and still lack therapies that halt or reverse disease progression to the point where patients can lead somewhat normal lives. Now more than ever we need new ideas that stimulate more research that we hope will translate into new and efficacious therapies.

Our approach originally centered on the use of inhaled nitric gas. Our group initiated studies designed to determine the efficacy of inhaled nitric oxide gas in treating experimentally produced neonatal PH. To accomplish this we used several neonatal animal models (pre-term lamb, postnatal lamb, and foal). In each experimental model inhaled nitric oxide gas was highly effective at reducing elevated pulmonary arterial pressure. Eventually, this led to a pioneering study of inhaled nitric oxide therapy to treat PH in preterm infants.

Our latest efforts are focused on whether activation of the intrapulmonary renin-angiotensin-aldosterone system can lead to development of PH. We recently reported that heterozygous male Ren2 rats, which express the murine renin gene in extrarenal tissues, including the lungs, exhibit increases in intrapulmonary NADPH oxidase activity and accumulation of reactive oxygen species, elevated pulmonary arterial pressure, and pulmonary vascular remodeling. Moreover, the superoxide scavenger, tempol, normalizes intrapulmonary NADPH oxidase activity and ROS accumulation and blunts the development of PH. We concluded that an activated intrapulmonary RAAS causes angiotensin II-induced oxidative stress which contributes to the pathogenesis of PH. Our goal is to further explore the contribution of the RAAS to the pathophysiology of PH in the hopes of identifying novel treatments to reduce the vascular remodeling associated with PH.

Selected Publications

1. DeMarco VG, J Habibi, AT Whaley-Connell, RI Schneider, RL Heller, JP Bosanquet, K Delcour, MR Hayden, SA Cooper, JR Sowers and KC Dellsperger. Oxidative stress contributes to pulmonary hypertension in the transgenic (mren2) 27 ren2 rat. Am J Physiol Heart Circ Physiol 2008 294: H2659–H2668.

2. Whaley-Connell, AT, SA Cooper, J Habibi, CS Stump, MR Hayden, VG DeMarco, D Link, CM Ferrario, JR Sowers. Effect of renin inhibition and AT1R blockade on myocardial remodeling in the transgenic Ren2 rat. Am J Physiol, Endocrinol Metab. 2008 Jul;295(1) :E103-9.

3. DeMarco, V., J.F. Skimming, T.M. Ellis, and S.Cassin. 1996. The effects of nitric oxide inhalation on the ovine neonatal pulmonary and systemic circulations. Reprod., Fertil., and Dev., 8:431-438.