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1 Child Health, University of Missouri, Columbia, Missouri, United States
2 Internal Medicine, University of Missouri, Columbia, Missouri, United States
3 Medical Pharmacology and Physiology, University of Missouri, Columbia, Missouri, United States
4 Internal Medicine, University of Missouri, Columbia, Missouri, United States; Medical Pharmacology and Physiology, University of Missouri, Columbia, Missouri, United States
* To whom correspondence should be addressed. E-mail: demarcov{at}missouri.edu.
The transgenic (mRen2)27 (Ren2) rat overexpresses mouse renin in extra-renal tissues causing increased local synthesis of angiotensin-II, oxidative stress, and hypertension. However, little is known about the role of oxidative stress induced by the tissue renin-angiotensin system (RAS) as a contributing factor in pulmonary hypertension (PH). Herein we test the hypothesis that lung tissue RAS overexpression and resultant oxidative stress contribute to PH and pulmonary vascular remodeling using male Ren2 rats. Mean arterial pressure (MAP), right ventricular systolic pressure (RVSP), and wall thickness of small pulmonary arteries (PA), as well as, intrapulmonary NADPH oxidase activity and subunit protein expression, and reactive oxygen species (ROS) were compared in age-matched Ren2 and SD rats pretreated with the superoxide/catalase mimetic, tempol for 21 days. In placebo treated Ren2 rats there were elevations in MAP and RVSP, as well as, in intrapulmonary NADPH oxidase activity and subunits (Nox2, p22phox, and Rac1), and ROS compared to placebo treated SD rats (P<0.05). Tempol treatment decreased RVSP (P<0.05) even though there were no reductions in MAP in the Ren2. Tempol treatment also reduced intrapulmonary NADPH oxidase activity, Nox2, p22phox and Rac1 protein expression, and ROS in the Ren2 (P<0.05). Compared to SD, the cross sectional surface area of small PA was 38% greater (P<0.001) and luminal surface area was 54% less (P<0.001) in Ren2 rats. Tempol treated SD and Ren2 rats had reduced wall surface area and increased luminal area compared to untreated controls (P<0.05). Collectively, the results of this investigation support a seminal role for enhanced tissue RAS/oxidative stress as factors in development of PH and pulmonary vascular remodeling.
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