Oxidative stress contributes to pulmonary hypertension in the transgenic (mRen2)27 rat.
The transgenic (mRen2)27 (Ren2) rat overexpresses mouse renin in extrarenal tissues, causing increased local synthesis of ANG 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). Using male Ren2 rats, we test the hypothesis that lung tissue RAS overexpression and resultant oxidative stress contribute to PH and pulmonary vascular remodeling. 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 Sprague-Dawley (SD) rats pretreated with the SOD/catalase mimetic tempol for 21 days. In placebo-treated Ren2 rats, MAP and RVSP, as well as intrapulmonary NADPH oxidase activity and subunits (Nox2, p22phox, and Rac-1) and ROS, were elevated compared with placebo-treated SD rats (P < 0.05). Tempol decreased RVSP (P < 0.05), but not MAP, in Ren2 rats. Tempol also reduced intrapulmonary NADPH oxidase activity, Nox2, p22phox, and Rac-1 protein expression, and ROS in Ren2 rats (P < 0.05). Compared with SD rats, 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. Wall surface area was reduced and luminal area was increased in tempol-treated SD and Ren2 rats compared with 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.
DeMarco
Vincent G
VG
Department of Child Health, University of Missouri School of Medicine, Columbia, Missouri 65210, USA. demarcov@missouri.edu
Habibi
Javad
J
Whaley-Connell
Adam T
AT
Schneider
Rebecca I
RI
Heller
Randall L
RL
Bosanquet
James P
JP
Hayden
Melvin R
MR
Delcour
Kimberly
K
Cooper
S A
SA
Andresen
Bradley T
BT
Sowers
James R
JR
Dellsperger
Kevin C
KC
D000818:Animals; D030801:Animals, Genetically Modified; D000975:Antioxidants / Q000494:pharmacology; D001794:Blood Pressure; D003497:Cyclic N-Oxides / Q000494:pharmacology; D004195:Disease Models, Animal; D006976:Hypertension, Pulmonary / Q000150:complications / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D017379:Hypertrophy, Left Ventricular / Q000209:etiology / Q000378:metabolism; D017380:Hypertrophy, Right Ventricular / Q000209:etiology / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D011651:Pulmonary Artery / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D012083:Renin / Q000235:genetics / Q000378:metabolism*; D012084:Renin-Angiotensin System / Q000187:drug effects; D013113:Spin Labels; D016278:Ventricular Function, Right; D017725:Ventricular Pressure; D020830:rac1 GTP-Binding Protein / Q000378:metabolism
D000975:Antioxidants; D003497:Cyclic N-Oxides; D008562:Membrane Glycoproteins; D017382:Reactive Oxygen Species; C473112:Ren2 protein, mouse; D013113:Spin Labels; C500593:Cybb protein, rat; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; C515768:Cyba protein, rat; D012083:Renin; C499134:Rac1 protein, rat; D020830:rac1 GTP-Binding Protein; C001803:tempol