Rosiglitazone attenuates chronic hypoxia-induced pulmonary hypertension in a mouse model.
Chronic hypoxia contributes to pulmonary hypertension through complex mechanisms that include enhanced NADPH oxidase expression and reactive oxygen species (ROS) generation in the lung. Stimulation of peroxisome proliferator-activated receptor gamma (PPARgamma) reduces the expression and activity of NADPH oxidase. Therefore, we hypothesized that activating PPARgamma with rosiglitazone would attenuate chronic hypoxia-induced pulmonary hypertension, in part, through suppressing NADPH oxidase-derived ROS that stimulate proliferative signaling pathways. Male C57Bl/6 mice were exposed to chronic hypoxia (CH, Fi(O2) 10%) or room air for 3 or 5 weeks. During the last 10 days of exposure, each animal was treated daily by gavage with either the PPARgamma ligand, rosiglitazone (10 mg/kg/d) or with an equal volume of vehicle. CH increased: (1) right ventricular systolic pressure (RVSP), (2) right ventricle weight, (3) thickness of the walls of small pulmonary vessels, (4) superoxide production and Nox4 expression in the lung, and (5) platelet-derived growth factor receptor beta (PDGFRbeta) expression and activity and reduced phosphatase and tensin homolog deleted on chromosome 10 (PTEN) expression. Treatment with rosiglitazone prevented the development of pulmonary hypertension at 3 weeks; reversed established pulmonary hypertension at 5 weeks; and attenuated CH-stimulated Nox4 expression and superoxide production, PDGFRbeta activation, and reductions in PTEN expression. Rosiglitazone also attenuated hypoxia-induced increases in Nox4 expression in pulmonary endothelial cells in vitro despite hypoxia-induced reductions in PPARgamma expression. Collectively, these findings indicate that PPARgamma ligands attenuated hypoxia-induced pulmonary vascular remodeling and hypertension by suppressing oxidative and proliferative signals providing novel insights for mechanisms underlying therapeutic effects of PPARgamma activation in pulmonary hypertension.
Nisbet
Rachel E
RE
Department of Medicine, Atlanta Veterans Affairs and Emory University Medical Centers, Atlanta, Georgia 30033, USA.
Bland
Jennifer M
JM
Kleinhenz
Dean J
DJ
Mitchell
Patrick O
PO
Walp
Erik R
ER
Sutliff
Roy L
RL
Hart
C Michael
CM
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D049109:Cell Proliferation; D002908:Chronic Disease; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects; D006352:Heart Ventricles / Q000378:metabolism / Q000473:pathology; D006801:Humans; D006976:Hypertension, Pulmonary / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D000860:Hypoxia / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D008024:Ligands; D008297:Male; D051379:Mice; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000378:metabolism; D009929:Organ Size; D047495:PPAR gamma / Q000819:agonists / Q000378:metabolism*; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000378:metabolism; D000077154:Rosiglitazone; D015398:Signal Transduction / Q000187:drug effects*; D013481:Superoxides / Q000378:metabolism; D045162:Thiazolidinediones / Q000494:pharmacology*; D014665:Vasodilator Agents / Q000494:pharmacology*
D008024:Ligands; D047495:PPAR gamma; D045162:Thiazolidinediones; D014665:Vasodilator Agents; D000077154:Rosiglitazone; D013481:Superoxides; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C422943:Nox4 protein, mouse; D020797:Receptor, Platelet-Derived Growth Factor beta; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse