Rosiglitazone Attenuates Chronic Hypoxia–Induced Pulmonary Hypertension in a Mouse Model

Abstract

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 g (PPARg) reduces the expression and activity of NADPH oxidase. Therefore, we hypothesized that activating PPARg 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 O 2 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 PPARg 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 b (PDGFRb) 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, PDGFRb 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 PPARg expression. Collectively, these findings indicate that PPARg ligands attenuated hypoxia-induced pulmonary vascular remodeling and hypertension by suppressing oxidative and proliferative signals providing novel insights for mechanisms underlying therapeutic effects of PPARg activation in pulmonary hypertension.

Update on Pulmonary Hypertension 2009

“…The therapeutic potential of PPARg agonists also reveals promise in animal models of PAH. In 2009, Nisbet and colleagues explored this pathway in the chronic hypoxic mouse PAH model (30). They found that treatment with rosiglitazone prevented the development of pulmonary hypertension at 3 weeks, reversed established pulmonary hypertension at 5 weeks, and from a mechanistic standpoint reduced NADPH oxidase (Nox4) expression, superoxide production, and platelet-derived growth factor (PDGF) receptor b activation.…”

Peroxisome Proliferator-Activated Receptor-γ Ameliorates Pulmonary Arterial Hypertension by Inhibiting 5-Hydroxytryptamine 2B Receptor

“…[28][29][30] The expression of PPARγ was reduced in lung tissue from PAH patients, rats with hypoxia-induced PAH, 31,32 as well as SMCs and endothelial cells isolated from mouse pulmonary arteries exposed to hypoxia. 33 Similarly, PAH developed in mice with SMC-or endothelial cellspecific deletion of PPARγ. 34,35 In contrast, PPARγ activation ameliorated PAH.…”

“…34,35 In contrast, PPARγ activation ameliorated PAH. [32][33][34][36][37][38] However, the effect of PPARγ agonists on the vasoconstriction in PAH remains unknown.…”

Advances in the Management of Pediatric Pulmonary Hypertension

“…[322][323][324][325][326][327][328][329][330][331] PPAR␥ expression was decreased in several studies that used rodent models of PH, and PPAR␥ agonist treatment attenuated pulmonary vascular remodeling. [332][333][334][335] In an interesting recent study, Falcetti and colleagues demonstrated that PPAR␥ expression was enhanced in the medial layer of arteries from patients with idiopathic PH, compared to controls. 322 Whether that finding conflicts with the previous description of decreased lung tissue expression in advanced PH is unclear, since the initial study did not quantitate expression in the medial muscle layers.…”