Loss-of-function mutations in bone morphogenetic protein receptor II (BMP-RII) are linked to pulmonary arterial hypertension (PAH); the ligand for BMP-RII, BMP-2, is a negative regulator of SMC growth. Here, we report an interplay between PPARγ and its transcriptional target apoE downstream of BMP-2 signaling. BMP-2/BMP-RII signaling prevented PDGF-BB-induced proliferation of human and murine pulmonary artery SMCs (PASMCs) by decreasing nuclear phospho-ERK and inducing DNA binding of PPARγ that is independent of Smad1/5/8 phosphorylation. Both BMP-2 and a PPARγ agonist stimulated production and secretion of apoE by SMCs. Using a variety of methods, including short hairpin RNAi in human PASMCs, PAH patient-derived BMP-RII mutant PASMCs, a PPARγ antagonist, and PASMCs isolated from PPARγ-and apoE-deficient mice, we demonstrated that the antiproliferative effect of BMP-2 was BMP-RII, PPARγ, and apoE dependent. Furthermore, we created mice with targeted deletion of PPARγ in SMCs and showed that they spontaneously developed PAH, as indicated by elevated RV systolic pressure, RV hypertrophy, and increased muscularization of the distal pulmonary arteries. Thus, PPARγ-mediated events could protect against PAH, and PPARγ agonists may reverse PAH in patients with or without BMP-RII dysfunction.

Background-Patients with pulmonary arterial hypertension (PAH) have reduced expression of apolipoprotein E (apoE)and peroxisome proliferator-activated receptor-␥ in lung tissues, and deficiency of both has been linked to insulin resistance. ApoE deficiency leads to enhanced platelet-derived growth factor signaling, which is important in the pathobiology of PAH. We therefore hypothesized that insulin-resistant apoE-deficient (apoE Ϫ/Ϫ ) mice would develop PAH that could be reversed by a peroxisome proliferator-activated receptor-␥ agonist (eg, rosiglitazone). Methods and Results-We report that apoEϪ/Ϫ mice on a high-fat diet develop PAH as judged by elevated right ventricular systolic pressure. Compared with females, male apoE Ϫ/Ϫ were insulin resistant, had lower plasma adiponectin, and had higher right ventricular systolic pressure associated with right ventricular hypertrophy and increased peripheral pulmonary artery muscularization. Because male apoE Ϫ/Ϫ mice were insulin resistant and had more severe PAH than female apoE Ϫ/Ϫ mice, we treated them with rosiglitazone for 4 and 10 weeks. This treatment resulted in markedly higher plasma adiponectin, improved insulin sensitivity, and complete regression of PAH, right ventricular hypertrophy, and abnormal pulmonary artery muscularization in male apoE Ϫ/Ϫ mice. We further show that recombinant apoE and adiponectin suppress platelet-derived growth factor-BB-mediated proliferation of pulmonary artery smooth muscle cells harvested from apoE Ϫ/Ϫ or C57Bl/6 control mice. Conclusions-We have shown that insulin resistance, low plasma adiponectin levels, and deficiency of apoE may be risk factors for PAH and that peroxisome proliferator-activated receptor-␥ activation can reverse PAH in an animal model. Key Words: apolipoproteins Ⅲ glucose Ⅲ hypercholesterolemia Ⅲ hypertension, pulmonary Ⅲ insulin Ⅲ metabolism Ⅲ PPAR gamma A lthough insulin resistance is associated with systemic cardiovascular disease, 1-3 it has not been implicated as a predisposing factor in pulmonary arterial hypertension (PAH). Several findings, however, support such an association. Patients with idiopathic PAH have reduced pulmonary mRNA expression of peroxisome proliferator-activated receptor gamma (PPAR␥), 4 a ligand-activated nuclear receptor and transcription factor that regulates adipogenesis and glucose metabolism. [5][6][7] They also have reduced pulmonary mRNA expression of apolipoprotein E (apoE), 8 a protective factor known to reduce circulating oxidized low-density lipoprotein and atherogenesis in the vessel wall. 9 Deficiency of both PPAR␥ and apoE has been linked to insulin resistance and the metabolic syndrome. 7,9 Elevated levels of several circulating factors that are normally repressed by PPAR␥ are associated with insulin resistance 3 and implicated in the pathobiology of PAH. These include interleukin-6, 10,11 fractalkine, 12,13 monocyte chemoattractant protein-1, 14 endothelin-1 (ET-1), [15][16][17] and the endogenous nitric oxide synthase inhibitor asymmetric dimethylarginine (ADM...