Pulmonary Arterial Hypertension Is Linked to Insulin Resistance and Reversed by Peroxisome Proliferator–Activated Receptor-γ Activation

Abstract

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...

Smooth Muscle Proliferation and Role of the Prostacyclin (IP) Receptor in Idiopathic Pulmonary Arterial Hypertension

“…Targeted deletion of PPARg in smooth muscle causes pulmonary hypertension and muscularization of distal pulmonary arteries (18), demonstrating the importance of PPARg in regulating lung function. The idea that PPARg might be a clinically relevant target in pulmonary vascular disease is supported by recent work showing that rosiglitazone can reverse mucularization of distal pulmonary arteries in male apoE2/2 mice with severe PAH (33).…”

The Sugen 5416/Hypoxia Mouse Model of Pulmonary Hypertension Revisited: Long‐Term Follow‐Up

“…10 Barium was prepared by mixing 50 g of gelatin (Sigma) and 400 mL of barium powder (Fisher Scientific, Pittsburgh, PA) in 550 mL of water and was injected at 60°-70°C into the MPA.…”

Plasma Levels of High-Density Lipoprotein Cholesterol and Outcomes in Pulmonary Arterial Hypertension

“…An emerging body of evidence suggests that the metabolic syndrome and insulin resistance may predispose to pulmonary vascular disease (17)(18)(19)(20). An apolipoprotein E-deficient mouse model on a highfat diet developed insulin resistance, pulmonary vascular remodeling, and right ventricular hypertrophy, changes that were reversed by rosiglitazone, an insulin-sensitizer drug (17). Insulin resistance defined as a triglyceride/HDL-C ratio greater than 3 has been found to be more common in female patients with PAH than in the general population (18).…”