Pulmonary arterial hypertension is linked to insulin resistance and reversed by peroxisome proliferator-activated receptor-γ activation

Background - Patients with pulmonary arterial hypertension (PAH) have reduced expression of apolipoprotein E (apoE) and peroxisome proliferator - activated receptor-gamma 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(-/-)) mice would develop PAH that could be reversed by a peroxisome proliferator-activated receptor-gamma agonist (eg, rosiglitazone). Methods and Results - We report that apoE(-/-) mice on a high-fat diet develop PAH as judged by elevated right ventricular systolic pressure. Compared with females, male apoE(-/-) 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(-/-) mice were insulin resistant and had more severe PAH than female apoE(-/-) 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(-/-) 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(-/-) or C57B1/6 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-gamma activation can reverse PAH in an animal model.