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

Background— Patients with pulmonary arterial hypertension (PAH) have reduced expression of apolipoprotein E (apoE) and peroxisome proliferator–activated receptor-&ggr; 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-&ggr; 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 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-&ggr; activation can reverse PAH in an animal model.