A potential role for insulin resistance in experimental pulmonary hypertension

Patients with pulmonary arterial hypertension have increased prevalence of insulin resistance. We aimed to determine whether metabolic defects are associated with bone morphogenic protein receptor type 2 (Bmpr2) mutations in mice, and whether these may contribute to pulmonary vascular disease development. Metabolic phenotyping was performed on transgenic mice with inducible expression of Bmpr2 mutation, R899X. Phenotypic penetrance in Bmpr2 R899X was assessed in a high-fat diet model of insulin resistance. Alterations in glucocorticoid responses were assessed in murine pulmonary microvascular endothelial cells and Bmpr2 R899X mice treated with dexamethasone. Compared to controls, Bmpr2 R899X mice showed increased weight gain and demonstrated insulin resistance as assessed by the homeostatic model assessment insulin resistance (1.0±0.4 versus 2.2±1.8) and by fat accumulation in skeletal muscle and decreased oxygen consumption. Bmpr2 R899X mice fed a high-fat diet had strong increases in pulmonary hypertension penetrance (seven out of 11 versus three out of 11). In cell culture and in vivo experiments, Bmpr2 mutation resulted in a combination of constitutive glucocorticoid receptor activation and insensitivity. Insulin resistance is present as an early feature of Bmpr2 mutation in mice. Exacerbated insulin resistance through high-fat diet worsened pulmonary phenotype, implying a possible causal role in disease. Impaired glucocorticoid responses may contribute to metabolic defects.