Abstract We0053: Leptin Upregulates Bone Morphogenetic Protein Receptor-2 (BMPR2) and Suppresses Growth Differentiation Factor 15 in an Endothelial Model of Pulmonary Arterial Hypertension

Introduction: Pulmonary arterial hypertension (PAH) is a rare, fatal disease affecting the distal precapillary pulmonary arterioles. BMPR2 mutations cause 70% of heritable PAH and BMPR2 expression is significantly reduced in plexiform lesions of patients with idiopathic PAH. In addition to genetic and other causes, obesity has been investigated as a PAH risk factor. Obesity increases leptin levels, resulting in oxidative stress, chronic inflammation, and endothelial dysfunction, which may exacerbate PAH. Notably, leptin can regulate growth differentiation factor-15 (GDF15), a pro-inflammatory, stress-induced cytokine and adipokine associated with PAH severity. Here, leptin effects on BMPR2 and GDF15 expression was investigated in human pulmonary artery endothelial cells (PAECs) with and without BMPR2 deficiency. Methods: Human PAECs were transfected with non-targeting siRNA or siRNA targeting BMPR2 for 48h, followed by incubation with vehicle or recombinant human leptin (10 ng/mL) for 24h. RNA and protein were harvested, and quantitative PCR and Western blotting were performed to determine the mRNA and protein expression of BMPR2, leptin receptor (LEPR), and GDF15. Secreted GDF15 was measured in cell culture supernatants by ELISA. Samples have been collected for genome-wide expression profiling to determine impact of leptin treatment in the presence and absence of BMPR2 silencing. Results: Human PAECs were found to express a functional LEPR, but as expected, not leptin. Leptin treatment induced LEPR mRNA expression and upregulated BMPR2 mRNA and protein expression. These effects were reduced in LEPR-silenced cells. Additionally, BMPR2 silencing was partially rescued by leptin exposure, suggesting that leptin signaling might exert beneficial effects on plexogenic pulmonary arteriopathy. BMPR2 loss alone significantly induced GDF15 expression and secretion, which was suppressed by leptin treatment. In contrast, leptin induced GDF15 in control PAECs, somewhat supporting the notion that leptin is harmful to vascular homeostasis. Recombinant human GDF15 decreased BMPR2 and LEPR mRNA and protein expression. Silencing GDF15 had no significant effect on BMPR2 but significantly upregulated LEPR expression. Conclusion: Leptin, acting via the LEPR, upregulates BMPR2 and suppresses GDF15 in a BMPR2 loss model of PAH. However, leptin suppression of the stress-induced cytokine/adipokine GDF15 was context-dependent and only seen in the setting of BMPR2 deficiency.