Modulation of symmetric dimethyarginine formation by apelin in human pulmonary endothelial cells

Abstract

Background: Dysfunctional nitric oxide (NO)/L-arginine-pathway is a key pathomechanism in the pathogenesis of pulmonary arterial hypertension (PAH). Apelin is involved in the maintenance of pulmonary vascular homeostasis as it regulates vasodilatation. Objective: To determine the regulatory influence of Apelin on the NO/L-arginine-pathway in human pulmonary endothelial cells and the clinical significance of Apelin levels in patients with PAH. Methods: Human pulmonary arterial and microvascular endothelial cells (HPAEC, HPMEC) were cultured under normoxic and hypoxic conditions, stimulated with Apelin and the expression of components and regulators of the NO/L-arginine-pathway were analysed. Apelin and a-/symmetric dimethyarginine (ADMA, SDMA) were measured in cell culture supernatants and PAH patients9 serum. Results: Apelin did not influence the expression of dimethylarginine Dimethylaminohydrolase 1 (DDAH1). However, under hypoxic conditions Apelin increased the expression of DDAH2 and reduced alanine-glyoxylate aminotranferase 2 (AGXT2) expression in HPMEC with subsequent decreased formation of SDMA. In this cohort of PAH patients (n=44) Apelin levels did not correlate with patients9 functional status. Conclusion: Apelin directly modulates the NO/l-arginine-pathway and mediates reduced formation of SDMA, which may cause diminished uncoupling of endothelial NO synthase.