Erythropoietin Upregulation in Pulmonary Arterial Hypertension

Abstract

The pathophysiologic alterations of patients with pulmonary arterial hypertension (PAH) are diverse. We aimed to determine novel pathogenic pathways from circulating proteins in patients with PAH. Multianalyte profiling (MAP) was used to measure 90 specifically selected antigens in the plasma of 113 PAH patients and 51 control patients. Erythropoietin (EPO) functional activity was assessed via in vitro pulmonary artery endothelial cell networking and smooth muscle cell proliferation assays. Fifty-eight patients had idiopathic PAH, whereas 55 had other forms of PAH; 5 had heritable PAH, 18 had connective tissue disease (15 with scleroderma and 3 with lupus erythematosis), 13 had portopulmonary hypertension, 6 had PAH associated with drugs or toxins, and 5 had congenital heart disease. The plasmaantigen profile of PAH revealed increased levels of several novel biomarkers, including EPO. Immune quantitative and histochemical studies revealed that EPO not only was significantly elevated in the plasma of PAH patients but also promoted pulmonary artery endothelial cell network formation and smooth muscle cell proliferation. MAP is a hypothesis-generating approach to identifying novel pathophysiologic pathways in PAH. EPO is upregulated in the circulation and lungs of patients with PAH and may affect endothelial and smooth muscle cell proliferation.

Local and systemic renin–angiotensin system participates in cardiopulmonary–renal interactions in monocrotaline-induced pulmonary hypertension in the rat

“…However, its elevation was observed in plasma and lungs of PAH patients [16]. We found increased level of EPO in plasma and kidneys from monocrotaline rats, correlating with decreased hemoglobin oxygen saturation, in line with the regulation of EPO by hypoxia [53].…”

“…We evaluated cardiopulmonary-renal changes in RAS in the monocrotaline-induced PAH, an established, reliable and reproducible experimental model for PAH leading to right ventricular failure and respiratory dysfunction [13,14]. In addition to cardiopulmonary-renal changes in the RAS, we also investigated indicators of renal injury, nephrin [15] and kidney injury molecule-1 (KIM-1), renal hypoxia marker erythropoietin (EPO) [16] and factors involved in the regulation of renin expressionneuronal nitric oxide synthase (NOS1) and cyclooxygenase-2 (COX-2) [17,18].…”

miR‐17/20 Controls Prolyl Hydroxylase 2 (PHD2)/Hypoxia‐Inducible Factor 1 (HIF1) to Regulate Pulmonary Artery Smooth Muscle Cell Proliferation

“…This may raise the question of whether the effects of the loss of miR‐17~92 on pulmonary vessels and hypoxia‐induced PH are due to the changes in circulating EPO. Interestingly, a recent study shows that there are increased levels of EPO in the plasma of PAH patients and that PAH serum or recombinant EPO promotes pulmonary artery endothelial cell network formation and smooth muscle cell proliferation in a cell culture system, respectively . However, multiple studies suggest that EPO is beneficial in protecting against murine models of MCT‐induced or hypoxia‐induced PH in vivo .…”

Systemic lupus erythematosus and pulmonary arterial hypertension: links, risks, and management strategies

“…Pulmonary vasoconstriction will lead to decreased oxygen saturation and hyperexpression of the hypoxia-inducible factor (HIF) and erythropoietin (EPO), which may promote smooth muscle cell proliferation and extensive vascular remodeling 20,27. Several distinct pathways are implicated in vascular remodeling such as impaired apoptosis with upregulation of antiapoptotic proteins and abnormal proliferation of endothelial and adventitial cells 15,20.…”