Adipokines in pulmonary hypertension: angels or demons?

Abstract

Pulmonary hypertension (PH) is a devastating cardiopulmonary disorder with poor prognosis and limited curative options. Recent studies revealed a strong association between adipose tissue dysfunction (e.g., obesity) and PH. Adipokines are bioactive polypeptides with pleiotropic effects mainly produced by adipose tissue, and it is suggested that imbalanced production of adipokines in obesity may play a key role in the pathogenesis of PH. Alternations in the production and secretion of adipokines have been observed in PH patients and rodents PH models. In this review, we summarize the expressions and functions of several well-recognized adipokines, the roles of adipokines in the pathogenesis of PH and recent advances in the pharmacological and molecular modulation of adipokines in the treatment of PH. We found that several adipokines (e.g., leptin, resistin, and chemerin) have been demonstrated to display pro-proliferation, pro-inflammatory, and pro-oxidative properties and exacerbate PH. Other adipokines (e.g., adiponectin, apelin, and omentin-1) have anti-proliferation, anti-inflammatory, anti-fibrotic and anti-oxidative impacts on the pulmonary vascular remodeling of PH and are suggested as protective factors against PH, and targeting imbalanced adipokines appears to be a potential novel therapeutic strategy for the treatment of PH.

Keywords: Adipokines; Adiponectin; Leptin; Obesity; Pulmonary hypertension; Vascular remodeling.

Fig. 1

Detrimental roles of selected adipokines in pulmonary hypertension A-H. Detrimental roles and underlying mechanisms of Leptin (A), Resistin (B), NAMPT (C), Chemerin (D), Lipocalin 2 (E), Gremlin-1 (F), DPP-4 (G) and SPARC (H) in the pathogenesis of pulmonary hypertension. I. Selected adipokines play detrimental roles in the pulmonary vascular remodeling of pulmonary hypertension. Abbreviation: BMP, bone morphogenetic protein; CaSR, calcium-sensing receptor; CMKRL1, chemerin chemokine-like receptor 1; DPP-4, dipeptidyl peptidase-4; ERK1/2, extracellular signal-regulated protein kinase 1/2; EndMT, endothelial to mesenchymal transition. ER stress, endoplasmic reticulum stress; GLP-1, glucagon-like peptide 1, HMGB1, high mobility group box 1; HIF-1, hypoxia inducible factor-1; MAPK, mitogen-activated protein kinase; NAMPT, nicotinamide phosphoribosyltansferase; PASMC, pulmonary artery smooth muscle cell; PAEC, pulmonary arterial endothelial cell; PPAR, peroxisome proliferation-activator receptor; PI3K, phosphatidylinositol 3 kinase; ROS, reactive oxygen species; SOD1/2, superoxide dismutases 1/2; SPARC, secreted protein acidic and rich in cysteine. STAT3, signal transduce and activator of transcription 3; Treg, regulatory T cell (Figures are created using Biorender. com).

Fig. 2

Beneficial roles of selected adipokines in pulmonary hypertension A-G. Detrimental roles and underlying mechanisms of Adiponectin (A), CTRP9 (B), FGF21 (C), Apelin (D), Omentin-1 (E), FSTL1 (F) and Vaspin (G) in the pathogenesis of pulmonary hypertension. H. Selected adipokines play detrimental roles in the pulmonary vascular remodeling of pulmonary hypertension. Abbreviation: AMPK, 5′-adenosine monophosphate-activated protein kinase; APJ, apelin receptor; CTRP9, C1q/TNF-related protein 9; eNOS, endothelial nitric oxide synthase; EIF4EBP1, eukaryotic translation initiation Factor 4E–binding protein 1; ER stress, endoplasmic reticulum stress; ERK1/2, extracellular signal-regulated protein kinase 1/2; ET-1, endothelin-1; mTORC, mechanistic target of rapamycin complex 1; FGF21; fibroblast growth factor 21; FGFR1, fibroblast growth factor receptor 1; FSTL1, follistatin-like 1; KLF2, krupple-like factor 2; MMP-2, matrix metalloproteinas-2; PASMC, pulmonary artery smooth muscle cell; PAEC, pulmonary arterial endothelial cell; PPARγ, peroxisome proliferation-activator receptor γ; PGC-1α, PPARγ coactivator--1α; PI3K, phosphatidylinositol 3 kinase; SRF, serum response factor; TGF-1, transforming growth factor 1; ROS, reactive oxygen species (Figures are created using BioRender.com).