Abstract
BackgroundWhile chemerin has been shown to increase proliferation and migration of systemic vascular smooth muscle cells (SMCs) contributing therefore to the development of hypertension, this remains to be clarified for the pulmonary circulation.MethodsExpression of chemerin and its three receptors (CMKRL1, CCRL2, GPR1) was examined by immunohistochemistry and RTq-PCR in lungs, pulmonary artery, and thoracic aorta from Wistar rats. Primary cultured rat pulmonary artery and thoracic aorta SMCs treated with recombinant chemerin (tested from 5.10–9 to 10–7 mol/L) were assessed for proliferation and migration (both with 10–7 mol/L endothelin-1), as well as for staurosporine-induced apoptosis.ResultsIn pulmonary artery and thoracic aorta, CMKLR1 expression was detected in both endothelial cells and SMCs. In primary cultured pulmonary artery SMCs, chemerin and its three receptors were expressed, and CMKLR1 expression was higher than those of CCRL2 and GPR1. Chemerin added to endothelin-1 increased pulmonary artery SMC proliferation, while chemerin or endothelin-1 alone did not. This effect was less pronounced in thoracic aorta SMCs. Chemerin induced pulmonary artery and thoracic aorta SMC migration, which was exacerbated by endothelin-1 and more pronounced in thoracic aorta SMCs. Chemerin concentration-dependently reduced staurosporine-induced apoptosis in both pulmonary artery and thoracic aorta SMCs. In pulmonary artery SMCs, endothelin-1 treatment increased the expression of CMKLR1, CCRL2, and GPR1, while these expressions were not altered in thoracic aorta SMCs.ConclusionChemerin/CMKRL1 signaling, in conjunction with a key mediator in the pathogenesis of pulmonary hypertensive diseases, endothelin-1, stimulated proliferation and migration, and increased resistance to apoptosis in rat primary cultured pulmonary artery SMCs. Our results suggest that this signaling could play a role in pulmonary artery remodeling observed in pulmonary hypertension.
Highlights
MATERIALS AND METHODSPulmonary hypertension due to left heart disease, which is often associated with metabolic syndrome, is the most prevalent form of pulmonary hypertension worldwide (Friedman and Andrus, 2012; Vachiery et al, 2019)
CMKLR1, chemerin, and its two other receptors chemokine receptor-like 2 (CCRL2) and G protein-coupled receptor 1 (GPR1) were all detected in primary cultured rat pulmonary artery and thoracic aorta smooth muscle cells (SMCs) (Figures 2A,B)
We evaluated the effects of chemerin on SMC migration, a phenomenon that plays a key role in arterial remodeling, such as those encountered in pulmonary arteries in pulmonary hypertension
Summary
MATERIALS AND METHODSPulmonary hypertension due to left heart disease (or group 2 pulmonary hypertension), which is often associated with metabolic syndrome, is the most prevalent form of pulmonary hypertension worldwide (Friedman and Andrus, 2012; Vachiery et al, 2019). Inflammation associated with metabolic syndrome, notably elevated pro-inflammatory cytokines, is known to contribute to adverse pulmonary vascular remodeling observed in group 2 pulmonary hypertension (Weiss et al, 2013; Ranchoux et al, 2019). Adipokines and cytokines have been incriminated in the pathogenesis of pulmonary artery remodeling in pulmonary arterial hypertension, independently of obesity or metabolic syndrome (Summer et al, 2009; Huertas et al, 2012; Savai et al, 2012). Described as a regulator of energetic metabolism and inflammatory/immune responses (Wittamer et al, 2003; Bozaoglu et al, 2007; Goralski et al, 2007), the adipokine chemerin was identified as a key mediator regulating systemic vascular homeostasis and tone, and contributing to the pathogenesis of hypertension (Watts et al, 2013). While chemerin has been shown to increase proliferation and migration of systemic vascular smooth muscle cells (SMCs) contributing to the development of hypertension, this remains to be clarified for the pulmonary circulation
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