Endothelin-1 signalling in vascular smooth muscle: Pathways controlling cellular functions associated with atherosclerosis

Ivey, Melanie E.; Osman, Narin; Little, Peter J.

doi:10.1016/j.atherosclerosis.2008.03.006

Cited by 128 publications

(105 citation statements)

References 130 publications

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“…ET-1 is known to induce this pathway in several types of smooth muscle cells (34,40), but additional signaling cascades are concomitantly activated, such as PI3K, PKC-d, and PKC-e, and p38 mitogen-activated protein kinase (41). Therefore, although we found significant contributions of the ERK system to the production of HA (Figures 6A and 6B) and inflammatory cytokines (Figures 4 and 5), the impact of other pathways in PASMC should be evaluated.…”

Section: Discussionmentioning

confidence: 99%

Endothelin-1, the Unfolded Protein Response, and Persistent Inflammation

Yeager

Belchenko

Nguyen

et al. 2012

Am J Respir Cell Mol Biol

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Endothelin-1 is a potent vasoactive peptide that occurs in chronically high levels in humans with pulmonary hypertension and in animal models of the disease. Recently, the unfolded protein response was implicated in a variety of diseases, including pulmonary hypertension. In addition, evidence is increasing for pathological, persistent inflammation in the pathobiology of this disease. We investigated whether endothelin-1 might engage the unfolded protein response and thus link inflammation and the production of hyaluronic acid by pulmonary artery smooth muscle cells. Using immunoblot, real-time PCR, immunofluorescence, and luciferase assays, we found that endothelin-1 induces both a transcriptional and posttranslational activation of the three major arms of the unfolded protein response. The pharmacologic blockade of endothelin A receptors, but not endothelin B receptors, attenuated the observed release, as did a pharmacologic blockade of extracellular signal-regulated kinases 1 and 2 (ERK-1/2) signaling. Using short hairpin RNA and ELISA, we observed that the release by pulmonary artery smooth muscle cells of inflammatory modulators, including hyaluronic acid, is associated with endothelin-1-induced ERK-1/2 phosphorylation and the unfolded protein response. Furthermore, the synthesis of hyaluronic acid induced by endothelin-1 is permissive for persistent THP-1 monocyte binding. These results suggest that endothelin-1, in part because it induces the unfolded protein response in pulmonary artery smooth muscle cells, triggers proinflammatory processes that likely contribute to vascular remodeling in pulmonary hypertension.Keywords: unfolded protein response; endothelin; pulmonary artery smooth muscle; hyaluronic acid; inflammation Pulmonary hypertension (PH) is a disease characterized by extensive pulmonary vascular remodeling, present along the entire length of the vascular tree (1). Eventually, the increased impedance to flow causes right heart failure and death (2). Evidence is mounting that the recruitment of inflammatory cells and the development of persistent inflammation are key components of the pathological vascular remodeling observed in PH (3). In patients with idiopathic PH, macrophages and lymphocytes are found in bronchovascular locations and in occlusive neointimal lesions, and express a panoply of chemokines including CCL2, CCL5, and CX3CL1 (4-7). Concentrations of proinflammatory cytokines, including IL-1 and IL-6, are elevated in both human idiopathic pulmonary artery hypertension (PAH) (8) and in the monocrotaline (MCT) model of PH (9, 10). Depletion of the circulating pool of macrophages is sufficient to prevent hypoxia-driven PH (11), and dexamethasone treatment reverses MCT PH (12). Taken together, these studies suggest that PH is a syndrome characterized by the complex disturbance of innate and acquired immune cells, and of mediators and effectors of inflammation.Building on studies that pointed to the importance of extracellular matrix metabolism in pulmonary vessel homeostasis (13,14), rec...

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Section: Discussionmentioning

confidence: 99%

Endothelin-1, the Unfolded Protein Response, and Persistent Inflammation

Yeager

Belchenko

Nguyen

et al. 2012

Am J Respir Cell Mol Biol

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“…ET-1 has been involved in essential hypertension, and several studies have associated single nucleotide polymorphisms (SNPs) in the ET-1 gene (EDN1) with resting blood pressure and hypertension [4][5][6] . In addition to its vasoconstrictor effect, ET-1 has proatherogenic activity, mediates smooth muscle cell proliferation via ET-1 receptors, acts as a chemoattractant for monocytes, and induces platelet aggregation and the expression of adhesion molecules [7][8][9][10][11] . The synthesis of ET-1 is stimulated at both tissue and plasma levels, and ET-1 levels positively correlate with CAD [12][13][14][15][16] .…”

Section: Introductionmentioning

confidence: 99%

Lack of Association between Endothelin-1 Gene Variants and Myocardial Infarction

Palacín

Rodrı́guez-Pascual

Reguero³

et al. 2009

JAT

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Aim: Endothelin-1 (ET-1) promotes vasoconstriction and cell proliferation, and has been implicated in hypertension and coronary artery disease. Our aim was to analyse the role of the ET-1 gene (EDN1) in the risk for atherosclerosis/myocardial infarction (MI) in a population with smoking as the prevalent risk factor. Methods: The study included 316 patients with early onset MI ( 55 yeras old). All were male with at least one diseased coronary vessel. Denaturing high performance liquid chromatography (DHPLC), single-strand conformation analysis (SSCA), and direct sequencing were used to search for DNA variants in the five EDN1 exons and the promoter region. To determine the association of EDN1 polymorphisms with MI, we genotyped the patients and controls (n 350) and compared the allele and genotype frequencies between groups.

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“…Circulating ET-1 concentrations are increased in most cardiovascular diseases (CVDs), playing a critical role in the structural and functional alterations associated with the development of diabetic vascular complications and hypertension (9). ET-1 is also elevated in atherosclerotic plaques and promotes the expression of inflammatory genes in VSMCs (8).…”

mentioning

confidence: 99%

“…ET-1 is not only a potent regulator of cardiovascular homeostasis but also a stimulator of vascular smooth muscle cell (VSMC) proliferation, migration, and synthesis of extracellular matrix (8), all features of a transition from a differentiated, contractile state to a more dedifferentiated, proliferative, and synthetic phenotype. Circulating ET-1 concentrations are increased in most cardiovascular diseases (CVDs), playing a critical role in the structural and functional alterations associated with the development of diabetic vascular complications and hypertension (9).…”

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confidence: 99%

Glucose-Dependent Insulinotropic Polypeptide Stimulates Osteopontin Expression in the Vasculature via Endothelin-1 and CREB

et al. 2015

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Glucose-dependent insulinotropic polypeptide (GIP) is an incretin hormone with extrapancreatic effects beyond glycemic control. Here we demonstrate unexpected effects of GIP signaling in the vasculature. GIP induces the expression of the proatherogenic cytokine osteopontin (OPN) in mouse arteries via local release of endothelin-1 and activation of CREB. Infusion of GIP increases plasma OPN concentrations in healthy individuals. Plasma endothelin-1 and OPN concentrations are positively correlated in patients with critical limb ischemia. Fasting GIP concentrations are higher in individuals with a history of cardiovascular disease (myocardial infarction, stroke) when compared with control subjects. GIP receptor (GIPR) and OPN mRNA levels are higher in carotid endarterectomies from patients with symptoms (stroke, transient ischemic attacks, amaurosis fugax) than in asymptomatic patients, and expression associates with parameters that are characteristic of unstable and inflammatory plaques (increased lipid accumulation, macrophage infiltration, and reduced smooth muscle cell content). While GIPR expression is predominantly endothelial in healthy arteries from humans, mice, rats, and pigs, remarkable upregulation is observed in endothelial and smooth muscle cells upon culture conditions, yielding a “vascular disease–like” phenotype. Moreover, the common variant rs10423928 in the GIPR gene is associated with increased risk of stroke in patients with type 2 diabetes.

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Endothelin-1 signalling in vascular smooth muscle: Pathways controlling cellular functions associated with atherosclerosis

Cited by 128 publications

References 130 publications

Endothelin-1, the Unfolded Protein Response, and Persistent Inflammation

Endothelin-1, the Unfolded Protein Response, and Persistent Inflammation

Lack of Association between Endothelin-1 Gene Variants and Myocardial Infarction

Glucose-Dependent Insulinotropic Polypeptide Stimulates Osteopontin Expression in the Vasculature via Endothelin-1 and CREB

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