Apelin Mediates the Induction of Profibrogenic Genes in Human Hepatic Stellate Cells

Melgar-Lesmes, Pedro; Casals, Gregori; Pauta, Montse; Ros, Josefa; Reichenbach, Vedrana; Bataller, Ramón; Morales-Ruíz, Manuel; Jiménez, Wladimiro

doi:10.1210/en.2010-0754

Cited by 60 publications

(78 citation statements)

References 27 publications

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“…Apelin has inhibitory activity against human immunodeficiency virus infection (3,58), reduces proinflammatory cytokine production in spleen cells (13) and in the mouse cardiovascular system, and lowers abdominal aortic aneurysm formation by reducing disease-associated vascular inflammation (23). Recent reports demonstrate an emerging role for the apelin-APJ axis in regulation of liver, kidney, and heart fibrosis (24,29,32,45).…”

Section: Discussionmentioning

confidence: 99%

“…In contrast to the inhibitory effect of apelin on pancreatic fibrosis, hepatic fibrosis is stimulated by apelin exposure (24). In human liver disease, apelin seems to mediate profibrogenic gene induction promoted by ANG II and endothelin-1 in hepatic stellate cells.…”

Section: G146 Apelin and Pancreatitismentioning

confidence: 92%

“…Our laboratory (16) reported that intestinal apelin is involved in the inflammatory response of the intestine. Emerging data indicate a role for apelin in regulation of fibrosis in the kidney, heart, and liver (24,29,32,45). Whether the apelin-APJ signaling system is involved in regulation of pancreatic fibrosis during pancreatitis has not been investigated.…”

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confidence: 99%

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Pancreatitis activates pancreatic apelin-APJ axis in mice

Han

Englander

Gómez

et al. 2013

American Journal of Physiology-Gastrointestinal and Liver Physi

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Pancreatitis is classified into acute pancreatitis (AP) and chronic pancreatitis (CP). Apelin, a small regulatory peptide, is the endogenous ligand for the APJ receptor. Apelin and APJ are expressed in the pancreas. The aims of this study were to examine whether apelin influences the inflammatory and fibrosis responses to pancreatitis in mice and to identify mechanisms behind apelin's activities. Supramaximal cerulein induction of AP or CP caused significant ( P < 0.05) elevations in pancreatic apelin and APJ expression. Levels declined during the recovery phases. In apelin gene-knockout mice with pancreatitis, pancreatic neutrophil invasion and myeloperoxidase activity were enhanced significantly, and apelin treatment suppressed both. Apelin exposure reduced CP-induced elevations of extracellular matrix-associated proteins. Apelin inhibited PDGF-simulated connective tissue growth factor production and proliferation of pancreatic stellate cells (PSCs). Serum granulocyte colony-stimulating factor and keratinocyte cytokine levels were higher in apelin gene-knockout than wild-type mice with pancreatitis. Apelin reduced AP- and CP-induced elevations in pancreatic NF-κB activation. Together, these findings imply that the pancreatic apelin-APJ system functions to curb the inflammatory and fibrosis responses during pancreatitis. Furthermore, findings suggest that apelin reduces inflammation and fibrosis by reducing neutrophil recruitment and PSC activity. Inhibition of neutrophil invasion may be mediated by reduced keratinocyte cytokine and granulocyte colony-stimulating factor secretion. Apelin-induced reductions in PSC proliferation and connective tissue growth factor production are putative mechanisms underlying apelin's inhibition of extracellular matrix production. The apelin-associated changes in NF-κB binding may be linked to apelin's regulation of pancreatic inflammatory and fibrosis responses during pancreatitis.

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Section: Discussionmentioning

confidence: 99%

Section: G146 Apelin and Pancreatitismentioning

confidence: 92%

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Pancreatitis activates pancreatic apelin-APJ axis in mice

Han

Englander

Gómez

et al. 2013

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…Apelin was found to be highly expressed by HSCs and in the same study the use of an antagonist of the apelin receptor was reported to inhibit not only angiogenesis but also hepatic fibrosis. In addition, exposure of LX-2, a human HSC line, to recombinant apelin resulted in an increased synthesis of type I collagen as well as of PDGF-β receptor [77]. Moreover, available data on LX2 cells at present suggest that apelin expression can be up-regulated by angiotensin II and endothelin-1 [77] whereas expression of the apelin receptor APJ is positively stimulated by exposure to hypoxia and lipopolysaccharide [78].…”

Section: Adipokinesmentioning

confidence: 97%

Cellular and molecular mechanisms in liver fibrogenesis

Novo

Cannito

Paternostro

et al. 2014

Archives of Biochemistry and Biophysics

178

194

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“…On the other hand, CB2 receptor agonism shows opposite antifibrogenic and anti-inflammatory effects in hepatic and nonhepatic tissue (Muñ oz-Luque et al, 2008;Akhmetshina et al, 2009) and protects against liver ischemia-reperfusion injury (Horvá th et al, 2011). Previous studies by our laboratory have demonstrated that the proangiogenic peptide, apelin (AP), is up-regulated in HSCs of patients with cirrhosis (Melgar-Lesmes et al, 2010). Furthermore, this peptide behaves as a paracrine mediator of fibrogenesis-related gene induction in human HSCs (Melgar-Lesmes et al, 2010), and apelin receptor (APJ) blockade has shown to be effective in reducing hepatic fibrosis and angiogenesis in rats with cirrhosis (Principe et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

Prevention of Fibrosis Progression in CCl₄-Treated Rats: Role of the Hepatic Endocannabinoid and Apelin Systems

Reichenbach

Ros²,

Fernández‐Varo³

et al. 2011

J Pharmacol Exp Ther

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Endocannabinoids behave as antifibrogenic agents by interacting with cannabinoid CB2 receptors, whereas the apelin (AP) system acts as a proangiogenic and profibrogenic mediator in the liver. This study assessed the effect of long-term stimulation of CB2 receptors or AP receptor (APJ) blockade on fibrosis progression in rats under a non-discontinued fibrosis induction program. The study was performed in control and CCl 4 -treated rats for 13 weeks. Fibrosis-induced rats received a CB2 receptor agonist (R,S)-3-(2-iodo-5-nitrobenzoyl)-1-(1-methyl-2-piperidinylmethyl)-1H-indole (AM1241) (1 mg/kg b.wt.), an APJ antagonist [Ala 13 ]-apelin-13 sequence: Gln-Arg-Pro-Arg-LeuSer-His-Lys-Gly-Pro-Met-Pro-Ala (F13A) (75 g/kg b.wt.), or vehicle daily during the last 5 weeks of the CCl 4 inhalation program. Mean arterial pressure (MAP), portal pressure (PP), hepatic collagen content, angiogenesis, cell infiltrate, and mRNA expression of a panel of fibrosis-related genes were measured in all animals. Fibrosis-induced rats showed increased hepatic collagen content, reduced MAP, portal hypertension, and increased expression of the assessed messengers in comparison with control rats. However, fibrotic rats treated with either AM1241 or F13A had reduced hepatic collagen content, improved MAP and PP, ameliorated cell viability, and reduced angiogenesis and cell infiltrate compared with untreated fibrotic rats. These results were associated with attenuated induction of platelet-derived growth factor receptor ␤, ␣-smooth muscle actin, matrix metalloproteinases, and tissue inhibitors of matrix metalloproteinase. CB2 receptor stimulation or APJ blockade prevents fibrosis progression in CCl 4 -treated rats. The mechanisms underlying these phenomena are coincident despite the marked dissimilarities between the CB2 and APJ signaling pathways, thus opening new avenues for preventing fibrosis progression in liver diseases.

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Apelin Mediates the Induction of Profibrogenic Genes in Human Hepatic Stellate Cells

Abstract: apelin mediates some of the fibrogenic effects triggered by AII and ET-1, thus suggesting that apelin could be an important mediator of fibrogenesis in human liver disease.

Cited by 60 publications

References 27 publications

Pancreatitis activates pancreatic apelin-APJ axis in mice

Pancreatitis activates pancreatic apelin-APJ axis in mice

Cellular and molecular mechanisms in liver fibrogenesis

Prevention of Fibrosis Progression in CCl₄-Treated Rats: Role of the Hepatic Endocannabinoid and Apelin Systems

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Apelin Mediates the Induction of Profibrogenic Genes in Human Hepatic Stellate Cells

Abstract: apelin mediates some of the fibrogenic effects triggered by AII and ET-1, thus suggesting that apelin could be an important mediator of fibrogenesis in human liver disease.

Cited by 60 publications

References 27 publications

Pancreatitis activates pancreatic apelin-APJ axis in mice

Pancreatitis activates pancreatic apelin-APJ axis in mice

Cellular and molecular mechanisms in liver fibrogenesis

Prevention of Fibrosis Progression in CCl4-Treated Rats: Role of the Hepatic Endocannabinoid and Apelin Systems

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Product

Resources

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Prevention of Fibrosis Progression in CCl₄-Treated Rats: Role of the Hepatic Endocannabinoid and Apelin Systems