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Angiotensin-II induces phosphorylation of ERK1/2 and promotes aortic adventitial fibroblasts differentiating into myofibroblasts during aortic dissection formation

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Abstract

The development of acute aortic dissection (AD) is attributed to unbearable wall tension superimposed on disordered of cells and extracellular matrix (ECM) in the aortic wall. Adventitial fibroblasts (AFs) phenotypic differentiation response to stress exhibits essential function to regulate the remolding of vascular. Little is known about the AFs phenotypic differentiation and its possible mechanism in patients with AD. In this study, we examined their roles in AD. Surgical specimens of the aorta from AD patients (n = 10) and controls (n = 10) were tested for α-smooth muscle actin (α-SMA), extracellular signal-regulated kinase 1,2 (ERK1/2) and phospho-ERK1/2 expression, respectively by western blot. When compared with controls, protein levels of α-SMA was significantly decreased and levels of phospho-ERK1/2 was increased significantly in the aortic wall from patients with AD. Immunohistochemistry results showed elevated staining of both α-SMA and phospho-ERK1/2 in the adventitia of the aortic wall from patients with AD, on the contrary, staining of α-SMA in the media was decreased compared with controls. In vitro, the Raf/MEK/ERK pathway was involved in Ang-II-induced phenotypic differentiation and matrix metalloproteinase-2 (MMP-2) mRNA expression in AFs. This study provides a new insight into the biological action of AFs and phospho-ERK1/2 promoting phenotypic differentiation and MMP-2 expression, suggesting an important role of AFs in leading to disorder the delicate balance of ECM metabolism in the aortic wall, so that AFs may be an essential participant during AD formation.

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References

  • Aimes RT, Quigley JP (1995) Matrix metalloproteinase-2 is an interstitial collagenase. Inhibitor-free enzyme catalyzes the cleavage of collagen fibrils and soluble native type I collagen generating the specific 3/4- and 1/4-length fragments. J Biol Chem 270(11):5872–5876

    Article  CAS  PubMed  Google Scholar 

  • Akiyama M et al (2006) Up-regulation of matrix metalloproteinase-2 and membrane-type 1-matrix metalloproteinase were coupled with that of type I procollagen in granulation tissue response after the onset of aortic dissection. Virchows Archiv 448:811–821

    Article  CAS  PubMed  Google Scholar 

  • Allaire E et al (2009) New insight in aetiopathogenesis of aortic diseases. Eur J Vasc Endovasc Surg 37(5):531–537

    Article  CAS  PubMed  Google Scholar 

  • Arenas IA et al (2004) Angiotensin II-induced MMP-2 release from endothelial cells is mediated by TNF-alpha. Am J Physiol Cell Physiol 286(4):C779–C784

    Article  CAS  PubMed  Google Scholar 

  • Barker SG et al (1994) The adventitia and atherogenesis: removal initiates intimal proliferation in the rabbit which regresses on generation of a ‘neoadventitia’. Atherosclerosis 105(2):131–144

    Article  CAS  PubMed  Google Scholar 

  • Belknap JK et al (1997) Hypoxia increases bromodeoxyuridine labeling indices in bovine neonatal pulmonary arteries. Am J Respir Cell Mol Biol 16(4):366–371

    Article  CAS  PubMed  Google Scholar 

  • Beltran AE et al (2009) p38 MAPK contributes to angiotensin II-induced COX-2 expression in aortic fibroblasts from normotensive and hypertensive rats. J Hypertens 27(1):142–154

    Article  CAS  PubMed  Google Scholar 

  • Castoldi G et al (2007) Angiotensin II increases tissue-specific inhibitor of metalloproteinase-2 expression in rat aortic smooth muscle cells in vivo: evidence of a pressure-independent effect. Clin Exp Pharmacol Physiol 34(3):205–209

    Article  CAS  PubMed  Google Scholar 

  • Coady MA et al (1999) Natural history, pathogenesis, and etiology of thoracic aortic aneurysms and dissections. Cardiol Clin 17(4):615–635

    Article  CAS  PubMed  Google Scholar 

  • Daugherty A, Cassis LA (2004) Mouse models of abdominal aortic aneurysms. Arterioscler Thromb Vasc Biol 24(3):429–434

    Article  CAS  PubMed  Google Scholar 

  • Daugherty A, Manning MW, Cassis LA (2000) Angiotensin II promotes atherosclerotic lesions and aneurysms in apolipoprotein E-deficient mice. J Clin Invest 105(11):1605–1612

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Davis V et al (1998) Matrix metalloproteinase-2 production and its binding to the matrix are increased in abdominal aortic aneurysms. Arterioscler Thromb Vasc Biol 18(10):1625–1633

    Article  CAS  PubMed  Google Scholar 

  • Freestone T et al (1995) Inflammation and matrix metalloproteinases in the enlarging abdominal aortic aneurysm. Arterioscler Thromb Vasc Biol 15(8):1145–1151

    Article  CAS  PubMed  Google Scholar 

  • Gabbiani G (2003) The myofibroblast in wound healing and fibrocontractive diseases. J Pathol 200(4):500–503

    Article  CAS  PubMed  Google Scholar 

  • Ghosh A et al (2012) The role of extracellular signal-related kinase during abdominal aortic aneurysm formation. J Am Coll Surg 215(5):668–680

    Article  PubMed Central  PubMed  Google Scholar 

  • Grotendorst GR, Rahmanie H, Duncan MR (2004) Combinatorial signaling pathways determine fibroblast proliferation and myofibroblast differentiation. FASEB J 18(3):469–479

    Article  CAS  PubMed  Google Scholar 

  • Hagan PG et al (2000) The international registry of acute aortic dissection (IRAD): new insights into an old disease. JAMA 283(7):897–903

    Article  CAS  PubMed  Google Scholar 

  • Hinz B et al (2007) The myofibroblast: one function, multiple origins. Am J Pathol 170(6):1807–1816

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Hirst AJ, Johns VJ, Kime SJ (1958) Dissecting aneurysm of the aorta: a review of 505 cases. Medicine (Baltimore) 37(3):217–279

    Article  Google Scholar 

  • Huang J et al (2010) Fibulin-4 deficiency results in ascending aortic aneurysms: a potential link between abnormal smooth muscle cell phenotype and aneurysm progression. Circ Res 106(3):583–592

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Ishii T, Asuwa N (2000) Collagen and elastin degradation by matrix metalloproteinases and tissue inhibitors of matrix metalloproteinase in aortic dissection. Hum Pathol 31(6):640–646

    Article  CAS  PubMed  Google Scholar 

  • Ji J et al (2010) Activation of adventitial fibroblasts in the early stage of the aortic transplant vasculopathy in rat. Transplantation 89(8):945–953

    Article  PubMed  Google Scholar 

  • Leung PS, Chan YC (2009) Role of oxidative stress in pancreatic inflammation. Antioxid Redox Signal 11(1):135–165

    Article  CAS  PubMed  Google Scholar 

  • Li L et al (2006) Increased migration of vascular adventitial fibroblasts from spontaneously hypertensive rats. Hypertens Res 29(2):95–103

    Article  CAS  PubMed  Google Scholar 

  • Liao S et al (2001) Suppression of experimental abdominal aortic aneurysms in the rat by treatment with angiotensin-converting enzyme inhibitors. J Vasc Surg 33(5):1057–1064

    Article  CAS  PubMed  Google Scholar 

  • Luchtefeld M et al (2005) Angiotensin II induces MMP-2 in a p47phox-dependent manner. Biochem Biophys Res Commun 328(1):183–188

    Article  CAS  PubMed  Google Scholar 

  • Milewicz DM et al (2008) Genetic basis of thoracic aortic aneurysms and dissections: focus on smooth muscle cell contractile dysfunction. Ann Rev Genomics Hum Genet 9:283–302

    Article  CAS  Google Scholar 

  • Nagashima H et al (2001) Angiotensin II type 2 receptor mediates vascular smooth muscle cell apoptosis in cystic medial degeneration associated with Marfan’s syndrome. Circulation 104(12 Suppl 1):I282–I287

    CAS  PubMed  Google Scholar 

  • Nishijo N et al (1998) Salt-sensitive aortic aneurysm and rupture in hypertensive transgenic mice that overproduce angiotensin II. Lab Invest 78(9):1059–1066

    CAS  PubMed  Google Scholar 

  • Pearson G et al (2001) Mitogen-activated protein (MAP) kinase pathways: regulation and physiological functions. Endocr Rev 22(2):153–183

    CAS  PubMed  Google Scholar 

  • Peng J et al (2002) Tumor necrosis factor-alpha-induced AT1 receptor upregulation enhances angiotensin II-mediated cardiac fibroblast responses that favor fibrosis. Circ Res 91(12):1119–1126

    Article  CAS  PubMed  Google Scholar 

  • Rayner K et al (2000) Localisation of mRNA for JE/MCP-1 and its receptor CCR2 in atherosclerotic lesions of the ApoE knockout mouse. J Vasc Res 37(2):93–102

    Article  CAS  PubMed  Google Scholar 

  • Sakalihasan N, Limet R, Defawe OD (2005) Abdominal aortic aneurysm. Lancet 365(9470):1577–1589

    Article  CAS  PubMed  Google Scholar 

  • Sakata N et al (2007) Possible involvement of myofibroblast in the development of inflammatory aortic aneurysm. Pathol Res Pract 203(1):21–29

    Article  PubMed  Google Scholar 

  • Scott NA et al (1996) Identification of a potential role for the adventitia in vascular lesion formation after balloon overstretch injury of porcine coronary arteries. Circulation 93(12):2178–2187

    Article  CAS  PubMed  Google Scholar 

  • Shen WL et al (2006) NAD(P)H oxidase-derived reactive oxygen species regulate angiotensin-II induced adventitial fibroblast phenotypic differentiation. Biochem Biophys Res Commun 339(1):337–343

    Article  CAS  PubMed  Google Scholar 

  • Shi Y et al (1996) Adventitial myofibroblasts contribute to neointimal formation in injured porcine coronary arteries. Circulation 94(7):1655–1664

    Article  CAS  PubMed  Google Scholar 

  • Shi-Wen X et al (2004) Endothelin-1 promotes myofibroblast induction through the ETA receptor via a rac/phosphoinositide 3-kinase/Akt-dependent pathway and is essential for the enhanced contractile phenotype of fibrotic fibroblasts. Mol Biol Cell 15(6):2707–2719

    Article  PubMed Central  PubMed  Google Scholar 

  • Tang MJ et al (1998) Collagen gel overlay induces apoptosis of polarized cells in cultures: disoriented cell death. Am J Physiol 275(4 Pt 1):C921–C931

    CAS  PubMed  Google Scholar 

  • Tieu BC et al (2009) An adventitial IL-6/MCP1 amplification loop accelerates macrophage-mediated vascular inflammation leading to aortic dissection in mice. J Clin Invest 119(12):3637–3651

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Touyz RM et al (1999) Role of extracellular signal-regulated kinases in angiotensin II-stimulated contraction of smooth muscle cells from human resistance arteries. Circulation 99(3):392–399

    Article  CAS  PubMed  Google Scholar 

  • Touyz RM et al (2004) Angiotensin II and endothelin-1 regulate MAP kinases through different redox-dependent mechanisms in human vascular smooth muscle cells. J Hypertens 22(6):1141–1149

    Article  CAS  PubMed  Google Scholar 

  • Tsunemi K et al (2002) Possible roles of angiotensin II-forming enzymes, angiotensin converting enzyme and chymase-like enzyme, in the human aneurysmal aorta. Hypertens Res 25(6):817–822

    Article  CAS  PubMed  Google Scholar 

  • Tsuruda T et al (2004) Adrenomedullin induces matrix metalloproteinase-2 activity in rat aortic adventitial fibroblasts. Biochem Biophys Res Commun 325(1):80–84

    Article  CAS  PubMed  Google Scholar 

  • Wang X et al (2006) Increased collagen deposition and elevated expression of connective tissue growth factor in human thoracic aortic dissection. Circulation 114(1 Suppl):I200–I205

    PubMed Central  PubMed  Google Scholar 

  • Wang HD et al (2010) Adventitial fibroblasts in vascular structure and function. Canad J Physiol Pharmacol 88(3):177–186

    Article  CAS  Google Scholar 

  • White M, Montezano AC, Touyz RM (2012) Angiotensin II signalling and calcineurin in cardiac fibroblasts: differential effects of calcineurin inhibitors FK506 and cyclosporine A. Ther Adv Cardiovasc Dis 6(1):5–14

    Article  CAS  PubMed  Google Scholar 

  • Wilcox JN et al (2001) Perivascular responses after angioplasty which may contribute to postangioplasty restenosis: a role for circulating myofibroblast precursors? Ann N Y Acad Sci 947:68–90; discussion 90-2

    Article  CAS  PubMed  Google Scholar 

  • Xu F et al (2007) Adventitial fibroblasts are activated in the early stages of atherosclerosis in the apolipoprotein E knockout mouse. Biochem Biophys Res Commun 352(3):681–688

    Article  CAS  PubMed  Google Scholar 

  • Yang W et al (2011) Angiotensin II downregulates catalase expression and activity in vascular adventitial fibroblasts through an AT1R/ERK1/2-dependent pathway. Mol Cell Biochem 358(1–2):21–29

    Article  CAS  PubMed  Google Scholar 

  • Zalewski A, Shi Y (1997) Vascular myofibroblasts. Lessons from coronary repair and remodeling. Arterioscler Thromb Vasc Biol 17(3):417–422

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by National Natural Science Foundation of China (grant number 30872537 to Zhiwei Wang) and Natural Science Foundation of Hubei Province of China (grant number 2008CHB421 and 2013CKB031 to Zhiwei Wang).

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Authors and Affiliations

  1. Department of Cardiothoracic Surgery, Renmin Hospital of Wuhan University, #99 Ziyang Road, Wuhan, 430060, Hubei, China

    Zhiwei Wang, Zongli Ren, Zhipeng Hu, Xiaoping Hu, Hao Zhang, Hongbing Wu & Min Zhang

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  1. Zhiwei Wang
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  2. Zongli Ren
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  3. Zhipeng Hu
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  4. Xiaoping Hu
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  5. Hao Zhang
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  6. Hongbing Wu
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  7. Min Zhang
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Correspondence to Zhiwei Wang.

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Zhiwei Wang and Zongli Ren contributed to the work equally and should be regarded as co-first authors.

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Wang, Z., Ren, Z., Hu, Z. et al. Angiotensin-II induces phosphorylation of ERK1/2 and promotes aortic adventitial fibroblasts differentiating into myofibroblasts during aortic dissection formation. J Mol Hist 45, 401–412 (2014). https://doi.org/10.1007/s10735-013-9558-8

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  • DOI: https://doi.org/10.1007/s10735-013-9558-8

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