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      Cross-talk between angiotensin II and IGF-1-induced connexin 43 expression in human saphenous vein smooth muscle cells

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          Abstract

          Vascular restenosis following coronary artery bypass graft can cause major clinical complications due to intimal hyperplasia in venous conduits. However, the precise underlying mechanisms of intimal hyperplasia are still unclear. We have recently reported that increased expression of connexin43 (Cx43) is involved in the proliferation of vascular smooth muscle cells (SMCs) in human saphenous vein (SV). In this study, we investigated the signalling transduction pathway involved in Cx43 expression and SV SMC proliferation. Angiotensin-II (AT-II, 100 ng/ml) increased AT-II receptor 1 (AT-1R) protein expression and insulin-like growth factor-1 (IGF-1) (100 ng/ml) up-regulated IGF-1 receptor (IGF-1R) protein expression in SV SMCs. Interestingly, AT-1R expression was also increased by IGF-1 treatment, and IGF-1R expression was increased by AT-II treatment, which was blocked by siRNA-IGF-1R and siRNA-AT-1R, respectively. Furthermore, the effect of AT-II and IGF-1 signal cross-talk i nducing up-regulation of their reciprocal receptors was blocked by siRNA against extracellular signal-regulated kinases 1/2 (Erk 1/2) in SMCs of SV. Moreover, AT-II and IGF-1-induced Cx43 expression via phosphorylation of Erk 1/2 and activation of transcription factor activator protein 1 (AP-1) through their reciprocal receptors in SV SMCs. These data demonstrate a cross-talk between IGF-1R and AT-1R in AT-II and IGF-1-induced Cx43 expression in SV SMCs involving Erk 1/2 and downstream activation of the AP-1 transcription factor.

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          Most cited references34

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          The gap junction communication channel.

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            IGF-1 reduces inflammatory responses, suppresses oxidative stress, and decreases atherosclerosis progression in ApoE-deficient mice.

            Whereas growth factors, via their ability to stimulate vascular smooth muscle cell (VSMC) proliferation and migration, have been thought to play a permissive role in atherosclerosis initiation and progression, the role of insulin-like growth factor-1 (IGF-1) is unknown. Here we report for the first time that IGF-1 infusion decreased atherosclerotic plaque progression in ApoE-deficient mice on a Western diet. ApoE-null mice (8 weeks) were infused with vehicle or recombinant human IGF-1 and fed a high-fat diet for 12 weeks. Analysis of aortic sinuses revealed that IGF-1 infusion decreased atherosclerotic plaque progression and macrophage infiltration into lesions. Furthermore, IGF-1 decreased vascular expression of the proinflammatory cytokines interleukin-6 and tumor necrosis factor-alpha, reduced aortic superoxide formation and urinary 8-isoprostane levels, and increased aortic pAkt and eNOS expression and circulating endothelial progenitor cells, consistent with an antiinflammatory, antioxidant, and prorepair effect on the vasculature. Our data indicate that an increase in circulating IGF-1 reduces vascular inflammatory responses, systemic and vascular oxidant stress and decreases atherosclerotic plaque progression. These findings have major implications for the treatment of atherosclerosis.
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              Angiotensin II induces smooth muscle cell proliferation in the normal and injured rat arterial wall.

              The present study was undertaken to explore the possibility that neointimal smooth muscle cells, the characteristic cells of restenosis and atherosclerosis, are selectively stimulated to replicate by a hypertensive stimulus. Angiotensin II (AII) was infused by osmotic minipumps for 2 weeks in 4.5-month-old rats. Group A received AII (200 ng/min) 2 weeks after a balloon catheter-induced injury of the thoracic aorta and left common carotid artery. Group B received only AII, group C only balloon denudation, and group D neither balloon injury nor AII. During the AII or Ringer's solution infusion, all animals received [3H]thymidine via a second minipump to measure DNA synthesis. AII increased the systolic pressure by more than 40 mm Hg. AII significantly increased DNA synthesis in the media of the carotid artery from 0.2 +/- 0.2% in group C to 2.5 +/- 1.5% in group A (mean +/- SD, n = 5 or 6). DNA synthesis in the neointima of the carotid artery significantly increased with AII from 4.8 +/- 4.2% in group C to 19.8 +/- 13.9% in group A. Cross-sectional area of the neointima almost doubled during AII infusion, and it increased approximately 25% in the media. Comparable results were obtained in the aorta. In a second experiment, AII was infused (125 ng/min) for 2 weeks in 11-week-old rats. Concomitantly, [3H]thymidine was given. Control rats received Ringer's solution and [3H]thymidine in their pumps. Blood pressures were elevated to the same extent as in the older animals.(ABSTRACT TRUNCATED AT 250 WORDS)
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                Author and article information

                Journal
                J Cell Mol Med
                J. Cell. Mol. Med
                jcmm
                Journal of Cellular and Molecular Medicine
                Blackwell Publishing Ltd (Oxford, UK )
                1582-1838
                1582-4934
                August 2011
                13 July 2011
                : 15
                : 8
                : 1695-1702
                Affiliations
                [a ]Center for Clinical and Translational Science, Creighton University School of Medicine Omaha, NE, USA
                [b ]Nebraska Heart Hospital Lincoln, NE, USA
                Author notes
                Devendra K. AGRAWAL, Ph.D., MBA, FAHA, Director, Center for Clinical and Translational Science, CRISS II Room 510, Creighton University School of Medicine, 2500 California Plaza, Omaha, NE 68178, USA. Tel.: (402)280-2938 Fax: (402)280-1421 E-mail: dkagr@ 123456creighton.edu

                These authors contributed equally to this study.

                Article
                10.1111/j.1582-4934.2010.01161.x
                3000445
                20731749
                fa0d356b-461f-479f-abfb-437ac5d866c0
                © 2011 The Authors Journal compilation © 2011 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd
                History
                : 02 April 2010
                : 20 July 2010
                Categories
                Articles

                Molecular medicine
                angiotensin ii,connexins,intimal hyperplasia,restenosis,vascular smooth muscle cells,vein graft disease

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