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C1q/TNF-related protein 1 prevents neointimal formation after arterial injury

      Highlights

      • Overexpression of CTRP1 resulted in reduced neointimal thickening after vascular injury and decreased cell proliferation in injured arteries.
      • CTRP1 deficiency led to an increase in injury-induced neointimal hyperplasia and cell growth in injured vessels.
      • CTRP1 suppressed growth factor-induced VSMC growth.
      • The ability of CTRP1 to modulate vascular remodeling was likely to be mediated through its ability to stimulate the cAMP signaling pathway in VSMCs.
      • CTRP1 acts as an adipokine that plays an important role in protecting the vasculature from damage.

      Abstract

      Background and aims

      Obesity contributes to the progression of vascular disorders. C1q/TNF-related protein (CTRP) 1 is a circulating adipokine, which is upregulated in obese complications including coronary artery disease. Here, we investigated the role of CTRP1 in regulation of vascular remodeling after mechanical injury and evaluated its potential mechanism.

      Methods

      Mice were subjected to wire-induced injury of left femoral arteries. An adenoviral vector encoding CTRP1 (Ad-CTRP1) or β-galactosidase as a control was injected into the jugular vein of mice 3 days prior to surgery.

      Results

      Systemic administration of Ad-CTRP1 to wild-type mice led to reduction of the neointimal thickening after wire-induced arterial injury and the number of bromodeoxyuridine-positive cells in injured vessels as compared with treatment with control vectors. Treatment of vascular smooth muscle cells (VSMCs) with CTRP1 protein attenuated proliferative activity and ERK phosphorylation in response to PDGF-BB. CTRP1 treatment increased cyclic AMP (cAMP) levels in VSMCs, and inhibition of adenylyl cyclase reversed the inhibitory effect of CTRP1 on VSMC growth and ERK phosphorylation. Antagonization of sphingosine-1-phosphaterote (S1P) receptor 2 blocked the effects of CTRP1 on cAMP production and VSMC growth. Furthermore, CTRP1-knockout mice had enhanced neointimal thickening following injury and increased numbers of proliferating cells in neointima compared to control WT mice.

      Conclusions

      These findings indicate that CTRP1 functions to prevent the development of pathological vascular remodeling by reducing VSMC growth through the cAMP-dependent pathway.

      Keywords

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      References

        • Matsuzawa Y.
        Therapy Insight: adipocytokines in metabolic syndrome and related cardiovascular disease.
        Nat. Clin. Pract. Cardiovasc. Med. 2006; 3: 35-42
        • Despres J.P.
        • Lemieux I.
        Abdominal obesity and metabolic syndrome.
        Nature. 2006; 444: 881-887
        • Nielsen S.
        • Jensen M.D.
        Obesity and cardiovascular disease: is body structure a factor?.
        Curr. Opin. Lipidol. 1997; 8: 200-204
        • Calle E.E.
        • Thun M.J.
        • Petrelli J.M.
        • et al.
        Body-mass index and mortality in a prospective cohort of U.S. adults.
        N. Engl. J. Med. 1999; 341: 1097-1105
        • Nikolsky E.
        • Kosinski E.
        • Mishkel G.J.
        • et al.
        Impact of obesity on revascularization and restenosis rates after bare-metal and drug-eluting stent implantation (from the TAXUS-IV trial).
        Am. J. Cardiol. 2005; 95: 709-715
        • Fantuzzi G.
        • Mazzone T.
        Adipose tissue and atherosclerosis: exploring the connection.
        Arterioscler. Thromb. Vasc. Biol. 2007; 27: 996-1003
        • Rana J.S.
        • Mittleman M.A.
        • Ho K.K.
        • et al.
        Obesity and clinical restenosis after coronary stent placement.
        Am. Heart J. 2005; 150: 821-826
        • Gorski D.H.
        • Walsh K.
        The role of homeobox genes in vascular remodeling and angiogenesis.
        Circ. Res. 2000; 87: 865-872
        • Schoenhagen P.
        • Ziada K.M.
        • Vince D.G.
        • et al.
        Arterial remodeling and coronary artery disease: the concept of “dilated” versus “obstructive” coronary atherosclerosis.
        J. Am. Coll. Cardiol. 2001; 38: 297-306
        • Ouchi N.
        • Parker J.L.
        • Lugus J.J.
        • et al.
        Adipokines in inflammation and metabolic disease.
        Nat. Rev. Immunol. 2011; 11: 85-97
        • Ouchi N.
        • Walsh K.
        Cardiovascular and metabolic regulation by the adiponectin/C1q/tumor necrosis factor-related protein family of proteins.
        Circulation. 2012; 125: 3066-3068
        • Wong G.W.
        • Krawczyk S.A.
        • Kitidis-Mitrokostas C.
        • et al.
        Molecular, biochemical and functional characterizations of C1q/TNF family members: adipose-tissue-selective expression patterns, regulation by PPAR-gamma agonist, cysteine-mediated oligomerizations, combinatorial associations and metabolic functions.
        Biochem. J. 2008; 416: 161-177
        • Wong G.W.
        • Wang J.
        • Hug C.
        • et al.
        A family of Acrp30/adiponectin structural and functional paralogs.
        Proc. Natl. Acad. Sci. U. S. A. 2004; 101: 10302-10307
        • Chalupova L.
        • Zakovska A.
        • Adamcova K.
        Development of a novel enzyme-linked immunosorbent assay (ELISA) for measurement of serum CTRP1: a pilot study: measurement of serum CTRP1 in healthy donors and patients with metabolic syndrome.
        Clin. Biochem. 2013; 46: 73-78
        • Pan X.
        • Lu T.
        • Wu F.
        • et al.
        Circulating complement-C1q TNF-related protein 1 levels are increased in patients with type 2 diabetes and are associated with insulin sensitivity in Chinese subjects.
        PLoS One. 2014; 9: e94478
        • Xin Y.
        • Lyu X.
        • Wang C.
        • et al.
        Elevated circulating levels of CTRP1, a novel adipokine, in diabetic patients.
        Endocr. J. 2014; 61: 841-847
        • Yuasa D.
        • Ohashi K.
        • Shibata R.
        • et al.
        Association of circulating C1q/TNF-related protein 1 levels with coronary artery disease in men.
        PLoS One. 2014; 9: e99846
        • Tang J.N.
        • Shen D.L.
        • Liu C.L.
        • et al.
        Plasma levels of C1q/TNF-related protein 1 and interleukin 6 in patients with acute coronary syndrome or stable angina pectoris.
        Am. J. Med. Sci. 2015; 349: 130-136
        • Peterson J.M.
        • Aja S.
        • Wei Z.
        • et al.
        CTRP1 protein enhances fatty acid oxidation via AMP-activated protein kinase (AMPK) activation and acetyl-CoA carboxylase (ACC) inhibition.
        J. Biol. Chem. 2012; 287: 1576-1587
        • Lasser G.
        • Guchhait P.
        • Ellsworth J.L.
        • et al.
        C1qTNF-related protein-1 (CTRP-1): a vascular wall protein that inhibits collagen-induced platelet aggregation by blocking VWF binding to collagen.
        Blood. 2006; 107: 423-430
        • Yuasa D.
        • Ohashi K.
        • Shibata R.
        • et al.
        C1q/TNF-related protein-1 functions to protect against acute ischemic injury in the heart.
        FASEB J. 2016; 30: 1065-1075
        • Lu L.
        • Zhang R.Y.
        • Wang X.Q.
        • et al.
        C1q/TNF-related protein-1: an adipokine marking and promoting atherosclerosis.
        Eur. Heart J. 2016 Jun 7; 37: 1762-1771
        • Uemura Y.
        • Shibata R.
        • Ohashi K.
        • et al.
        Adipose-derived factor CTRP9 attenuates vascular smooth muscle cell proliferation and neointimal formation.
        FASEB J. 2013; 27: 25-33
        • Sata M.
        • Maejima Y.
        • Adachi F.
        • et al.
        A mouse model of vascular injury that induces rapid onset of medial cell apoptosis followed by reproducible neointimal hyperplasia.
        J. Mol. Cell. Cardiol. 2000; 32: 2097-2104
        • Uemura Y.
        • Shibata R.
        • Kanemura N.
        • et al.
        Adipose-derived protein omentin prevents neointimal formation after arterial injury.
        FASEB J. 2015; 29: 141-151
        • Smith R.C.
        • Branellec D.
        • Gorski D.H.
        • et al.
        p21CIP1-mediated inhibition of cell proliferation by overexpression of the gax homeodomain gene.
        Genes Dev. 1997; 11: 1674-1689
        • Matter C.M.
        • Chadjichristos C.E.
        • Meier P.
        • et al.
        Role of endogenous Fas (CD95/Apo-1) ligand in balloon-induced apoptosis, inflammation, and neointima formation.
        Circulation. 2006; 113: 1879-1887
        • Kataoka Y.
        • Shibata R.
        • Ohashi K.
        • et al.
        Omentin prevents myocardial ischemic injury through AMPK- and Akt-dependent mechanisms.
        J. Am. Coll. Cardiol. 2014; 63 (2722–2233)
        • Miyabe M.
        • Ohashi K.
        • Shibata R.
        • et al.
        Muscle-derived follistatin-like 1 functions to reduce neointimal formation after vascular injury.
        Cardiovasc. Res. 2014 Jul 1; 103: 111-120
        • Indolfi C.
        • Avvedimento E.V.
        • Di Lorenzo E.
        • et al.
        Activation of cAMP-PKA signaling in vivo inhibits smooth muscle cell proliferation induced by vascular injury.
        Nat. Med. 1997; 3: 775-779
        • Wu Y.J.
        • Bond M.
        • Sala-Newby G.B.
        • et al.
        Altered S-phase kinase-associated protein-2 levels are a major mediator of cyclic nucleotide-induced inhibition of vascular smooth muscle cell proliferation.
        Circ. Res. 2006; 98: 1141-1150
        • Wamhoff B.R.
        • Lynch K.R.
        • Macdonald T.L.
        • et al.
        Sphingosine-1-phosphate receptor subtypes differentially regulate smooth muscle cell phenotype.
        Arterioscler. Thromb. Vasc. Biol. 2008; 28: 1454-1461
        • Grabski A.D.
        • Shimizu T.
        • Deou J.
        • et al.
        Sphingosine-1-phosphate receptor-2 regulates expression of smooth muscle alpha-actin after arterial injury.
        Arterioscler. Thromb. Vasc. Biol. 2009; 29: 1644-1650
        • Gennaro G.
        • Menard C.
        • Michaud S.E.
        • et al.
        Inhibition of vascular smooth muscle cell proliferation and neointimal formation in injured arteries by a novel, oral mitogen-activated protein kinase/extracellular signal-regulated kinase inhibitor.
        Circulation. 2004; 110: 3367-3371
        • Kubota N.
        • Terauchi Y.
        • Yamauchi T.
        • et al.
        Disruption of adiponectin causes insulin resistance and neointimal formation.
        J. Biol. Chem. 2002; 277: 25863-25866
        • Matsuda M.
        • Shimomura I.
        • Sata M.
        • et al.
        Role of adiponectin in preventing vascular stenosis. The missing link of adipo-vascular axis.
        J. Biol. Chem. 2002; 277: 37487-37491
        • Arita Y.
        • Kihara S.
        • Ouchi N.
        • et al.
        Adipocyte-derived plasma protein adiponectin acts as a platelet-derived growth factor-BB-binding protein and regulates growth factor-induced common postreceptor signal in vascular smooth muscle cell.
        Circulation. 2002; 105: 2893-2898
        • Wang Y.
        • Lam K.S.
        • Xu J.Y.
        • et al.
        Adiponectin inhibits cell proliferation by interacting with several growth factors in an oligomerization-dependent manner.
        J. Biol. Chem. 2005; 280: 18341-18347
        • Damirin A.
        • Tomura H.
        • Komachi M.
        • et al.
        Sphingosine 1-phosphate receptors mediate the lipid-induced cAMP accumulation through cyclooxygenase-2/prostaglandin I2 pathway in human coronary artery smooth muscle cells.
        Mol. Pharmacol. 2005; 67: 1177-1185
        • Wang X.Q.
        • Liu Z.H.
        • Xue L.
        • et al.
        C1q/TNF-related protein 1 links macrophage lipid metabolism to inflammation and atherosclerosis.
        Atherosclerosis. 2016; 250: 38-45