Involvement of transient receptor potential canonical 1 (TRPC1) in angiotensin II-induced vascular smooth muscle cell hypertrophy


      Angiotensin II (Ang II) induces vascular smooth muscle cell (VSMC) hypertrophy as one of the major events leading to atherosclerosis. Increased Ca2+ entry is an important stimulus for VSMC hypertrophy, but the association with Ang II remains to be determined. Transient receptor potential canonical 1 (TRPC1) forms store-operated Ca2+ (SOC) channels that are involved in Ca2+ homeostasis. Our aim was to ascertain the potential involvement of TRPC1 in Ang II-induced VSMC hypertrophy. For this purpose, we used cultured human coronary artery smooth muscle cells (hCASMCs). Store-operated Ca2+ entry (SOCE) increased in the Ang II-induced hypertrophied cells, and SOC channel blocker inhibited the Ang II-induced hypertrophic response. Although hCASMCs constitutively expressed TRPC1, C3, C4, C5, and C6, only TRPC1 increased in response to Ang II stimulation. TRPC1 siRNA decreased SOCE and prevented Ang II-induced hypertrophy. We found NF-κB binding sites in the 5′-regulatory region of the human TRPC1 gene. An electrophoretic mobility shift assay showed that Ang II increased the TRPC1 promoter's NF-κB binding activity. Co-treatment with NF-κB decoy oligonucleotides not only reduced TRPC1 expression, but also inhibited the hypertrophic responses. In conclusion, our data suggest that Ang II and subsequent NF-κB activation induces hCASMC hypertrophy through an enhancement of TRPC1 expression.


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        • Touyz R.
        • Schiffrin E.L.
        Signal transduction mechanisms mediating the physiological and pathophysiological actions of angiotensin II in vascular smooth muscle cells.
        Pharmacol Rev. 2000; 52: 639-672
        • Owens G.K.
        • Schwartz S.M.
        Alterations in vascular smooth muscle mass in the spontaneously hypertensive rat. Role of cellular hypertrophy, hyperploidy, and hyperplasia.
        Circ Res. 1982; 51: 280-289
        • Touyz R.M.
        Reactive oxygen species as mediators of calcium signaling by angiotensin II: implications in vascular physiology and pathophysiology.
        Antioxid Redox Signal. 2005; 7: 1302-1314
        • Eguchi S.
        • Numaguchi K.
        • Iwasaki H.
        • et al.
        Calcium-dependent epidermal growth factor receptor transactivation mediates the angiotensin II-induced mitogen-activated protein kinase activation in vascular smooth muscle cells.
        J Biol Chem. 1998; 273: 8890-8896
        • Schmitz U.
        • Ishida T.
        • Ishida M.
        • et al.
        Angiotensin II stimulates p21-activated kinase in vascular smooth muscle cells: role in activation of JNK.
        Circ Res. 1998; 82: 1272-1278
        • Lipskaia L.
        • Lompre A.M.
        Alteration in temporal kinetics of Ca2+ signaling and control of growth and proliferation.
        Biol Cell. 2004; 96: 55-68
        • Gallois A.
        • Bueb J.L.
        • Tschirhart E.
        Effect of SK&F 96365 on extracellular Ca2+-dependent O2 production in neutrophil-like HL-60 cells.
        Eur J Pharmacol. 1998; 361: 293-298
        • Shimoda L.A.
        • Sham J.S.
        • Shimoda T.H.
        • Sylvester J.T.
        L-type Ca2+ channels, resting [Ca2+]i, and ET-1-induced responses in chronically hypoxic pulmonary myocytes.
        Am J Physiol Lung Cell Mol Physiol. 2000; 279: L884-L894
        • Golovina V.A.
        • Platoshyn O.
        • Bailey C.L.
        • et al.
        Upregulated TRP and enhanced capacitative Ca2+ entry in human pulmonary artery myocytes during proliferation.
        Am J Physiol Heart Circ Physiol. 2001; 280: H746-H755
        • Abritton N.L.
        • Oancea E.
        • Kuhn M.A.
        • Meyer T.
        Source of nuclear calcium signals.
        Proc Natl Acad Sci USA. 1995; 91: 12458-12462
        • Albert A.P.
        • Large W.A.
        Store-operated Ca2+-permeable non-selective cation channels in smooth muscle cells.
        Cell Calcium. 2003; 33: 345-356
        • Mori Y.
        • Wakamori M.
        • Miyakawa T.
        • et al.
        Transient receptor potential 1 regulates capacitative Ca2+ entry and Ca2+ release from endoplasmic reticulum in B lymphocytes.
        J Exp Med. 2002; 195: 673-681
        • Parekh A.B.
        • Putney Jr., J.W.
        Store-operated calcium channels.
        Physiol Rev. 2005; 85: 757-810
        • Chen J.
        • Barritt G.J.
        Evidence that TRPC1 (transient receptor potential canonical 1) forms a Ca2+-permeable channel linked to the regulation of cell volume in liver cells obtained using small interfering RNA targeted against TRPC1.
        Biochem J. 2003; 15: 327-336
        • Watanabe H.
        • Vriens J.
        • Prenen J.
        • et al.
        Anandamide and arachidonic acid use epoxyeicosatrienoic acids to activate TRPV4 channels.
        Nature. 2003; 424: 434-438
        • Murakami M.
        • Ohba T.
        • Xu F.
        • et al.
        Genomic organization and functional analysis of murine PKD2L1.
        J Biol Chem. 2005; 280: 5626-5635
        • Xu S.Z.
        • Beech D.J.
        TrpC1 is a membrane-spanning subunit of store-operated Ca2+ channels in native vascular smooth muscle cells.
        Circ Res. 2001; 88: 84-87
        • Moissac M.
        • Mustapha S.
        • Greenberg A.H.
        • Kirshenbaum L.
        Bcl-2 activates the transcription factor NF-κB through the degradation of the cytoplasmic inhibitor IκB.
        J Biol Chem. 1998; 273: 23946-23951
        • Morishita R.
        • Sugimoto T.
        • Aoki M.
        • et al.
        In vivo transfection of cis element “decoy” against nuclear factor-κB binding site prevents myocardial infarction.
        Nature Med. 1997; 3: 894-899
        • He L.P.
        • Hewavitharana T.
        • Soboloff J.
        • Spassova M.A.
        • Gill D.L.
        A functional link between store-operated and TRPC channels revealed by the 3,5-bis(trifluoromethyl)pyrazole derivative, BTP2.
        J Biol Chem. 2005; 280: 10997-11006
        • Bootman M.D.
        • Collins T.J.
        • Mackenzie L.
        • et al.
        2-aminoethoxydiphenyl borate (2-APB) is a reliable blocker of store-operated Ca2+ entry but an inconsistent inhibitor of InsP3-induced Ca2+ release.
        FASEB J. 2002; 10: 1145-1150
        • Wang J.
        • Shimoda L.A.
        • Sylvester J.T.
        Capacitative calcium entry and TRPC channel proteins are expressed in rat distal pulmonary arterial smooth muscle.
        Am J Physiol Lung Cell Mol Physiol. 2004; 286: 848-858
        • Paria B.C.
        • Malik A.B.
        • Kwiatek A.M.
        • et al.
        Tumor necrosis factor-alpha induces nuclear factor-κB dependent TRPC1 expression in endothelial cells.
        J Biol Chem. 2003; 278: 37195-37203
        • Zahradka P.
        • Werner J.P.
        • Buhay S.
        • et al.
        NF-kappaB activation is essential for angiotensin II-dependent proliferation and migration of vascular smooth muscle cells.
        J Mol Cell Cardiol. 2002; 34: 1609-1621
        • Woolfolk E.A.
        • Eguchi S.
        • Ohtsu H.
        • et al.
        Angiotensin II-induced activation of p21-activated kinase 1 requires Ca2+ and protein kinase C{delta} in vascular smooth muscle cells.
        Am J Physiol Cell Physiol. 2005; 289: C1286-C1294
        • Frank G.D.
        • Saito S.
        • Motley E.D.
        • et al.
        Requirement of Ca2+ and PKCdelta for Janus kinase 2 activation by angiotensin II: involvement of PYK2.
        Mol Endocrinol. 2002; 16: 367-377
        • Zhang S.
        • Yuan J.X.
        • Barrett K.E.
        • Dong H.
        Role of Na+/Ca2+ exchange in regulating cytosolic Ca2+ in cultured human pulmonary artery smooth muscle cells.
        Am J Physiol Cell Physiol. 2005; 288: C245-C252
        • Funakoshi Y.
        • Ichiki T.
        • Takeda K.
        • et al.
        Critical role of cAMP-response element-binding protein for Angiotensin II-induced hypertrophy of vascular smooth muscle cells.
        J Biol Chem. 2002; 277: 18710-18717
        • Pulver R.A.
        • Rose-Curtis P.
        • Roe M.W.
        • Wellman G.C.
        • Lounsbury K.M.
        Store-operated Ca2+ entry activates the CREB transcription factor in vascular smooth muscle.
        Circ Res. 2004; 94: 1351-1358
        • Pulver-Kaste R.A.
        • Barlow C.A.
        • Bond J.
        • et al.
        Ca2+ source-dependent transcription of CRE-containing genes in VSMC.
        Am J Heart Circ Physiol. 2006; 291: 97-105
        • Zagranichnaya T.K.
        • Wu X.
        • Villereal M.L.
        Endogenous TRPC1, TRPC3, and TRPC7 proteins combine to form native store-operated channels in HEK-293 cells.
        J Biol Chem. 2005; 280: 29559-29569
        • Beech D.J.
        • Muraki K.
        • Flemming R.
        Non-selective cationic channels of smooth muscle and the mammalian homologues of Drosophila TRP.
        J Physiol. 2004; 559: 685-706
        • Bergdahl A.
        • Gomez M.F.
        • Wihlborg A.K.
        • et al.
        Plasticity of TRPC expression in arterial smooth muscle: correlation with store-operated Ca2+ entry.
        Am J Physiol Cell Physiol. 2005; 288: C872-C880
        • Kumar B.
        • Dreja K.
        • Shah S.
        • et al.
        Upregulated TRPC1 channel in vascular injury in vivo and its role in human neointimal hyperplasia.
        Circ Res. 2006; 98: 557-563
        • Mehrhof F.B.
        • Schmidt-Ullrich R.
        • Dietz R.
        • Scheidereit C.
        Regulation of vascular smooth muscle cell proliferation: role of NF-κB revisited.
        Circ Res. 2005; 96: 958-964
        • Wolfgang D.
        • Eva-Maria S.
        • Klaudia M.
        • et al.
        Countervailing effects of rapamycin (sirolimus) on nuclear factor-κB activities in neointimal and medial smooth muscle cells.
        Atherosclerosis. 2006; 186: 321-330
        • Sasu S.
        • Beasley D.
        Essential roles of IκB kinases and ß in serum- and IL-1-induced human VSMC proliferation.
        Am J Phys. 2000; 278: 1823-1831
        • Hoshi S.
        • Goto M.
        • Koyama N.
        • Nomoto K.
        • Tanaka H.
        Regulation of vascular smooth muscle cell proliferation by nuclear factor-kappaB and its inhibitor, I-kappaB.
        J Biol Chem. 2000; 275: 883-889