Advertisement
Canadian Journal of Cardiology

NF-κB-Dependent Upregulation of NCX1 Induced by Angiotensin II Contributes to Calcium Influx in Rat Aortic Smooth Muscle Cells

Published:February 26, 2016DOI:https://doi.org/10.1016/j.cjca.2016.02.060

      Abstract

      Background

      The reverse mode of Na+/Ca2+ exchanger (NCX) 1 can transport Ca2+ into cells and is involved in the contractile regulation of vascular smooth muscle cells (VSMCs) and the development of hypertension. We hypothesized that upregulation of NCX1 expression induced by angiotensin II (Ang II) could be dependent on activation of nuclear factor–kappa B (NF-κB) and contributes to Ca2+ influx in VSMCs.

      Methods

      An osmotic minipump was implanted for administration of Ang II in Sprague-Dawley rats, and blood pressure, as well as NCX1 expression, in the aorta was measured. VSMCs were cultured to verify that Ang II–upregulated NCX1 expression is dependent on activation of NF-κB and contributes to Ca2+ influx.

      Results

      Ang II–upregulated NCX1 expression in rat aortas (2.1-fold at day 6) and VSMCs (1.7-fold at 24 hours) and NF-κB knockdown and p38 mitogen-activated protein kinase (MAPK) inhibitor resulted in 2.1- and 2.0-fold decreases in Ang II–upregulated NCX1 expression in VSMCs. KB-R7943 (an inhibitor of NCX1 reversal) and NCX1 knockdown decreased Ang II–induced Ca2+ influx 1.4- and 1.3- fold, respectively. KB-R7943 and removal of extracellular Na+ decreased Ang II–initiated store depletion–mediated Ca2+ entry by 1.5- and 1.3-fold, respectively. Moreover, NF-κB knockdown and use of a p38 MAPK inhibitor resulted in about 1.3-fold decreases in Ang II–induced Ca2+ influx through activation of reverse-mode NCX1.

      Conclusions

      Ang II upregulates NCX1 expression through p38 MAPK and NF-κB pathways, and reverse-mode NCX1 plays an important part in Ang II-induced Ca2+ influx in VSMCs, which may be associated with Ang II–initiated store-operated channel entry.

      Résumé

      Introduction

      Le fonctionnement de la protéine échangeuse d’ions Na+-Ca2+ 1 (NCX1) en mode inverse permet l’entrée d’ions Ca2+ dans les cellules, ce qui a une incidence sur la régulation de la contractilité des cellules musculaires lisses vasculaires (CMLV) et l’apparition de l’hypertension. Nous sommes partis de l’hypothèse voulant que la régulation positive de l’expression de la NCX1 induite par l’angiotensine II pouvait dépendre de l’activation du facteur nucléaire kappa B (NF-κB) et contribuer à l’influx d’ions Ca2+ dans les CLMV.

      Méthodes

      À la suite de l’implantation d’une mini pompe osmotique permettant l’administration d’angiotensine II à des rats Sprague-Dawley, on a mesuré la pression artérielle et l’expression de la NCX1 dans l’aorte de ces animaux. Les CMLV ont ensuite été mises en culture pour vérifier si la régulation positive de l’expression de la NCX1 induite par l’angiotensine II était liée à l’activation du NF-κB et contribuait à l’influx d’ions Ca2+.

      Résultats

      L’administration d’un inhibiteur de la protéine kinase activée par le mitogène (MAPK) p38, l’inactivation du NF-κB et la régulation positive de l’expression de la NCX1 induite par l’angiotensine II dans l’aorte des rats (2,1 fois au jour 6) et les CMLV (1,7 fois après 24 heures) ont entraîné une diminution de la régulation positive de la NCX1 induite par l’angiotensine II et de son expression dans les CMLV de l’ordre de 2,1 et de 2,0 fois, respectivement. Le KB-R7943 (un inhibiteur du fonctionnement en mode inverse de la NCX1) et l’inactivation de l’expression de la NCX1 ont permis de réduire l’influx d’ions Ca2+ induit par l’angiotensine II de l’ordre de 1,4 et de 1,3 fois, respectivement. Le KB-R7943 et la suppression des ions Na+ du milieu extracellulaire ont pour leur part diminué l’influx d’ions Ca2+ produit par la déplétion des stocks intracellulaires induite par l’angiotensine II de l’ordre de 1,5 et de 1,3 fois, respectivement. De plus, l’inactivation du NF-κB et l’administration de l’inhibiteur de la MAPK p38 ont réduit d’environ 1,3 fois de l’influx d’ions Ca2+ induit par l’angiotensine II en permettant le fonctionnement en mode inverse de la NCX1.

      Conclusions

      L’angiotensine II entraîne une régulation positive de l’expression de la NCX1 par les voies MAPK p38 et NF-κB, et le fonctionnement en mode inverse de la NCX1 a une incidence importante sur l’influx d’ions Ca2+ induit par l’angiotensine II dans les CMLV, phénomène qui pourrait être associé à l’ouverture des canaux activée par la variation des stocks intracellulaires induite par l’angiotensine II.
      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Canadian Journal of Cardiology
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Prasad A.M.
        • Nuno D.W.
        • Koval O.M.
        • et al.
        Differential control of calcium homeostasis and vascular reactivity by Ca2+/calmodulin-dependent kinase II.
        Hypertension. 2013; 62: 434-441
        • Guo R.W.
        • Wang H.
        • Gao P.
        • et al.
        An essential role for stromal interaction molecule 1 in neointima formation following arterial injury.
        Cardiovasc Res. 2009; 81: 660-668
        • Ander B.P.
        • Hurtado C.
        • Raposo C.S.
        • et al.
        Differential sensitivities of the NCX1.1 and NCX1.3 isoforms of the Na+-Ca2+ exchanger to alpha-linolenic acid.
        Cardiovasc Res. 2007; 73: 395-403
        • Hnatowich M.
        • Le H.D.
        • DeMoissac D.
        • et al.
        μ-Calpain-mediated deregulation of cardiac, brain, and kidney NCX1 splice variants.
        Cell Calcium. 2012; 51: 164-170
        • Lytton J.
        Na+/Ca2+ exchangers: three mammalian gene families control Ca2+ transport.
        Biochem J. 2007; 406: 365-382
        • Zhang J.
        New insights into the contribution of arterial NCX to the regulation of myogenic tone and blood pressure.
        Adv Exp Med Biol. 2013; 961: 329-343
        • Iwamoto T.
        • Kita S.
        Topics on the Na+/Ca2+ exchanger: role of vascular NCX1 in salt-dependent hypertension.
        J Pharmacol Sci. 2006; 102: 32-36
        • Iwamoto T.
        • Kita S.
        • Zhang J.
        • et al.
        Salt-sensitive hypertension is triggered by Ca2+ entry via Na+/Ca2+ exchanger type-1 in vascular smooth muscle.
        Nat Med. 2004; 10: 1193-1199
        • Guo R.W.
        • Yang L.X.
        • Li M.Q.
        • et al.
        Stim1- and Orai1-mediated store-operated calcium entry is critical for angiotensin II-induced vascular smooth muscle cell proliferation.
        Cardiovasc Res. 2012; 93: 360-370
        • Zhao D.
        • Zhang J.
        • Blaustein M.P.
        • Navar L.G.
        Attenuated renal vascular responses to acute angiotensin II infusion in smooth muscle-specific Na+/Ca2+ exchanger knockout mice.
        Am J Physiol Renal Physiol. 2011; 301: F574-F579
        • Taniguchi S.
        • Furukawa K.
        • Sasamura S.
        • et al.
        Gene expression and functional activity of sodium/calcium exchanger enhanced in vascular smooth muscle cells of spontaneously hypertensive rats.
        J Cardiovasc Pharmacol. 2004; 43: 629-637
        • Aiello E.A.
        • De Giusti V.C.
        Regulation of the cardiac sodium/bicarbonate cotransporter by angiotensin II: potential contribution to structural, ionic and electrophysiological myocardial remodelling.
        Curr Cardiol Rev. 2013; 9: 24-32
        • Sirabella R.
        • Secondo A.
        • Pannaccione A.
        • et al.
        Anoxia-induced NF-kappaB-dependent upregulation of NCX1 contributes to Ca2+ refilling into endoplasmic reticulum in cortical neurons.
        Stroke. 2009; 40: 922-929
        • Thomas C.M.
        • Yong Q.C.
        • Rosa R.M.
        • et al.
        Cardiac-specific suppression of NF-κB signaling prevents diabetic cardiomyopathy via inhibition of the renin-angiotensin system.
        Am J Physiol Heart Circ Physiol. 2014; 307: H1036-H1045
        • Guo R.W.
        • Yang L.X.
        • Wang H.
        • Liu B.
        • Wang L.
        Angiotensin II induces matrix metalloproteinase-9 expression via a nuclear factor-kappaB-dependent pathway in vascular smooth muscle cells.
        Regul Pept. 2008; 147: 37-44
        • Tsai S.H.
        • Huang P.H.
        • Peng Y.J.
        • et al.
        Zoledronate attenuates angiotensin II-induced abdominal aortic aneurysm through inactivation of Rho/ROCK-dependent JNK and NF-κB pathway.
        Cardiovasc Res. 2013; 100: 501-510
        • Neves M.F.
        • Amiri F.
        • Virdis A.
        • Diep Q.N.
        • Schiffrin E.L.
        CIHR Multidisciplinary Research Group on Hypertension. Role of aldosterone in angiotensin II-induced cardiac and aortic inflammation, fibrosis, and hypertrophy.
        Can J Physiol Pharmacol. 2005; 83: 999-1006
        • Blaustein M.P.
        • Zhang J.
        • Chen L.
        • et al.
        The pump, the exchanger, and endogenous ouabain: signaling mechanisms that link salt retention to hypertension.
        Hypertension. 2009; 53: 291-298
        • Gabor A.
        • Leenen F.H.
        Central mineralocorticoid receptors and the role of angiotensin ii and glutamate in the paraventricular nucleus of rats with angiotensin II-induced hypertension.
        Hypertension. 2013; 61: 1083-1090
        • Chen A.
        • Huang B.S.
        • Wang H.W.
        • et al.
        Knockdown of mineralocorticoid or angiotensin II type 1 receptor gene expression in the paraventricular nucleus prevents angiotensin II hypertension in rats.
        J Physiol. 2014; 592: 3523-3536
        • Hamlyn J.M.
        • Linde C.I.
        • Gao J.
        • et al.
        Neuroendocrine humoral and vascular components in the pressor pathway for brain angiotensin II: a new axis in long term blood pressure control.
        PLoS One. 2014; 9: e108916
        • Rincón J.
        • Correia D.
        • Arcaya J.L.
        • et al.
        Role of angiotensin II type 1 receptor on renal NAD(P)H oxidase, oxidative stress and inflammation in nitric oxide inhibition induced-hypertension.
        Life Sci. 2015; 124: 81-90
        • Hou X.L.
        • Tong Q.
        • Wang W.Q.
        • et al.
        Suppression of inflammatory responses by dihydromyricetin, a flavonoid from ampelopsis grossedentata, via inhibiting the activation of NF-κB and MAPK signaling pathways.
        J Nat Prod. 2015; 78: 1689-1696
        • Sirabella R.
        • Secondo A.
        • Pannaccione A.
        • et al.
        ERK1/2, p38, and JNK regulate the expression and the activity of the three isoforms of the Na+/Ca2+ exchanger, NCX1, NCX2, and NCX3, in neuronal PC12 cells.
        J Neurochem. 2012; 122: 911-922
        • Shaikh S.
        • Samanta K.
        • Kar P.
        • et al.
        m-Calpain-mediated cleavage of Na+/Ca2+ exchanger-1 in caveolae vesicles isolated from pulmonary artery smooth muscle.
        Mol Cell Biochem. 2010; 341: 167-180
        • Chen L.
        • Song H.
        • Wang Y.
        • et al.
        Arterial α2 Na+ pump expression influences blood pressure: lessons from novel, genetically-engineered smooth muscle-specific α2 mice.
        Am J Physiol Heart Circ Physiol. 2015; 309: H958-H968
        • Ikeda K.
        • Nakajima T.
        • Yamamoto Y.
        • et al.
        Roles of transient receptor potential canonical (TRPC) channels and reverse-mode Na+/Ca2+ exchanger on cell proliferation in human cardiac fibroblasts: effects of transforming growth factor β1.
        Cell Calcium. 2013; 54: 213-225
        • Pulina M.V.
        • Zulian A.
        • Baryshnikov S.G.
        • et al.
        Cross talk between plasma membrane Na(+)/Ca(2+) exchanger-1 and TRPC/Orai-containing channels: key players in arterial hypertension.
        Adv Exp Med Biol. 2013; 961: 365-374
        • Zulian A.
        • Baryshnikov S.G.
        • Linde C.I.
        • et al.
        Upregulation of Na+/Ca2+ exchanger and TRPC6 contributes to abnormal Ca2+ homeostasis in arterial smooth muscle cells from Milan hypertensive rats.
        Am J Physiol Heart Circ Physiol. 2010; 299: H624-H633
        • Fellner S.K.
        • Arendshorst W.J.
        Angiotensin II-stimulated Ca2+ entry mechanisms in afferent arterioles: role of transient receptor potential canonical channels and reverse Na+/Ca2+ exchange.
        Am J Physiol Renal Physiol. 2008; 294: F212-F219
        • Eder P.
        • Probst D.
        • Rosker C.
        • et al.
        Phospholipase C-dependent control of cardiac calcium homeostasis involves a TRPC3-NCX1 signaling complex.
        Cardiovasc Res. 2007; 73: 111-119