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Current Vascular Pharmacology

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ISSN (Print): 1570-1611
ISSN (Online): 1875-6212

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Review Article

Involvement of Intracellular pH in Vascular Insulin Resistance

Author(s): Marco A. Ramírez*, Ana R. Beltrán, Jorge E. Araya, Marcelo Cornejo, Fernando Toledo, Gonzalo Fuentes and Luis Sobrevia*

Volume 17, Issue 5, 2019

Page: [440 - 446] Pages: 7

DOI: 10.2174/1570161116666180911104012

Price: $65

Abstract

The maintenance of the pH homeostasis is maintained by several mechanisms including the efflux of protons (H+) via membrane transporters expressed in almost all mammalian cells. Along these membrane transporters the sodium/H+ exchangers (NHEs), mainly NHE isoform 1 (NHE1), plays a key role in this phenomenon. NHE1 is under modulation by several environmental conditions (e.g. hyperglycaemia, protein kinase C activity) as well as hormones, including insulin. NHE1 activation causes intracellular alkalization in human endothelial cells leading to activation of the endothelial Nitric Oxide Synthase (eNOS) to generate NO. Intracellular alkalization is a phenomenon that also results in upregulation of the glucose transporter GLUT4 in cells that are responsive to insulin. A reduction in the removal of the extracellular D-glucose is seen in states of insulin resistance, such as in diabetes mellitus and obesity. Since insulin is a potent activator of eNOS in human endothelium, therefore causing vasodilation, and its vascular effect is reduced in insulin resistance it is likely that a defective signal to activate NHE1 in insulin target cells is expected. This phenomenon results in lower redistribution and activation of GLUT4 leading to reduced uptake of D-glucose and hyperglycaemia. The general concept of a role for NHE1, and perhaps other NHEs isoforms, in insulin resistance in the human vasculature is proposed.

Keywords: pH, insulin resistance, insulin, endothelium, diabetes, human, glucose.

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[1]
Yang X, Wang D, Dong W, Song Z, Dou K. Expression and modulation of Na+/H+ exchanger 1 gene in hepatocellular carcinoma: A potential therapeutic target. J Gastroenterol Hepatol 2011; 26: 364-70.
[2]
Chen S, Mackintosh C. Differential regulation of NHE1 phosphorylation and glucose uptake by inhibitors of the ERK pathway and p90RSK in 3T3-L1 adipocytes. Cell Signal 2009; 21: 1984-93.
[3]
Kahn AM, Yang M. Insulin increases acid production and may directly stimulate Na+/H+ exchange activity in cultured vascular smooth muscle cells. J Vasc Res 2011; 48: 505-12.
[4]
Czepán M, Rakonczay Z, Varró A, et al. NHE1 activity contributes to migration and is necessary for proliferation of human gastric myofibroblasts. Pflugers Arch 2012; 463: 459-75.
[5]
Reshkin SJ, Greco MR, Cardone RA. Role of pHi, and proton transporters in oncogene-driven neoplastic transformation. Philos Trans R Soc Lond B Biol Sci 2014; 36920130100
[6]
Provost JJ, Wallert MA. Inside out: Targeting NHE1 as an intracellular and extracellular regulator of cancer progression. Chem Biol Drug Des 2013; 81: 85-101.
[7]
Araos J, Silva L, Salsoso R, et al. Intracellular and extracellular pH dynamics in the human placenta from diabetes mellitus. Placenta 2016; 43: 47-53.
[8]
Celis N, Araos J, Sanhueza C, et al. Intracellular acidification increases adenosine transport in human umbilical vein endothelial cells. Placenta 2017; 51: 10-7.
[9]
Sanhueza C, Araos J, Naranjo L, et al. Sodium/proton exchanger isoform 1 regulates intracellular pH and cell proliferation in human ovarian cancer. Biochim Biophys Acta Mol Basis Dis 2017; 1863: 81-91.
[10]
Ramírez MA, Morales J, Cornejo M, et al. Intracellular acidification reduces L-arginine transport via system y+L but not via system y+/CATs and nitric oxide synthase activity in human umbilical vein endothelial cells. Biochim Biophys Acta Mol Basis Dis 2018; 1864: 1192-202.
[11]
Slepkov ER, Rainey JK, Sykes BD, Fliegel L. Structural and functional analysis of the Na+/H+ exchanger. Biochem J 2017; 401: 623-33.
[12]
Fuster DG, Alexander RT. Traditional and emerging roles for the SLC9 Na+/H+ exchangers. Pflugers Arch 2014; 466: 61-76.
[13]
Sibley CP, Glazier JD, Greenwood SL, et al. Regulation of placental transfer: The Na+/H+ exchanger – a review. Placenta 2002; 23: 39-46.
[14]
Sanhueza C, Araos J, Naranjo L, et al. Nitric oxide and pH modulation in gynaecological cancer. J Cell Mol Med 2016; 20: 2223-30.
[15]
Madonna R, De Caterina R. Sodium-hydrogen exchangers (NHE) in human cardiovascular diseases: Interfering strategies and their therapeutic applications. Vascul Pharmacol 2013; 59: 127-30.
[16]
Kusumoto K, Haist JV, Karmazyn M. Na+/H+ exchange inhibition reduces hypertrophy and heart failure after myocardial infarction in rats. Am J Physiol 2001; 280: 738-45.
[17]
Baartscheer A, Schumacher CA, Van Borren MMGJ, et al. Chronic inhibition of Na+/H+-exchanger attenuates cardiac hypertrophy and prevents cellular remodeling in heart failure. Cardiovasc Res 2005; 65: 83-92.
[18]
Nakamura TY, Iwata Y, Arai Y, Komamura K, Wakabayashi S. Activation of Na+/H+ exchanger 1 is sufficient to generate Ca2+ signals that induce cardiac hypertrophy and heart failure. Circ Res 2008; 103: 891-9.
[19]
Jandeleit-Dahm K, Hannan KM, Farrelly CA, et al. Diabetes-induced vascular hypertrophy is accompanied by activation of Na+-H+ exchange and prevented by Na+-H+ exchange inhibition. Circ Res 2000; 87: 1133-40.
[20]
Vial G, Dubouchaud H, Couturier K, Lanson M, Leverve X, Demaison L. Na+/H+ exchange inhibition with cariporide prevents alterations of coronary endothelial function in streptozotocin-induced diabetes. Mol Cell Biochem 2008; 310: 93-102.
[21]
Sarigianni M, Tsapas A, Mikhailidis DP, Kaloyianni M, Koliakos G, Paletas K. Na+/H+ exchanger-1: A link with atherogenesis? Expert Opin Investig Drugs 2010; 19: 1545-56.
[22]
Packer M. Activation and inhibition of sodium-hydrogen exchanger is a mechanism that links the pathophysiology and treatment of diabetes mellitus with that of heart failure. Circulation 2017; 136: 1548-59.
[23]
Yu L, Hales CA. Silencing of sodium-hydrogen exchanger 1 attenuates the proliferation, hypertrophy, and migration of pulmonary artery smooth muscle cells via E2F1. Am J Respir Cell Mol Biol 2011; 45: 923-30.
[24]
Mizuno S, Demura Y, Ameshima S, Okamura S, Miyamori I, Ishizaki T. Alkalosis stimulates endothelial nitric oxide synthase in cultured human pulmonary arterial endothelial cells. Am J Physiol 2002; 283: 113-9.
[25]
Silva NL, Wang H, Harris CV, Singh D, Fliegel L. Characterization of the Na+/H+ exchanger in human choriocarcinoma (BeWo) cells. Pflugers Arch 1997; 433: 792-802.
[26]
Aharonovitz O, Granot Y. Stimulation of mitogen-activated protein kinase and Na+/H+ exchanger in human platelets. Differential effect of phorbol ester and vasopressin. J Biol Chem 1996; 271: 16494-9.
[27]
Bianchini L, L’Allemain G, Pouysségur J. The p42/p44 mitogen-activated protein kinase cascade is determinant in mediating activation of the Na+/H+ exchanger (NHE1 isoform) in response to growth factors. J Biol Chem 1997; 272: 271-9.
[28]
Kaloyianni M, Tsagias N, Liakos P, Zolota Z, Christophorides E, Koliakos GG. Stimulation of Na+/H+ antiport and pyruvate kinase activities by high glucose concentration in human erythrocytes. Mol Cells 2004; 17: 415-21.
[29]
Aravena C, Beltrán AR, Cornejo M, et al. Potential role of sodium-proton exchangers in the low concentration arsenic trioxide-increased intracellular pH and cell proliferation. PLoS One 2012; 7e51451
[30]
Coccaro E, Karki P, Cojocaru C, et al. Phenylephrine and sustained acidosis activate the neonatal rat cardiomyocyte Na+/H+ exchanger through phosphorylation of amino acids Ser 770 and Ser 771. Am J Physiol 2009; 297: 846-58.
[31]
Boedtkjer E, Kim S, Aalkjaer C. Endothelial alkalinisation inhibits gap junction communication and endothelium-derived hyperpolarisations in mouse mesenteric arteries. J Physiol 2013; 591: 1447-61.
[32]
Parks SK, Cormerais Y, Durivault J, Pouyssegur J. Genetic disruption of the pHi-regulating proteins Na+/H+ exchanger 1 (SLC9A1) and carbonic anhydrase 9 severely reduces growth of colon cancer cells. Oncotarget 2017; 8: 10225-37.
[33]
Putney LK, Barber DL. Na-H exchange-dependent increase in intracellular pH times G2/M entry and transition. J Biol Chem 2003; 278: 44645-9.
[34]
Amith SR, Fliegel L. Regulation of the Na+/H+ exchanger (NHE1) in breast cancer metastasis. Cancer Res 2013; 73: 1259-64.
[35]
Xie R, Wang H, Jin H, Wen G, Tuo B, Xu J. NHE1 is upregulated in gastric cancer and regulates gastric cancer cell proliferation, migration and invasion. Oncol Rep 2017; 37: 1451-60.
[36]
Mather KJ, Steinberg HO, Baron AD. Insulin resistance in the vasculature. J Clin Invest 2013; 123: 1003-4.
[37]
Silva L, Subiabre M, Araos J, et al. Insulin/adenosine axis linked signalling. Mol Aspects Med 2017; 55: 45-61.
[38]
Villalobos-Labra R, Silva L, Subiabre M, et al. Akt/mTOR role in human foetoplacental vascular insulin resistance in diseases of pregnancy. J Diab Res 2017; 20175947859
[39]
Haeusler RA, McGraw TE, Accili D. Biochemical and cellular properties of insulin receptor signalling. Nat Rev Mol Cell Biol 2018; 19: 31-44.
[40]
Sobrevia L, Salsoso R, Fuenzalida B, et al. Insulin is a key modulator of fetoplacental endothelium metabolic disturbances in gestational diabetes mellitus. Front Physiol 2016; 7: 119.
[41]
Subiabre M, Silva L, Villalobos-Labra R, et al. Maternal insulin therapy does not restore foetoplacental endothelial dysfunction in gestational diabetes mellitus. Biochim Biophys Acta Mol Basis Dis 2017; 1863: 2987-98.
[42]
Westermeier F, Sáez T, Arroyo P, et al. Insulin receptor isoforms: an integrated view focused on gestational diabetes mellitus. Diabetes Metab Res Rev 2016; 32: 350-65.
[43]
Boucher J, Kleinridders A, Kahn CR. Insulin receptor signaling in normal and insulin-resistant states. Cold Spring Harb Perspect Biol 2014; 6a009191
[44]
Ong SH, Hadari YR, Gotoh N, Guy GR, Schlessinger J, Lax I. Stimulation of phosphatidylinositol 3-kinase by fibroblast growth factor receptors is mediated by coordinated recruitment of multiple docking proteins. Proc Natl Acad Sci USA 2001; 98: 6074-9.
[45]
Manchester KL. Speculations on the mechanism of action of insulin. Hormones 1970; 1: 342-51.
[46]
Moore RD. Effect of insulin upon the sodium pump in frog skeletal muscle. J Physiol 1973; 232: 23-45.
[47]
Saltiel AR, Pessin JE. Insulin signaling pathways in time and space. Trends Cell Biol 2002; 12: 65-71.
[48]
Bergman RN, Iyer MS. Indirect regulation of endogenous glucose production by insulin: The single gateway hypothesis revisited. Diabetes 2017; 66: 1742-7.
[49]
Ségalen C, Longnus SL, Baetz D, Counillon L, Van Obberghen E. 5-Aminoimidazole-4-carboxamide-1-β-d-ribofuranoside reduces glucose uptake via the inhibition of Na+/H+ exchanger 1 in isolated rat ventricular cardiomyocytes. Endocrinology 2008; 149: 1490-8.
[50]
Fidelman ML, Seeholzer SH, Walsh KB, Moore RD. Intracellular pH mediates action of insulin on glycolysis in frog skeletal muscle. Am J Physiol 1982; 242: 87-93.
[51]
Klip A, Ramlal T, Cragoe EJ. Insulin-induced cytoplasmic alkalinization and glucose transport in muscle cells. Am J Physiol 1986; 250: 720-8.
[52]
Incerpi S, Baldini P, Bellucci V, Zannetti A, Luly P. Modulation of the Na-H antiport by insulin: Interplay between protein kinase C, tyrosine kinase, and protein phosphatases. J Cell Physiol 1994; 159: 205-12.
[53]
Kaloyianni M, Bourikas D, Koliakos G. The effect of insulin on Na+-H+ antiport activity of obese and normal subjects’ erythrocytes. Cell Physiol Biochem 2001; 11: 253-8.
[54]
Yang J, Gillingham AK, Hodel A, Koumanov F, Woodward B, Holman GD. Insulin-stimulated cytosol alkalinization facilitates optimal activation of glucose transport in cardiomyocytes. Am J Physiol 2002; 283: 1299-307.
[55]
Haworth RS, Fröhlich O, Fliegel L. Multiple carbohydrate moieties on the Na+/H+ exchanger. Biochem J 1993; 289: 637-40.
[56]
Sauvage M, Mazière P, Fathallah H, Giraud F. Insulin stimulates NHE1 activity by sequential activation of phosphatidylinositol 3-kinase and protein kinase C zeta in human erythrocytes. Eur J Biochem 2000; 267: 955-62.
[57]
Sarigianni M, Tsapas A, Mikhailidis DP, Kaloyianni M, Koliakos G, Paletas K. Involvement of signaling molecules on Na+/H+ exchanger-1 activity in human monocytes. Open Cardiovasc Med J 2010; 4: 181-8.
[58]
Boedtkjer E, Aalkjaer C. Insulin inhibits Na+/H+ exchange in vascular smooth muscle and endothelial cells in situ: Involvement of H2O2 and tyrosine phosphatase SHP-2. Am J Physiol 2009; 296: 247-55.
[59]
Fleming I. Molecular mechanisms underlying the activation of eNOS. Pflugers Arch 2010; 459: 793-806.
[60]
Fleming I, Hecker M, Busse R. Intracellular alkalinization induced by bradykinin sustains activation of the constitutive nitric oxide synthase in endothelial cells. Circ Res 1994; 74: 1220-6.
[61]
Capellini VK, Restini CB, Bendhack LM, Evora PR, Celotto AC. The effect of extracellular pH changes on intracellular pH and nitric oxide concentration in endothelial and smooth muscle cells from rat aorta. PLoS One 2013; 8e62887
[62]
Russell JC, Proctor SD, Kelly SE, Löhn M, Busch AE, Schäfer S. Insulin-sensitizing and cardiovascular effects of the sodium-hydrogen exchange inhibitor, cariporide, in the JCR: LA-cp rat and db/db mouse. J Cardiovasc Pharmacol 2005; 46: 746-53.
[63]
Klip A, Ramlal T, Koivisto UM. Stimulation of Na+/H+ exchange by insulin and phorbol ester during differentiation of 3T3-L1 cells. Relation to hexose uptake. Endocrinology 1988; 123: 296-304.
[64]
Holman GD, Sandoval IV. Moving the insulin-regulated glucose transporter GLUT4 into and out of storage. Trends Cell Biol 2001; 11: 173-9.
[65]
Mihaylova MM, Shaw RJ. The AMPK signalling pathway coordinates cell growth, autophagy and metabolism. Nat Cell Biol 2011; 13: 1016-23.
[66]
Salsoso R, Guzmán-Gutiérrez E, Sáez T, et al. Insulin restores L-arginine transport requiring adenosine receptors activation in umbilical vein endothelium from late-onset preeclampsia. Placenta 2015; 36: 287-96.
[67]
Pardo F, Silva L, Sáez T, et al. Human supraphysiological gestational weight gain and fetoplacental vascular dysfunction. Int J Obes 2015; 39: 1264-73.
[68]
Koliakos G, Zolota Z, Paletas K, Kaloyianni M. High glucose concentrations stimulate human monocyte sodium/hydrogen exchanger activity and modulate atherosclerosis-related functions. Pflugers Arch 2004; 449: 298-306.
[69]
González M, Rojas S, Avila P, et al. Insulin reverses D-glucose–increased nitric oxide and reactive oxygen species generation in human umbilical vein endothelial cells. PLoS One 2015; 10e0122398
[70]
Sáez T, de Vos P, Kuipers J, Sobrevia L, Faas MM. Fetoplacental endothelial exosomes modulate high D-glucose-induced endothelial dysfunction. Placenta 2018; 66: 26-35.
[71]
Wang S, Peng Q, Zhang J, Liu L. Na+/H+ exchanger is required for hyperglycaemia-induced endothelial dysfunction via calcium-dependent calpain. Cardiovasc Res 2008; 80: 255-62.

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