nach oben

Erschienen in:

01.07.2011 | Original Contribution

Regulation of vascular guanylyl cyclase by endothelial nitric oxide-dependent posttranslational modification

verfasst von: Marc Oppermann, Tatsiana Suvorava, Till Freudenberger, Vu Thao-Vi Dao, Jens W. Fischer, Martina Weber, Georg Kojda

Erschienen in: Basic Research in Cardiology | Ausgabe 4/2011

Einloggen, um Zugang zu erhalten

Abstract

In isolated cells, soluble guanylyl cyclase (sGC) activity is regulated by exogenous nitric oxide (NO) via downregulation of expression and posttranslational S-nitrosylation. The aim of this study was to investigate whether such regulatory mechanism impact on endothelium-dependent vasodilation in a newly developed mouse strain carrying an endothelial-specific overexpression of eNOS (eNOS⁺⁺). When compared with transgene negative controls (eNOSⁿ), eNOS⁺⁺-mice showed a 3.3-fold higher endothelial-specific aortic eNOS expression, increased vascular cGMP and VASP phosphorylation, a L-nitroarginine (L-NA)-inhibitable decrease in systolic blood pressure, but normal levels of peroxynitrite and nitrotyrosine formation, endothelium-dependent aortic vasodilation and vasodilation to NO donors. Western blot analysis for sGC showed similar protein levels of sGC-α1 and sGC-β1 subunits in eNOSⁿ and eNOS⁺⁺. In striking contrast, the activity of isolated sGC was strongly decreased in lungs of eNOS⁺⁺. Semiquantitative evaluation of sGC-β1-S-nitrosylation demonstrated that this loss of sGC activity is associated with increased nitrosylation of the enzyme in eNOS⁺⁺, a difference that disappeared after L-NA-treatment. Our data suggest the existence of a physiologic NO-dependent posttranslational regulation of vascular sGC in mammals involving S-nitrosylation as a key mechanism. Because this mechanism can compensate for reduction in vascular NO bioavailability, it may mask the development of endothelial dysfunction.

Nur mit Berechtigung zugänglich

Barnett DJ, McAninly J, Williams DLH (1994) Transnitrosation between nitrosothiols and thiols. J Chem Soc Perkin Trans 21131–21133. doi:10.1039/P29940001131

Batenburg WW, De Vries R, Saxena PR, Danser AH (2004) L-S-Nitrosothiols: endothelium-derived hyperpolarizing factors in porcine coronary arteries? J Hypertens 22:1927–1936PubMedCrossRef

Bellamy TC, Wood J, Goodwin DA, Garthwaite J (2000) Rapid desensitization of the nitric oxide receptor, soluble guanylyl cyclase, underlies diversity of cellular cGMP responses. Proc Natl Acad Sci USA 97:2928–2933PubMedCrossRef

Brandes RP, Kim DY, Schmitz-Winnenthal FH, Amidi M, Gödecke A, Mülsch A, Busse R (2000) Increased nitrovasodilator sensitivity in endothelial nitric oxide synthase knockout mice—role of soluble guanylyl cyclase. Hypertension 35:231–236PubMed

Buechler WA, Nakane M, Murad F (1991) Expression of soluble guanylate cyclase activity requires both enzyme subunits. Biochem Biophys Res Commun 174:351–357. doi:10.1016/0006-291X(91)90527-E PubMedCrossRef

Desjardins F, Lobysheva I, Pelat M, Gallez B, Feron O, Dessy C, Balligand JL (2008) Control of blood pressure variability in caveolin-1-deficient mice: role of nitric oxide identified in vivo through spectral analysis. Cardiovasc Res 79:527–536. doi:10.1093/cvr/cvn080 PubMedCrossRef

Dikalov S, Fink B (2005) ESR techniques for the detection of nitric oxide in vivo and in tissues. Methods Enzymol 396:597–610. doi:10.1016/S0076-6879(05)96052-7 PubMedCrossRef

Drab M, Verkade P, Elger M, Kasper M, Lohn M, Lauterbach B, Menne J, Lindschau C, Mende F, Luft FC, Schedl A, Haller H, Kurzchalia TV (2001) Loss of caveolae, vascular dysfunction, and pulmonary defects in caveolin-1 gene-disrupted mice. Science 293:2449–2452. doi:10.1126/science.1062688 PubMedCrossRef

Filippov G, Bloch DB, Bloch KD (1997) Nitric oxide decreases stability of mRNAs encoding soluble guanylate cyclase subunits in rat pulmonary artery smooth muscle cells. J.Clin.Invest. 100:942–948. doi:10.1172/JCI119610 PubMedCrossRef

10.

Frantz S, Adamek A, Fraccarollo D, Tillmanns J, Widder JD, Dienesch C, Schafer A, Podolskaya A, Held M, Ruetten H, Ertl G, Bauersachs J (2009) The eNOS enhancer AVE 9488: a novel cardioprotectant against ischemia reperfusion injury. Basic Res Cardiol 104:773–779. doi:10.1007/s00395-009-0041-3 PubMedCrossRef

11.

Gewaltig MT, Kojda G (2002) Vasoprotection by nitric oxide: mechanisms and therapeutic potential. Cardiovasc Res 55:250–260. doi:10.1016/S0008-6363(02)00327-9 PubMedCrossRef

12.

Godecke A, Schrader J (2000) Adaptive mechanisms of the cardiovascular system in transgenic mice—lessons from eNOS and myoglobin knockout mice. Basic Res Cardiol 95:492–498PubMedCrossRef

13.

Hamid SA, Totzeck M, Drexhage C, Thompson I, Fowkes RC, Rassaf T, Baxter GF (2010) Nitric oxide/cGMP signalling mediates the cardioprotective action of adrenomedullin in reperfused myocardium. Basic Res Cardiol 105:257–266. doi:10.1007/s00395-009-0058-7 PubMedCrossRef

14.

Hussain MB, Hobbs AJ, MacAllister RJ (1999) Autoregulation of nitric oxide-soluble guanylate cyclase-cyclic GMP signalling in mouse thoracic aorta. Br J Pharmacol 128:1082–1088. doi:10.1038/sj.bjp.0702874 PubMedCrossRef

15.

Ignarro LJ, Cirino G, Casini A, Napoli C (1999) Nitric oxide as a signaling molecule in the vascular system: an overview. J Cardiovasc Pharmacol 34:879–886PubMedCrossRef

16.

Jaffrey SR, Erdjument-Bromage H, Ferris CD, Tempst P, Snyder SH (2001) Protein S-nitrosylation: a physiological signal for neuronal nitric oxide. Nat Cell Biol 3:193–197. doi:10.1038/35055104 PubMedCrossRef

17.

Jaffrey SR, Snyder SH (2001) The biotin switch method for the detection of S-nitrosylated proteins. Sci STKE 2001:L1. doi:10.1126/stke.2001.86.pl1

18.

Keefer LK, Nims RW, Davies KM, Wink DA (1996) “NONOates” (1-substituted diazen-1-ium-1, 2-diolates) as nitric oxide donors: convenient nitric oxide dosage forms. Methods Enzymol 268:281–293. doi:10.1016/S0076-6879(96)68030-6 PubMedCrossRef

19.

Kelm M, Rath J (2001) Endothelial dysfunction in human coronary circulation: relevance of the l-arginine-NO pathway. Basic Res Cardiol 96:107–127. doi:10.1007/s003950170061 PubMedCrossRef

20.

Kojda G, Hambrecht R (2005) Molecular mechanisms of vascular adaptations to exercise. Physical activity as an effective antioxidant therapy? Cardiovasc Res 67:187–197. doi:10.1016/j.cardiores.2005.04.032 PubMedCrossRef

21.

Kojda G, Kottenberg K, Hacker A, Noack E (1998) Alterations of the vascular and the myocardial guanylate cyclase/cGMP-system induced by long-term hypertension in rats. Pharm Acta Helv 73:27–35. doi:10.1016/S0031-6865(97)00044-7 PubMed

22.

Kojda G, Laursen JB, Ramasamy S, Kent JD, Kurz S, Burchfield J, Shesely EG, Harrison DG (1999) Protein expression, vascular reactivity and soluble guanylate cyclase activity in mice lacking the endothelial nitric oxide synthase: contributions of NOS isoforms to blood pressure and heart rate control. Cardiovasc Res 42:206–213. doi:10.1016/S0008-6363(98)00315-0 PubMedCrossRef

23.

Kojda G, Patzner M, Hacker A, Noack E (1998) Nitric oxide inhibits vascular bioactivation of glyceryl trinitrate. A novel mechanism to explain preferential venodilation of organic nitrates. Mol Pharmacol 53:547–554PubMed

24.

Kuzkaya N, Weissmann N, Harrison DG, Dikalov S (2005) Interactions of peroxynitrite with uric acid in the presence of ascorbate and thiols: implications for uncoupling endothelial nitric oxide synthase. Biochem Pharmacol 70:343–354. doi:10.1016/j.bcp.2005.05.009 PubMedCrossRef

25.

Lauer N, Suvorava T, Rüther U, Jacob R, Meyer A, Harrison DG, Kojda G (2005) Critical involvement of hydrogen peroxide in exercise-induced upregulation of endothelial NO-synthase. Cardiovasc Res 65(1):254–262. doi:10.1016/j.cardiores.2004.09.010 PubMedCrossRef

26.

Mayer B, Kleschyov AL, Stessel H, Russwurm M, Munzel T, Koesling D, Schmidt K (2009) Inactivation of soluble guanylate cyclase by stoichiometric S-nitrosation. Mol Pharmacol 75:886–891. doi:10.1124/mol.108.052142 PubMedCrossRef

27.

Meyer DJ, Kramer H, Özer N, Coles B, Ketterer B (1994) Kinetics and equilibria of S-nitrosothiol-thiol exchange between glutathione, cysteine, penicillamines and serum albumin. FEBS Lett 345:177–180. doi:10.1016/0014-5793(94)00429-3 PubMedCrossRef

28.

Moncada S, Higgs A (1993) Mechanisms of disease: the l-arginine-nitric oxide pathway. N Engl J Med 329:2002–2012PubMedCrossRef

29.

Moncada S, Rees DD, Schulz R, Palmer RMJ (1991) Development and mechanism of a specific supersensitivity to nitrovasodilators after inhibition of vascular nitric oxide synthesis in vivo. Proc Natl Acad Sci USA 88:2166–2170PubMedCrossRef

30.

Mullershausen F, Russwurm M, Koesling D, Friebe A (2003) The enhanced NO-induced cGMP response induced by long-term L-NAME treatment is not due to enhanced expression of NO-sensitive guanylyl cyclase. Vascul Pharmacol 40:161–165. doi:10.1016/S1537-1891(03)00049-1 PubMedCrossRef

31.

Ohashi Y, Kawashima S, Hirata K, Yamashita T, Ishida T, Inoue N, Sakoda T, Kurihara H, Yazaki Y, Yokoyama M (1998) Hypotension and reduced nitric oxide-elicited vasorelaxation in transgenic mice overexpressing endothelial nitric oxide synthase (see comments). J Clin Invest 102:2061–2071. doi:10.1172/JCI4394 PubMedCrossRef

32.

Oppermann M, Dao VT, Suvorava T, Bas M, Kojda G (2008) Effect of oral organic nitrates on expression and activity of vascular soluble guanylyl cyclase. Br J Pharmacol 155:335–342. doi:10.1038/bjp.2008.269 PubMedCrossRef

33.

Ozaki M, Kawashima S, Yamashita T, Hirase T, Namiki M, Inoue N, Hirata K, Yasui H, Sakurai H, Yoshida Y, Masada M, Yokoyama M (2002) Overexpression of endothelial nitric oxide synthase accelerates atherosclerotic lesion formation in apoE-deficient mice. J Clin Invest 110:331–340. doi:10.1172/JCI15215 PubMed

34.

Riego JA, Broniowska KA, Kettenhofen NJ, Hogg N (2009) Activation and inhibition of soluble guanylyl cyclase by S-nitrosocysteine: involvement of amino acid transport system L. Free Radic Biol Med 47:269–274. doi:10.1016/j.freeradbiomed.2009.04.027 PubMedCrossRef

35.

Russwurm M, Koesling D (2004) NO activation of guanylyl cyclase. EMBO J 23:4443–4450. doi:10.1038/sj.emboj.7600422 PubMedCrossRef

36.

Sayed N, Baskaran P, Ma X, van den Beuve A AF (2007) Desensitization of soluble guanylyl cyclase, the NO receptor, by S-nitrosylation. Proc Natl Acad Sci USA 104:12312–12317. doi:10.1073/pnas.0703944104 PubMedCrossRef

37.

Schmidt K, Andrew P, Schrammel A, Groschner K, Schmitz V, Kojda G, Mayer B (2001) Comparison of neuronal and endothelial isoforms of nitric oxide synthase in stably transfected HEK 293 cells. Am J Physiol Heart Circ Physiol 281:H2053–H2061PubMed

38.

Schultz G, Böhme E (1984) Guanylate Cyclase. In: Bergmeyer HU (ed) Methods of enzymatic analysis. Verlag Chemie, Weinheim, FRG, pp 379–389

39.

Scott WS, Nakayama DK (1998) Escherichia coli lipopolysaccharide downregulates soluble guanylate cyclase in pulmonary artery smooth muscle. J Surg Res 80:309–314. doi:10.1006/jsre.1998.5442 PubMedCrossRef

40.

Suvorava T, Lauer N, Kojda G (2004) Physical inactivity causes endothelial dysfunction in healthy young mice. J Am Coll Cardiol 44:1320–1327. doi:10.1016/j.jacc.2004.06.030 PubMedCrossRef

41.

Szelid Z, Pokreisz P, Liu X, Vermeersch P, Marsboom G, Gillijns H, Pellens M, Verbeken E, Van de WF, Collen D, Janssens SP (2010) Cardioselective nitric oxide synthase 3 gene transfer protects against myocardial reperfusion injury. Basic Res Cardiol 105:169–179. doi:10.1007/s00395-009-0077-4

42.

Weber M, Lauer N, Mulsch A, Kojda G (2001) The effect of peroxynitrite on the catalytic activity of soluble guanylyl cyclase. Free Radic Biol Med 31:1360–1367. doi:10.1016/S0891-5849(01)00706-7 PubMedCrossRef

43.

Yamashita T, Kawashima S, Ohashi Y, Ozaki M, Rikitake Y, Inoue N, Hirata K, Akita H, Yokoyama M (2000) Mechanisms of reduced nitric oxide/cGMP-mediated vasorelaxation in transgenic mice overexpressing endothelial nitric oxide synthase. Hypertension 36:97–102PubMed

44.

Zhao YY, Zhao YD, Mirza MK, Huang JH, Potula HH, Vogel SM, Brovkovych V, Yuan JX, Wharton J, Malik AB (2009) Persistent eNOS activation secondary to caveolin-1 deficiency induces pulmonary hypertension in mice and humans through PKG nitration. J Clin Invest 119:2009–2018. doi:10.1172/JCI33338 PubMedCrossRef

Titel: Regulation of vascular guanylyl cyclase by endothelial nitric oxide-dependent posttranslational modification
verfasst von: Marc Oppermann
Tatsiana Suvorava
Till Freudenberger
Vu Thao-Vi Dao
Jens W. Fischer
Martina Weber
Georg Kojda
Publikationsdatum: 01.07.2011
Verlag: Springer-Verlag
Erschienen in: Basic Research in Cardiology / Ausgabe 4/2011
Print ISSN: 0300-8428
Elektronische ISSN: 1435-1803
DOI: https://doi.org/10.1007/s00395-011-0160-5

Neu im Fachgebiet Kardiologie

Screening-Mammografie offenbart erhöhtes Herz-Kreislauf-Risiko

26.04.2024 Mammografie Nachrichten

Routinemäßige Mammografien helfen, Brustkrebs frühzeitig zu erkennen. Anhand der Röntgenuntersuchung lassen sich aber auch kardiovaskuläre Risikopatientinnen identifizieren. Als zuverlässiger Anhaltspunkt gilt die Verkalkung der Brustarterien.

Niedriger diastolischer Blutdruck erhöht Risiko für schwere kardiovaskuläre Komplikationen

25.04.2024 Hypotonie Nachrichten

Wenn unter einer medikamentösen Hochdrucktherapie der diastolische Blutdruck in den Keller geht, steigt das Risiko für schwere kardiovaskuläre Ereignisse: Darauf deutet eine Sekundäranalyse der SPRINT-Studie hin.

Therapiestart mit Blutdrucksenkern erhöht Frakturrisiko

25.04.2024 Hypertonie Nachrichten

Beginnen ältere Männer im Pflegeheim eine Antihypertensiva-Therapie, dann ist die Frakturrate in den folgenden 30 Tagen mehr als verdoppelt. Besonders häufig stürzen Demenzkranke und Männer, die erstmals Blutdrucksenker nehmen. Dafür spricht eine Analyse unter US-Veteranen.

Adipositas-Medikament auch gegen Schlafapnoe wirksam

24.04.2024 Adipositas Nachrichten

Der als Antidiabetikum sowie zum Gewichtsmanagement zugelassene Wirkstoff Tirzepatid hat in Studien bei adipösen Patienten auch schlafbezogene Atmungsstörungen deutlich reduziert, informiert der Hersteller in einer Vorab-Meldung zum Studienausgang.

Update Kardiologie

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.

Newsletter bestellen

Springer Medizin

Abstract

Bitte loggen Sie sich ein, um Zugang zu diesem Inhalt zu erhalten

Weitere Artikel der Ausgabe 4/2011

EGFR trans-activation by urotensin II receptor is mediated by β-arrestin recruitment and confers cardioprotection in pressure overload-induced cardiac hypertrophy

Chronic cardiac pressure overload induces adrenal medulla hypertrophy and increased catecholamine synthesis

Desmoglein 2 mutant mice develop cardiac fibrosis and dilation

Role of endothelial Nox2 NADPH oxidase in angiotensin II-induced hypertension and vasomotor dysfunction