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Pflügers Archiv - European Journal of Physiology

, Volume 463, Issue 2, pp 257–268 | Cite as

Heterogeneity in relaxation of different sized porcine coronary arteries to nitrovasodilators: role of PKG and MYPT1

  • Lei Ying
  • Xiaojian Xu
  • Juan Liu
  • Dou Dou
  • Xiaoxing Yu
  • Liping Ye
  • Qiong He
  • Yuansheng GaoEmail author
Cardiovascular Physiology

Abstract

The present study was to determine the role of the type I isoform of cGMP-dependent protein kinase (PKG I) and its downstream effector myosin phosphatase target subunit 1 (MYPT1) in the responses of different sized coronary arteries to nitrovasodilators. Relaxations of isolated porcine coronary arteries were determined by isometric tension recording technique. Protein levels of PKG I and its effectors were analyzed by Western blotting. The activities of PKG I and MYPT1 were studied by analyzing phosphorylation of vasodilator-stimulated phosphoprotein (VASP) and MYPT1, respectively. Nitroglycerin, DETA NONOate, and 8-Br-cGMP caused greater relaxations in large than in small coronary arteries. Relaxations were attenuated to a greater extent by Rp-8-Br-PET-cGMPS (a PKG inhibitor) in large vs. small arteries. The expressions of PKG I and MYPT1 in large arteries were more abundant than in small arteries. DETA NONOate stimulated phosphorylation of VASP at Ser239 and inhibited phosphorylation of MYPT1 at Thr853 to a greater extent in large than in small arteries. A suppressed phosphorylation of MYPT1 at Thr853 was caused by 8-Br-cGMP in large but not small arteries, which was inhibited by Rp-8-Br-PET-cGMPS. These results suggest that the greater responsiveness of large coronary arteries to nitrovasodilators result in part from greater activities of PKG I and MYPT1. Dysfunction in nitric oxide signaling is implicated in the vulnerability of large coronary arteries to certain disorders such as atherosclerosis and spasm. Augmentation of PKG I–MYPT1 signaling may be of therapeutic benefit for combating these events.

Keywords

Coronary artery Nitric oxide Cyclic guanosine monophosphate Protein kinase G Vasodilatation 

Notes

Acknowledgment

This study was supported in part by the National Natural Science Foundation of China, Grant #30870938, #30900511, and #81001433.

Conflict of interest

The authors state no conflict of interest.

References

  1. 1.
    Batenburg WW, Kappers MH, Eikmann MJ, Ramzan SN, de Vries R, Danser AH (2009) Light-induced vs. bradykinin-induced relaxation of coronary arteries: do S-nitrosothiols act as endothelium-derived hyperpolarizing factors? J Hypertens 27:1631–1640PubMedCrossRefGoogle Scholar
  2. 2.
    Biel M, Altenhofen W, Hullin R, Ludwig J, Freichel M, Flockerzi V, Dascal N, Kaupp UB, Hofmann F (1993) Primary structure and functional expression of a cyclic nucleotide-gated channel from rabbit aorta. FEBS Lett 23(329):13413–13418Google Scholar
  3. 3.
    Bowles DK, Hu Q, Laughlin MH, Sturek M (1997) Heterogeneity of L-type calcium current density in coronary smooth muscle. Am J Physiol Heart Circ Physiol 273:H2083–H2089Google Scholar
  4. 4.
    Butt E, Pohler D, Genieser HG, Huggins JP, Bucher B (1995) Inhibition of cyclic GMP-dependent protein kinase-mediated effects by (Rp)-8-bromo-PET-cyclic GMPS. Br J Pharmacol 116:3110–3116PubMedGoogle Scholar
  5. 5.
    Cheng HC, Kemp BE, Pearson RB, Smith AJ, Misconi L, Van Patten SM, Walsh DA (1986) A potent synthetic peptide inhibitor of the cAMP dependent protein kinase. J Biol Chem 261:989–992PubMedGoogle Scholar
  6. 6.
    Cheng KT, Chan FL, Huang Y, Chan WY, Yao X (2003). Expression of olfactory-type cyclic nucleotide-gated channel (CNGA2) in vascular tissues. Histochem Cell Biol. 2003 Dec;120(6):475–481Google Scholar
  7. 7.
    Chu A, Morris KG, Kuehl WD, Cusma J, Navetta F, Cobb FR (1989) Effects of atrial natriuretic peptide on the coronary arterial vasculature in humans. Circulation 80:1627–1635PubMedCrossRefGoogle Scholar
  8. 8.
    Coleman RA, Humphrey PP, Kennedy I, Levy GP, Lumley P (1981) Comparison of the actions of U-46619, a prostaglandin H2-analogue, with those of prostaglandin H2 and thromboxane A2 on some isolated smooth muscle preparations. Br J Pharmacol 73:773–778PubMedGoogle Scholar
  9. 9.
    Dhanakoti S, Gao Y, Nguyen MQ, Raj JU (2000) Involvement of cGMP-dependent protein kinase in the relaxation of ovine pulmonary arteries to cGMP and cAMP. J Appl Physiol 88:1637–1642PubMedGoogle Scholar
  10. 10.
    Dou D, Ma H, Zheng X, Ying L, Guo Y, Yu X, Gao Y (2010) Degradation of leucine zipper positive isoform of MYPT1 may contribute to development of nitrate tolerance. Cardiovasc Res 86:151–159PubMedCrossRefGoogle Scholar
  11. 11.
    Edwards G, Félétou M, Weston AH (2010) Endothelium-derived hyperpolarising factors and associated pathways: a synopsis. Pflugers Arch Eur J Physiol 459:863–879CrossRefGoogle Scholar
  12. 12.
    Friebe A, Koesling D (2009) The function of NO-sensitive guanylyl cyclase: what we can learn from genetic mouse models. Nitric Oxide 21:149–156PubMedCrossRefGoogle Scholar
  13. 13.
    Gangopahyay A, Oran M, Bauer EM, Wertz JW, Comhair SA, Erzurum SC, Bauer PM (2011) Bone morphogenetic protein receptor II is a novel mediator of endothelial nitric-oxide synthase activation. J Biol Chem 286:33134–33140PubMedCrossRefGoogle Scholar
  14. 14.
    Gao Y (2010) The multiple actions of NO. Pflügers Arch Eur J Physiol 459:829–839CrossRefGoogle Scholar
  15. 15.
    Gao Y, Portugal AD, Negash S, Zhou W, Longo LD, Raj JU (2007) Role of Rho kinases in PKG-mediated relaxation of pulmonary arteries of fetal lambs exposed to chronic high altitude hypoxia. Am J Physiol Lung Cell Mol Physiol 272:L678–L684Google Scholar
  16. 16.
    Gao Y, Tolsa J-F, Shen H, Raj JU (1998) Effect of selective phosphodiesterase inhibitors on the responses of ovine pulmonary veins to prostaglandin E2. J Appl Physiol 84:13–18PubMedGoogle Scholar
  17. 17.
    Garthwaite J, Southam E, Boulton CL, Nielsen EB, Schmidt K, Mayer B (1995) Potent and selective inhibition of nitric oxide-sensitive guanylyl cyclase by 1H-[1, 2, 4]oxadiazolo4,3-a]quinoxalin-1-one. Mol Pharmacol 48:184–188PubMedGoogle Scholar
  18. 18.
    Goel M, Zuo CD, Schilling WP (2010) Role of cAMP/PKA signaling cascade in vasopressin-induced trafficking of TRPC3 channels in principal cells of the collecting duct. Am J Physiol Renal Physiol 298:F988–F996PubMedCrossRefGoogle Scholar
  19. 19.
    Grönros J, Wikström J, Hägg U, Wandt B, Gan LM (2006) Proximal to middle left coronary artery flow velocity ratio, as assessed using color Doppler echocardiography, predicts coronary artery atherosclerosis in mice. Arterioscler Thromb Vasc Biol 26:1126–1131PubMedCrossRefGoogle Scholar
  20. 20.
    Hartshorne DJ, Ito M, Erdödi F (2004) Role of protein phosphatase type 1 in contractile functions: myosin phosphatase. J Biol Chem 279:37211–37214PubMedCrossRefGoogle Scholar
  21. 21.
    Halushka PV (2000) Thromboxane A2 receptors: where have you gone? Prostaglandins Other Lipid Mediat 60:175–189PubMedCrossRefGoogle Scholar
  22. 22.
    Hofmann F, Bernhard D, Lukowski R, Weinmeister P (2009) cGMP regulated protein kinases (cGK). Handb Exp Pharmacol 191:137–162PubMedCrossRefGoogle Scholar
  23. 23.
    Huang QQ, Fisher SA, Brozovich FV (2004) Unzipping the role of myosin light chain phosphatase in smooth muscle cell relaxation. J Biol Chem 279:597–603PubMedCrossRefGoogle Scholar
  24. 24.
    Ishizaki T, Uehata M, Tamechika I, Keel J, Nonomura K, Maekawa M, Narumiya S (2000) Pharmacological properties of Y-27632, a specific inhibitor of rho-associated kinases. Mol Pharmacol 57:976–983PubMedGoogle Scholar
  25. 25.
    Karim SM, Rhee AY, Given AM, Faulx MD, Hoit BD, Brozovich FV (2004) Vascular reactivity in heart failure: role of myosin light chain phosphatase. Circ Res 95:612–618PubMedCrossRefGoogle Scholar
  26. 26.
    Kato M, Shiode N, Yamagata T, Matsuura H, Kajiyama G (1997) Bradykinin induced dilatation of human epicardial and resistance coronary arteries in vivo: effect of inhibition of nitric oxide synthesis. Heart 78:493–498PubMedGoogle Scholar
  27. 27.
    Kawabata T, Fujii T, Hiro T, Yasumoto K, Yamada J, Yano M, Miura T, Matsuzaki M (2000) Vasodilator responses of coronary conduit and resistance arteries to continuous nitroglycerin infusion in humans: a Doppler guide wire study. J Cardiovasc Pharmacol 36:764–769PubMedCrossRefGoogle Scholar
  28. 28.
    Kawano H, Node K (2011) The role of vascular failure in coronary artery spasm. J Cardiol 57:2–7PubMedCrossRefGoogle Scholar
  29. 29.
    Keefer LK, Nims RW, Davies KM (1996) “NONOates” (1-substituted diazen-1-ium-1,2-diolates) as nitric oxide donors: convenient nitric oxide dosage forms. Methods Enzymol 268:281–293PubMedCrossRefGoogle Scholar
  30. 30.
    Kurz MA, Lamping KG, Bates JN, Eastham CL, Marcus ML, Harrison DG (1991) Mechanisms responsible for the heterogeneous coronary microvascular response to nitroglycerin. Circ Res 68:847–855PubMedGoogle Scholar
  31. 31.
    Kwan HY, Cheng KT, Ma Y, Huang Y, Tang NL, Yu S, Yao X (2010) CNGA2 contributes to ATP-induced noncapacitative Ca2+ influx in vascular endothelial cells. J Vasc Res 47:148–156PubMedCrossRefGoogle Scholar
  32. 32.
    Ma H, He Q, Dou D, Zheng X, Ying L, Wu Y, Raj JU, Gao Y (2010) Increased degradation of MYPT1 contributes to the development of tolerance to nitric oxide in porcine pulmonary artery. Am J Physiol Lung Cell Mol Physiol 299:L117–L123PubMedCrossRefGoogle Scholar
  33. 33.
    Makarova AM, Lebedeva TV, Nassar T, Higazi AA, Xue J, Carinato ME, Bdeir K, Cines DB, Stepanova V (2011) Urokinase-type plasminogen activator (uPA) induces pulmonary microvascular endothelial permeability through low density lipoprotein receptor-related protein (LRP)-dependent activation of endothelial nitric-oxide synthase. J Biol Chem 286:23044–23053PubMedCrossRefGoogle Scholar
  34. 34.
    Matsumoto T, Takahashi M, Omura T, Takaoka A, Liu Q, Nakae I, Kinoshita M (1997) Heterogeneity in the vasorelaxing effect of nicorandil on dog epicardial coronary arteries: comparison with other no donors. J Cardiovasc Pharmacol 29:772–779PubMedCrossRefGoogle Scholar
  35. 35.
    Meyer RB Jr, Miller JP (1974) Analogs of cyclic AMP and cyclic GMP: general methods of synthesis and the relationship of structure to enzymic activity. Life Sci 14:1019–1040PubMedCrossRefGoogle Scholar
  36. 36.
    Payne MC, Zhang HY, Prosdocimo T, Joyce KM, Koga Y, Ikebe M, Fisher SA (2006) Myosin phosphatase isoform switching in vascular smooth muscle development. J Mol Cell Cardiol 40:274–282PubMedCrossRefGoogle Scholar
  37. 37.
    Ogut O, Brozovich FV (2008) The potential role of MLC phosphatase and MAPK signalling in the pathogenesis of vascular dysfunction in heart failure. J Cell Mol Med 12:2158–2164PubMedCrossRefGoogle Scholar
  38. 38.
    Qi H, Zheng X, Qin X, Dou D, Xu H, Raj JU, Gao Y (2007) PKG regulates the basal tension and plays a major role in nitrovasodilator-induced relaxation of porcine coronary veins. Br J Pharmacol 152:1060–1069PubMedCrossRefGoogle Scholar
  39. 39.
    Qin X, Zheng X, Qi H, Dou D, Raj JU, Gao Y (2007) cGMP-dependent protein kinase in regulation of basal tone and in nitroglycerin and nitric oxide induced relaxation in porcine coronary artery. Pflügers Arch Eur J Physiol 454:913–923CrossRefGoogle Scholar
  40. 40.
    Sellke FW, Myers PR, Bates JN, Harrison DG (1990) Influence of vessel size on the sensitivity of porcine coronary microvessels to nitroglycerin. Am J Physiol Heart Circ Physiol 258:H515–H520Google Scholar
  41. 41.
    Smolenski A, Bachmann C, Reinhard K, Hönig-Liedl P, Jarchau T, Hoschuetzky H, Walter U (1998) Analysis and regulation of vasodilator-stimulated phosphoprotein serine 239 phosphorylation in vitro and in intact cells using a phosphospecific monoclonal antibody. J Biol Chem 273:20029–20035PubMedCrossRefGoogle Scholar
  42. 42.
    Somlyo AP, Somlyo AV (2003) Ca2+ sensitivity of smooth muscle and nonmuscle myosin II: modulated by G proteins, kinases, and myosin phosphatase. Physiol Rev 83:1325–1358PubMedGoogle Scholar
  43. 43.
    Vanhoutte PM, Shimokawa H, Tang EH, Feletou M (2009) Endothelial dysfunction and vascular disease. Acta Physiol (Oxf) 196:193–222CrossRefGoogle Scholar
  44. 44.
    Wentworth JK, Pula G, Poole AW (2006) Vasodilator-stimulated phosphoprotein (VASP) is phosphorylated on Ser157 by protein kinase C-dependent and -independent mechanisms in thrombin-stimulated human platelets. Biochem J 393:555–564PubMedCrossRefGoogle Scholar
  45. 45.
    Young MA, Vatner SF (1986) Regulation of large coronary arteries. Circ Res 59:579–96PubMedGoogle Scholar
  46. 46.
    Zhang J, Somers M, Cobb FR (1993) Heterogeneous effects of nitroglycerin on the conductance and resistance coronary arterial vasculature. Am J Physiol Heart Circ Physiol 264:H1960–H1968Google Scholar

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Lei Ying
    • 1
  • Xiaojian Xu
    • 1
  • Juan Liu
    • 1
  • Dou Dou
    • 1
    • 2
  • Xiaoxing Yu
    • 1
  • Liping Ye
    • 1
  • Qiong He
    • 1
  • Yuansheng Gao
    • 1
    • 2
    Email author
  1. 1.Department of Physiology and PathophysiologyPeking University Health Science CenterBeijingChina
  2. 2.Key Laboratory of Molecular Cardiovascular ScienceMinistry of EducationBeijingChina

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