Download PDF
Horm Metab Res 2014; 46(08): 581-586
DOI: 10.1055/s-0034-1375611
Endocrine Care
© Georg Thieme Verlag KG Stuttgart · New York

Osteoprotegerin is Secreted Into the Coronary Circulation: A Possible Association with the Renin-Angiotensin System and Cardiac Hypertrophy

S. Koyama
1   Department of Internal Medicine, Circulatory and Body Fluid Regulation, University of Miyazaki, Miyazaki, Japan
,
T. Tsuruda
1   Department of Internal Medicine, Circulatory and Body Fluid Regulation, University of Miyazaki, Miyazaki, Japan
,
T. Ideguchi
1   Department of Internal Medicine, Circulatory and Body Fluid Regulation, University of Miyazaki, Miyazaki, Japan
,
J. Kawagoe
1   Department of Internal Medicine, Circulatory and Body Fluid Regulation, University of Miyazaki, Miyazaki, Japan
,
H. Onitsuka
1   Department of Internal Medicine, Circulatory and Body Fluid Regulation, University of Miyazaki, Miyazaki, Japan
,
T. Ishikawa
1   Department of Internal Medicine, Circulatory and Body Fluid Regulation, University of Miyazaki, Miyazaki, Japan
,
H. Date
1   Department of Internal Medicine, Circulatory and Body Fluid Regulation, University of Miyazaki, Miyazaki, Japan
,
K. Hatakeyama
2   Department of Pathology, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan
,
Y. Asada
2   Department of Pathology, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan
,
J. Kato
3   Frontier Science Research Center, University of Miyazaki, Miyazaki, Japan
,
K. Kitamura
1   Department of Internal Medicine, Circulatory and Body Fluid Regulation, University of Miyazaki, Miyazaki, Japan
› Author Affiliations
Further Information

Publication History

received 28 November 2013

accepted 03 April 2014

Publication Date:
08 May 2014 (online)

Also available at
    Permissions and Reprints

Abstract

The circulating osteoprotegerin (OPG) level reflects a series of cardiovascular diseases; however, the source(s) of circulating OPG remain(s) to be determined. This study explored whether OPG is released in the coronary circulation and whether it is associated with cardiac structure and function. Fifty-six patients (67±10 years old, male 57%, hypertension 73%, coronary artery disease 50%) were enrolled, and blood samples were collected simultaneously from the orifice of the left coronary artery (CA) and the coronary sinus (CS) after angiography. The concentration of OPG was higher in the CS than in the CA (7.7±4.1 vs. 6.7±3.6 pmol/l, p<0.001). The trans-cardiac OPG concentration was significantly (p=0.019) decreased in patients who have been prescribed either an angiotensin converting enzyme inhibitor or an angiotensin II type 1 receptor blocker (ACEI/ARB). In patients subgroup who did not take an ACEI/ARB (n=27), the trans-cardiac OPG level was positively correlated with age (r=0.396, p=0.041) and relative wall thickness of left ventricle (r=0.534, p=0.004). In multivariate linear regression analysis, relative wall thickness remained to be the independent variable for the trans-cardiac OPG level (p=0.004). Moreover, trans-cardiac OPG was significantly (p=0.021) increased in patients with relative wall thickness greater than 0.45 but it did not differ if the left ventricular mass index was increased (≥116 for males, or ≥ 104 for females, g/m2) or not (p=0.627). This study suggests that OPG is secreted into the coronary circulation and is associated with concentric remodeling/hypertrophy of LV, possibly in interactions with the renin-angiotensin system.

Key words

angiotensin II - concentric hypertrophy - remodeling

Supporting Information

    for this article is available online at http://www.thieme-connect.de/ejournals/toc/hmr
  • Supporting Information
 

  • References

  • 1 Najjar SS, Scuteri A, Lakatta EG. Arterial aging: Is it an immutable cardiovascular risk factor?. Hypertension 2005; 46: 454-462
    CrossrefPubMedSearch in Google Scholar
  • 2 Ganau A, Devereux RB, Roman MJ, de Simone G, Pickering TG, Saba PS, Vargiu P, Simongini I, Laragh JH. Patterns of left ventricular hypertrophy and geometric remodeling in essential hypertension. J Am Coll Cardiol 1992; 19: 1550-1558
    CrossrefPubMedSearch in Google Scholar
  • 3 Levy D, Anderson KM, Savage DD, Kannel WB, Christiansen JC, Castelli WP. Echocardiographically detected left ventricular hypertrophy: Prevalence and risk factors. The framingham heart study. Ann Intern Med 1988; 108: 7-13
    CrossrefPubMedSearch in Google Scholar
  • 4 Sadoshima J, Izumo S. Molecular characterization of angiotensin ii-induced hypertrophy of cardiac myocytes and hyperplasia of cardiac fibroblasts. Critical role of the at1 receptor subtype. Circ Res 1993; 73: 413-423
    CrossrefPubMedSearch in Google Scholar
  • 5 Heymes C, Silvestre JS, Llorens-Cortes C, Chevalier B, Marotte F, Levy BI, Swynghedauw B, Samuel JL. Cardiac senescence is associated with enhanced expression of angiotensin ii receptor subtypes. Endocrinology 1998; 139: 2579-2587
    PubMedSearch in Google Scholar
  • 6 Dai DF, Santana LF, Vermulst M, Tomazela DM, Emond MJ, MacCoss MJ, Gollahon K, Martin GM, Loeb LA, Ladiges WC, Rabinovitch PS. Overexpression of catalase targeted to mitochondria attenuates murine cardiac aging. Circulation 2009; 119: 2789-2797
    CrossrefPubMedSearch in Google Scholar
  • 7 Wang M, Takagi G, Asai K, Resuello RG, Natividad FF, Vatner DE, Vatner SF, Lakatta EG. Aging increases aortic mmp-2 activity and angiotensin ii in nonhuman primates. Hypertension 2003; 41: 1308-1316
    CrossrefPubMedSearch in Google Scholar
  • 8 Basso N, Cini R, Pietrelli A, Ferder L, Terragno NA, Inserra F. Protective effect of long-term angiotensin ii inhibition. Am J Physiol Heart Circ Physiol 2007; 293: H1351-H1358
    CrossrefPubMedSearch in Google Scholar
  • 9 Michel JB, Heudes D, Michel O, Poitevin P, Philippe M, Scalbert E, Corman B, Levy BI. Effect of chronic ang i-converting enzyme inhibition on aging processes. II. Large arteries. Am J Physiol 1994; 267: R124-R135
    PubMedSearch in Google Scholar
  • 10 Simonet WS, Lacey DL, Dunstan CR, Kelley M, Chang MS, Lüthy R, Nguyen HQ, Wooden S, Bennett L, Boone T, Shimamoto G, DeRose M, Elliott R, Colombero A, Tan HL, Trail G, Sullivan J, Davy E, Bucay N, Renshaw-Gegg L, Hughes TM, Hill D, Pattison W, Campbell P, Sander S, Van G, Tarpley J, Derby P, Lee R, Boyle WJ. Osteoprotegerin: A novel secreted protein involved in the regulation of bone density. Cell 1997; 89: 309-319
    CrossrefPubMedSearch in Google Scholar
  • 11 Tsuda E, Goto M, Mochizuki S, Yano K, Kobayashi F, Morinaga T, Higashio K. Isolation of a novel cytokine from human fibroblasts that specifically inhibits osteoclastogenesis. Biochem Biophys Res Commun 1997; 234: 137-142
    CrossrefPubMedSearch in Google Scholar
  • 12 Yasuda H, Shima N, Nakagawa N, Yamaguchi K, Kinosaki M, Mochizuki S, Tomoyasu A, Yano K, Goto M, Murakami A, Tsuda E, Morinaga T, Higashio K, Udagawa N, Takahashi N, Suda T. Osteoclast differentiation factor is a ligand for osteoprotegerin/osteoclastogenesis-inhibitory factor and is identical to trance/rankl. Proc Natl Acad Sci USA 1998; 95: 3597-3602
    CrossrefPubMedSearch in Google Scholar
  • 13 Yasuda H, Shima N, Nakagawa N, Mochizuki S, Yano K, Fujise N, Sato Y, Goto M, Yamaguchi K, Kuriyama M, Kanno T, Murakami A, Tsuda E, Morinaga T, Higashio K. Identity of osteoclastogenesis inhibitory factor (ocif) and osteoprotegerin (opg): A mechanism by which opg/ocif inhibits osteoclastogenesis in vitro. Endocrinology 1998; 139: 1329-1337
    PubMedSearch in Google Scholar
  • 14 Schoppet M, Ruppert V, Hofbauer LC, Henser S, Al-Fakhri N, Christ M, Pankuweit S, Maisch B. Tnf-related apoptosis-inducing ligand and its decoy receptor osteoprotegerin in nonischemic dilated cardiomyopathy. Biochem Biophys Res Commun 2005; 338: 1745-1750
    CrossrefPubMedSearch in Google Scholar
  • 15 Simionescu A, Simionescu DT, Vyavahare NR. Osteogenic responses in fibroblasts activated by elastin degradation products and transforming growth factor-β1: Role of myofibroblasts in vascular calcification. Am J Pathol 2007; 171: 116-123
    CrossrefPubMedSearch in Google Scholar
  • 16 Zhang J, Fu M, Myles D, Zhu X, Du J, Cao X, Chen YE. Pdgf induces osteoprotegerin expression in vascular smooth muscle cells by multiple signal pathways. FEBS Lett 2002; 521: 180-184
    CrossrefPubMedSearch in Google Scholar
  • 17 Moran CS, Cullen B, Campbell JH, Golledge J. Interaction between angiotensin ii, osteoprotegerin, and peroxisome proliferator-activated receptor-γ in abdominal aortic aneurysm. J Vasc Res 2008; 46: 209-217
    PubMedSearch in Google Scholar
  • 18 Mainini G, Incoronato M, Urso L, Scaffa C. Serum osteoprotegerin correlates with age and bone mass in postmenopausal, but not in fertile age women. Clin Exp Obstet Gynecol 2011; 38: 355-359
    PubMedSearch in Google Scholar
  • 19 Kudlacek S, Schneider B, Woloszczuk W, Pietschmann P, Willvonseder R. Metabolism ASGoNVoB. Serum levels of osteoprotegerin increase with age in a healthy adult population. Bone 2003; 32: 681-686
    CrossrefPubMedSearch in Google Scholar
  • 20 Jono S, Ikari Y, Shioi A, Mori K, Miki T, Hara K, Nishizawa Y. Serum osteoprotegerin levels are associated with the presence and severity of coronary artery disease. Circulation 2002; 106: 1192-1194
    CrossrefPubMedSearch in Google Scholar
  • 21 Omland T, Drazner MH, Ueland T, Abedin M, Murphy SA, Aukrust P, de Lemos JA. Plasma osteoprotegerin levels in the general population: Relation to indices of left ventricular structure and function. Hypertension 2007; 49: 1392-1399
    CrossrefPubMedSearch in Google Scholar
  • 22 Ueland T, Yndestad A, Øie E, Florholmen G, Halvorsen B, Frøland SS, Simonsen S, Christensen G, Gullestad L, Aukrust P. Dysregulated osteoprotegerin/rank ligand/rank axis in clinical and experimental heart failure. Circulation 2005; 111: 2461-2468
    CrossrefPubMedSearch in Google Scholar
  • 23 Ueland T, Jemtland R, Godang K, Kjekshus J, Hognestad A, Omland T, Squire IB, Gullestad L, Bollerslev J, Dickstein K, Aukrust P. Prognostic value of osteoprotegerin in heart failure after acute myocardial infarction. J Am Coll Cardiol 2004; 44: 1970-1976
    CrossrefPubMedSearch in Google Scholar
  • 24 Noheria A, Mosley TH, Kullo IJ. Association of serum osteoprotegerin with left ventricular mass in african american adults with hypertension. Am J Hypertens 2010; 23: 767-774
    CrossrefPubMedSearch in Google Scholar
  • 25 World Medical Association . World Medical Association Declaration of Helsinki. Ethical Principles for Medical Research Involving Human Subjects. JAMA 2013; 310: 2191-2194
    CrossrefPubMedSearch in Google Scholar
  • 26 Matsuo S, Imai E, Horio M, Yasuda Y, Tomita K, Nitta K, Yamagata K, Tomino Y, Yokoyama H, Hishida A. Revised equations for estimated gfr from serum creatinine in japan. Am J Kidney Dis 2009; 53: 982-992
    CrossrefPubMedSearch in Google Scholar
  • 27 Date H, Imamura T, Ideguchi T, Kawagoe J, Sumi T, Masuyama H, Onitsuka H, Ishikawa T, Nagoshi T, Eto T. Adiponectin produced in coronary circulation regulates coronary flow reserve in nondiabetic patients with angiographically normal coronary arteries. Clin Cardiol 2006; 29: 211-214
    CrossrefPubMedSearch in Google Scholar
  • 28 Yamaguchi M, Tsuruda T, Watanabe Y, Onitsuka H, Furukawa K, Ideguchi T, Kawagoe J, Ishikawa T, Kato J, Takenaga M, Kitamura K. Reduced fractional shortening of right ventricular outflow tract is associated with adverse outcomes in patients with left ventricular dysfunction. Cardiovasc Ultrasound 2013; 11: 19
    CrossrefPubMedSearch in Google Scholar
  • 29 Devereux RB, Alonso DR, Lutas EM, Gottlieb GJ, Campo E, Sachs I, Reichek N. Echocardiographic assessment of left ventricular hypertrophy: Comparison to necropsy findings. Am J Cardiol 1986; 57: 450-458
    CrossrefPubMedSearch in Google Scholar
  • 30 Devereux RB, Wachtell K, Gerdts E, Boman K, Nieminen MS, Papademetriou V, Rokkedal J, Harris K, Aurup P, Dahlöf B. Prognostic significance of left ventricular mass change during treatment of hypertension. JAMA 2004; 292: 2350-2356
    CrossrefPubMedSearch in Google Scholar
  • 31 Sadler DB, Aurigemma GP, Williams DW, Reda DJ, Materson BJ, Gottdiener JS. Systolic function in hypertensive men with concentric remodeling. Hypertension 1997; 30: 777-781
    CrossrefPubMedSearch in Google Scholar
  • 32 Røysland R, Masson S, Omland T, Milani V, Bjerre M, Flyvbjerg A, Di Tano G, Misuraca G, Maggioni AP, Tognoni G, Tavazzi L, Latini R. Investigators G-H . Prognostic value of osteoprotegerin in chronic heart failure: The gissi-hf trial. Am Heart J 2010; 160: 286-293
    CrossrefPubMedSearch in Google Scholar
  • 33 Ueland T, Dahl CP, Kjekshus J, Hulthe J, Böhm M, Mach F, Goudev A, Lindberg M, Wikstrand J, Aukrust P, Gullestad L. Osteoprotegerin predicts progression of chronic heart failure: Results from corona. Circ Heart Fail 2011; 4: 145-152
    CrossrefPubMedSearch in Google Scholar
  • 34 Jaumdally R, Varma C, Macfadyen RJ, Lip GY. Coronary sinus blood sampling: An insight into local cardiac pathophysiology and treatment?. Eur Heart J 2007; 28: 929-940
    CrossrefPubMedSearch in Google Scholar
  • 35 Schoppet M, Preissner KT, Hofbauer LC. Rank ligand and osteoprotegerin: Paracrine regulators of bone metabolism and vascular function. Arterioscler Thromb Vasc Biol 2002; 22: 549-553
    CrossrefPubMedSearch in Google Scholar
  • 36 Moran CS, McCann M, Karan M, Norman P, Ketheesan N, Golledge J. Association of osteoprotegerin with human abdominal aortic aneurysm progression. Circulation 2005; 111: 3119-3125
    CrossrefPubMedSearch in Google Scholar
  • 37 Helske S, Kovanen PT, Lindstedt KA, Salmela K, Lommi J, Turto H, Werkkala K, Kupari M. Increased circulating concentrations and augmented myocardial extraction of osteoprotegerin in heart failure due to left ventricular pressure overload. Eur J Heart Fail 2007; 9: 357-363
    CrossrefPubMedSearch in Google Scholar
  • 38 Browner WS, Lui LY, Cummings SR. Associations of serum osteoprotegerin levels with diabetes, stroke, bone density, fractures, and mortality in elderly women. J Clin Endocrinol Metab 2001; 86: 631-637
    CrossrefPubMedSearch in Google Scholar
  • 39 Bharti AC, Takada Y, Shishodia S, Aggarwal BB. Evidence that receptor activator of nuclear factor (nf)-kappab ligand can suppress cell proliferation and induce apoptosis through activation of a nf-kappab-independent and traf6-dependent mechanism. J Biol Chem 2004; 279: 6065-6076
    CrossrefPubMedSearch in Google Scholar
  • 40 Pritzker LB, Scatena M, Giachelli CM. The role of osteoprotegerin and tumor necrosis factor-related apoptosis-inducing ligand in human microvascular endothelial cell survival. Mol Biol Cell 2004; 15: 2834-2841
    CrossrefPubMedSearch in Google Scholar
  • 41 Mangan SH, Van Campenhout A, Rush C, Golledge J. Osteoprotegerin upregulates endothelial cell adhesion molecule response to tumor necrosis factor-alpha associated with induction of angiopoietin-2. Cardiovasc Res 2007; 76: 494-505
    CrossrefPubMedSearch in Google Scholar
  • 42 Lawrie A, Waterman E, Southwood M, Evans D, Suntharalingam J, Francis S, Crossman D, Croucher P, Morrell N, Newman C. Evidence of a role for osteoprotegerin in the pathogenesis of pulmonary arterial hypertension. Am J Pathol 2008; 172: 256-264
    CrossrefPubMedSearch in Google Scholar
  • 43 Candido R, Toffoli B, Corallini F, Bernardi S, Zella D, Voltan R, Grill V, Celeghini C, Fabris B. Human full-length osteoprotegerin induces the proliferation of rodent vascular smooth muscle cells both in vitro and in vivo. J Vasc Res 2010; 47: 252-261
    CrossrefPubMedSearch in Google Scholar
  • 44 Bystrom CE, Salameh W, Reitz R, Clarke NJ. Plasma renin activity by lc-ms/ms: Development of a prototypical clinical assay reveals a subpopulation of human plasma samples with substantial peptidase activity. Clin Chem 2010; 56: 1561-1569
    CrossrefPubMedSearch in Google Scholar