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)

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.

Supporting Information

 
  • References

  • 1 Najjar SS, Scuteri A, Lakatta EG. Arterial aging: Is it an immutable cardiovascular risk factor?. Hypertension 2005; 46: 454-462
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 25 World Medical Association . World Medical Association Declaration of Helsinki. Ethical Principles for Medical Research Involving Human Subjects. JAMA 2013; 310: 2191-2194
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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