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

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/m(2)) 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.

Osteoprotegerin concentration and risk of cardiovascular outcomes in nine general population studies: Literature-based meta-analysis involving 26,442 participants

“…On the other hand, accumulating evidence supports the concept that sustained prominent upregulation of OPG provokes detrimental pro-fibrotic, pro-inflammatory (e.g. facilitation of monocyte chemotaxis) and paradoxically also pro-apoptotic (smooth muscle cells) and plaque destabilizing MMP-releasing effects for OPG [ 10 – 15 ]. Accordingly, under certain circumstances, OPG may also act as a risk factor for CVD.…”

Serum osteoprotegerin in prevalent hemodialysis patients: associations with mortality, atherosclerosis and cardiac function

“…OPG mRNA is widely distributed in several organs, including the heart [ 30 ]. There is evidence of its intra-cardiac production and release into the coronary circulation, and it has been hypothesized that it may be involved in the development of LVH [ 31 , 32 ]. Circulating OPG levels also reflect the severity of cardiovascular disorders, such as coronary artery disease, cardiac hypertrophy, and heart failure in the general population [ 33 ].…”

Angiotensin II Stimulation of Cardiac Hypertrophy and Functional Decompensation in Osteoprotegerin-Deficient Mice

“…27 Thus, we hypothesized that Ang II stimulation of osteoprotegerin might exert a protective mechanism for LV dilation. To clarify the pathophysiological roles of endogenous osteoprotegerin in Ang II-induced cardiac hypertrophy, we conducted experiments using mice lacking the osteoprotegerin gene.…”

“…25,26 We reported a possible association of osteoprotegerin production and RAS activation in human heart. 27 Whether the relationship between increased serum osteoprotegerin and heart disease is compensatory, causal, or merely an association is an important unanswered question. This study aimed at addressing whether endogenous RANKL/RANK/osteoprotegerin axis may contribute to the pathogenesis of cardiac hypertrophy and heart failure interacted with RAS in parallel with osteoporosis, using mice lacking the osteoprotegerin gene and overexpressing the RANKL gene.…”