Circulating osteogenic proteins are associated with coronary artery calcification and increase after myocardial infarction

Abstract

BackgroundCoronary artery calcification (CAC) and atherosclerotic inflammation associate with increased risk of myocardial infarction (MI). Vascular calcification is regulated by osteogenic proteins (OPs). It is unknown whether an association exists between CAC and plasma OPs and if they are affected by atherothrombotic inflammation. We tested the association of osteogenic and inflammatory proteins with CAC and assessed these biomarkers after MI.MethodsCirculating OPs (osteoprotegerin, RANKL, fetuin-A, Matrix Gla protein [MGP]) and inflammatory proteins (C-reactive protein, oxidized-LDL, tumoral necrosis factor-α, transforming growth factor [TGF]-β1) were compared between stable patients with CAC (CAC ≥ 100 AU, n = 100) and controls (CAC = 0 AU, n = 30). The association between biomarkers and CAC was tested by multivariate analysis. In patients with MI (n = 40), biomarkers were compared between acute phase and 1–2 months post-MI, using controls as a baseline.ResultsMGP and fetuin-A levels were higher within individuals with CAC. Higher levels of MGP and RANKL were associated with CAC (OR 3.12 [95% CI 1.20–8.11], p = 0.02; and OR 1.75 [95% CI 1.04–2.94] respectively, p = 0.035). After MI, C-reactive protein, OPG and oxidized-LDL levels increased in the acute phase, whereas MGP and TGF-β1 increased 1–2 months post-MI.ConclusionsHigher MGP and RANKL levels associate with CAC. These findings highlight the potential role of these proteins as modulators and markers of CAC. In addition, the post-MI increase in OPG and MGP, as well as of inflammatory proteins suggest that the regulation of these OPs is affected by atherothrombotic inflammation.

Pathophysiological and Genetic Aspects of Vascular Calcification

“…In a prospective study of 130 patients, Pessaro et al showed that elevated RANKL levels were associated with CHD (OR 1.75 (95% CI 1.04-2.94, P � 0.035) [75]. Recently, Choe et al analyzed genetic variations using SNPs representative of OPG (rs2073618), RANK (rs1805034), and RANKL (rs2073618) and investigated the association with atherosclerotic plaque instability assessed by cardiac catheterization.…”

Involvement of Vitamin K-Dependent Proteins in Vascular Calcification

“…6,[48][49][50][51] Vitamin K-Dependent Biomarkers Circulating levels of vitamin K-dependent g-carboxylated MGP and GRP are inversely correlated with vascular calcification. 52,53 Plasma-undercarboxylated MGP and GRP could be potential markers for vascular calcification risk. 9 Low levels of carboxylated and phosphorylated MGP are associated with vascular calcification.…”

“…51,58 An imbalance in the osteoprotegerin/RANKL signaling pathway favors calcification, and thus, it could be used as a marker of vascular calcification. 48,50,53 Pyrophosphate acts by direct physicochemical inhibition of calcium phosphate precipitation and prevents hydroxyapatite formation. 60,61 Circulating inorganic pyrophosphate in blood plasma is negatively associated with calcification; thus, it serves as an endogenous inhibitor of hydroxyapatite formation.…”

“…51,58 An imbalance in the osteoprotegerin/RANKL signaling pathway favors calcification, and thus, it could be used as a marker of vascular calcification. 48,50,53…”

The Relationship between Serum and Gene Expression Levels of RANK, RANKL and Osteoprotegerin Inflammatory Pathway with Unstable Angina: A Case-control Study

“…12 Some studies have confirmed the involvement of the OPG/RANKL/RANK axis in modulating the inherent and acquired immune responses elaborated in myocardial damage. These studies have shown the involvement OPG/RANKL/RANK axis through its circulatory serum 1819,20 as well as gene expression 19 levels. However, such findings have shown contradictory results yet not solved in the clinical utility of the OPG/RANKL/RANK inflammatory pathway in UA patients.…”