MMP inhibition not only reduces cardiac mechanical dysfunction but also reduces endothelial damage resulting from cardiac I/R injury.

Background: Interaction of advanced glycation end products (AGEs) with their receptor (RAGE) increases expression of inflammatory mediators (tumor necrosis factor alpha [TNF-α] and soluble vascular cell adhesion molecule-1 [sVCAM-1]) and induces oxygen radicals that are implicated in atherosclerosis. Balloon-injuryinduced atherosclerosis is associated with increased expression of AGEs and RAGE. The soluble receptor for AGE (sRAGE), which acts as a decoy for RAGE ligands (AGEs), prevents atherosclerosis in this model. Hypothesis: We evaluated: 1) whether post-percutaneous coronary intervention (PCI) restenosis is associated with low pre-PCI serum sRAGE, high serum AGEs, TNF-α, and sVCAM-1, and high AGE/sRAGE ratio; 2) whether pre-PCI and post-PCI levels of these markers are similar in patients with or without restenosis; and 3) whether sRAGE and AGE/sRAGE ratio have predictive value for post-PCI restenosis. Methods: Angiography was performed in 46 patients with non-ST-segment elevation myocardial infarction for assessment of restenosis. Serum sRAGE, AGEs, TNF-α, and sVCAM-1 were measured in these patients and 20 control subjects. Results: Nineteen of the 46 patients developed post-PCI restenosis, which was associated with lower sRAGE and higher TNF-α and sVCAM-1 levels, and higher AGE/sRAGE ratio compared with patients without restenosis. Pre-PCI and post-PCI levels of these biomarkers were similar in both groups, except in patients with restenosis, in whom the post-PCI level of sRAGE was lower and TNF-α was higher than the pre-PCI levels. The sensitivity and negative predictive value of sRAGE were 100%, and were higher than those of AGE/sRAGE ratio in identifying post-PCI restenosis. Conclusions: Both low serum sRAGE levels and high AGE/sRAGE ratio have predictive value for post-PCI restenosis.

A dvanced glycation end products (AGEs) are a heterogeneous group of irreversible adducts resulting from nonenzymatic glycation and oxidation of proteins, lipids and nucleic acids (1,2). AGEs act on cell receptors for AGEs (RAGEs). There are three forms of RAGEs (2-5) -full-length, N-truncated and C-truncated soluble RAGEs (sRAGE). The interaction of full-length RAGE with AGEs leads to increased expression of adhesion molecules, including soluble vascular cell adhesion molecule-1 (sVCAM-1) and the cytokine tumor necrosis factor-alpha (TNF-α) (2,6,7); activation of nuclear factor-kappa B (6), which in turn leads to increased expression of proinflammatory genes for adhesion molecules and cytokines (2); and generation of oxygen radicals (8,9). sRAGE circulates in the plasma (4) and acts as a decoy for RAGE ligands, competing with full-length RAGE for ligand binding (10). It has a protective role by preventing the activation of full-length RAGE.Adhesion molecules, cytokines and oxygen radicals are involved in atherosclerosis, progression of lesions and lesion instability (11)(12)(13)(14). The AGEs and RAGE axis has been implicated in the pathogenesis of atherosclerosis in diabetes (15)(16)(17). sRAGE in animal models reduces atherosclerotic lesions, aortic vascular cell adhesion molecule-1 and tissue factor (18)(19)(20). The proximate cause of acute coronary syndrome (ACS) is thrombosis and the principal underlying cause is atherosclerosis. Because the combination of AGEs, RAGEs and sRAGE determines the extent of vascular injury, the measurement of these factors is appropriate for determining vascular complications. However, it is not possible to measure RAGE in humans, which is on the cell surface of the artery.It is hypothesized that non-ST elevation myocardial infarction (NSTEMI) patients have lower levels of serum sRAGE and/or higher levels of AGEs, and a higher ratio of AGEs to sRAGE (AGEs/sRAGE) than healthy subjects. Because the interaction of RAGE with AGEs results in increased expression of cytokines and adhesion molecules, and because sRAGE neutralizes AGEs, low sRAGE levels would be associated with high levels of TNF-α and sVCAM-1. Therefore, the main objectives of the present study are to determine whether levels of serum sRAGE are lower, and whether levels of serum AGEs and AGEs/ sRAGE are higher in NSTEMI patients than in healthy subjects; whether low levels of serum sRAGE, and high levels of serum AGEs and AGEs/sRAGE are associated with high levels of serum TNF-α and sVCAM-1; whether the number of diseased , activation of nuclear factor-kappa B and induction of oxidative stress -all of which have been implicated in atherosclerosis. Soluble RAGE (sRAGE) acts as a decoy for the RAGE ligand and is protective against atherosclerosis. oBJECTIvES: To determine whether levels of serum sRAGE are lower, and whether levels of serum AGEs, TNF-α and sVCAM-1 are higher in non-ST elevation myocardial infarction (NSTEMI) patients than in healthy control subjects; and whether sRAGE or the ratio of AGEs to sRAGE (AGEs...

High sensitivity C-reactive protein (hs-CRP) is synthesized mainly by hepatocytes in response to tumor necrosis factor-alpha (TNF-alpha), interleukin-1 (IL-1), and interleukin-6 (IL-6). The interaction of advanced glycation end products (AGEs) with the receptor for advanced glycation end products (RAGE) increases the expression of the cytokines TNF-alpha, IL-1, and IL-6. Soluble receptor for advanced glycation end products (sRAGE) competes with RAGE for binding with AGEs. Hence, low sRAGE levels may increase interaction of AGEs with RAGE resulting in the increased production of cytokines. It is hypothesized that serum levels of sRAGE modulate serum levels of hs-CRP. The objectives are to determine if (i) serum levels of sRAGE are lower and those of TNF-alpha and hs-CRP are higher in non-ST-segment elevation myocardial infarction (NSTEMI) patients compared to control subjects; (ii) serum levels of TNF-alpha and hs-CRP are positively correlated; and (iii) sRAGE is negatively correlated with hs-CRP and TNF-alpha. The study consisted of 36 patients with NSTEMI and 30 age-matched healthy male subjects. Serum levels of sRAGE and TNF-alpha were determined by enzyme-linked immunoassay and hs-CRP was measured using near infrared immunoassay. Serum levels of sRAGE were lower, while those of TNF-alpha and hs-CRP were higher in patients with NSTEMI compared to controls. The levels of sRAGE were negatively correlated with those of TNF-alpha and hs-CRP, while TNF-alpha was positively correlated with hs-CRP in both the control subjects and NSTEMI patients. The data suggest that sRAGE modulates the synthesis of hs-CRP through TNF-alpha.

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