Relation of matrix metalloproteinase-9/tissue inhibitor of metalloproteinase-1 ratio in peripheral circulating CD14+ monocytes to progression of coronary artery disease.

Atherosclerosis is an inflammatory disease in which systemic inflammation correlates with disease activity. Matrix metalloproteinases (MMPs) contribute to collagen breakdown in atherosclerotic plaques. In the present study, we investigated whether the ratio of MMP-9 and its endogenous inhibitor, tissue inhibitor of metalloproteinase (TIMP)-1, in circulating monocytes correlates with the clinical stages of coronary artery disease. We studied 18 patients with stable angina pectoris (SAP), 14 patients with unstable angina pectoris and non-ST-segment elevation myocardial infarction (UAP/NSTEMI), 14 patients with ST-elevation myocardial infarction (STEMI), and 16 healthy controls. The protein and mRNA levels of MMP-9 and TIMP-1 in CD14+ monocytes were analyzed using real-time polymerase chain reaction and enzyme-linked immunosorbent assay. The activity of serum MMP-9 was assessed using zymography. Compared to the controls (0.07 +/- 0.01 relative units) and patients with SAP (0.25 +/- 0.1 relative units, p = NS), the monocytic MMP-9 mRNA levels were increased in those with UAP/NSTEMI (0.9 +/- 0.3 relative units, p <0.05 vs SAP) or STEMI (1.6 +/- 0.4 relative units, p <0.05 vs UAP/NSTEMI). In contrast, the protein and mRNA expression of monocytic TIMP-1 levels was 4.5- to 4.7-fold lower in patients with STEMI than in the controls or those with SAP or UAP/NSTEMI (p <0.05). Changes in monocytic expression of MMP-9 and TIMP-1 tracked with the serum levels of MMP-9 and TIMP-1. The activity of serum MMP-9 correlated with the individual MMP-9/TIMP-1 ratio in the peripheral circulating monocytes (r(2) = 0.82, p <0.02). In conclusion, the progression of coronary artery disease was mirrored by an increasing MMP-9/TIMP-1 ratio in the peripheral circulating CD14+ monocytes and serum, respectively. Circulating monocytes displayed the same pattern of imbalance in the expression of MMP-9 and TIMP-1 as previously reported for monocyte-derived macrophages within atherosclerotic plaques, supporting the notion of atherosclerosis as a systemic inflammatory disease.