Serum Matrix Metalloproteinase-8 Concentrations Are Associated With Cardiovascular Outcome in Men

Abstract

Objective-In culture studies matrix metalloproteinase (MMP)-8 thins the protecting fibrous cap of the atherosclerotic plaque thereby increasing its vulnerability. Results on the association of serum MMP-8 concentrations and cardiovascular diseases (CVD) are, however, scarce and contradictory. Methods and Results-We analyzed the association between CVD or subclinical atherosclerosis and serum MMP-8 and tissue inhibitor of metalloproteinase-1 (TIMP-1) concentrations of 1018 men with the follow-up time of 10 years. MMP-8 concentrations or MMP-8/TIMP-1 ratios were higher in men with prevalent CVD or subclinical atherosclerosis at baseline than those without. In men free of CVD at baseline, MMP-8 concentrations associated with acute myocardial infarction, death from coronary heart disease (CHD), CVD, or from any cause with relative risks (RR) (95% Key Words: inflammation Ⅲ atherosclerosis Ⅲ cardiovascular diseases Ⅲ myocardial infarction Ⅲ metalloproteinases M atrix metalloproteinases (MMPs) are involved in the breakdown of the extracellular matrix occurring during, eg, tissue repair but also in pathogenic conditions such as rheumatoid arthritis, periodontitis, and atherosclerosis. 1-3 Collagenase MMP-8 (neutrophil collagenase or collagenase-2) is capable to initiate the degradation of the fibrillar collagens such as collagen type I, which is the major load-bearing molecule of the fibrous cap in atherosclerotic lesions. Several other MMPs, such as MMP-2 and MMP-9, can further degrade the cleaved collagen fragments. 3 Additionally, MMP-8 can process various noncollagenous molecules thereby participating also in immune responses. 4 Tissue inhibitors of metalloproteinases (TIMPs) are specific MMP inhibitors. TIMPs also exert a wide range of additional biological functions such as effects on cell growth and viability. 5 In humans, plasma TIMP-1 concentration is increased in acute coronary syndrome, and serum TIMP-1 associates with the presence of carotid lesions. 6,7 Expression of TIMP-1 is slightly upregulated in abdominal aortic aneurysm. 8 In cell culture studies, MMP-8 has been implicated in atherosclerotic plaque destabilization through its capacity to thin the protecting fibrous cap, thus rendering it more vulnerable to rupture. 9 In human atherosclerotic plaque samples, MMP-8 protein and mRNA colocalize with macrophages. 10 In addition, abdominal aorta aneurysm contains significantly higher MMP-8 concentrations than normal aortic tissue. 11 Increased plaque MMP-8 activity has been observed in asymptomatic patients with plaque progression. 12 Also plaques prone to rupture express more immunoreactive MMP-8 compared with lesions with more stable morphology. 9 Hitherto, however, only a few studies have investigated the associations of serum MMP-8 concentrations with cardiovascular diseases (CVD). Results from 2 case-control studies with small populations suggest that serum MMP-8 concentrations of patients with heart failure and cerebral ischemia are decreased. 13,14 In 2 most recent larger studies, plasma MMP-8 concen...

The balance of serum matrix metalloproteinase-8 and its tissue inhibitor in acute coronary syndrome and its recurrence

“…In the ROC analyses, MMP-8 and MMP-8/TIMP-1 were clearly able to distinguish the UAP or the AMI patients from the healthy controls despite the strongest confounding factors, smoking and CRP [16]. After the acute phase, the decrease of MMP-8 and TIMP-1 was most notable in the UAP patients, who faced another cardiovascular event in the six year follow-up.…”

“…In publications earlier, high circulating MMP-8 levels have been related to the presence and severity of coronary artery disease [25], carotid artery plaque progression [13], and subclinical atherosclerosis [16], whereas the concentrations have been reported to be decreased in patients with heart failure [26] or cerebral ischemia [27]. In our previous prospective study with a follow-up time of 10 years, serum MMP-8 concentrations associated with AMI as well as death from coronary heart disease, CVD, or from any cause in men free of CVD at baseline.…”

“…Serum MMP-8 concentrations were determined by a time-resolved immunofluorometric assay (IFMA) [16]. The inter-assay coefficient of variation (CV) was 7.3% (n=28) and detection limit for the assay 0.08 ng/ml.…”

Evaluation of plasmatic MMP-8, MMP-9, TIMP-1 and MPO levels in obese and lean women

“…In addition, clinical studies have shown that alteration in the expression or activity of MMPs and/or TIMPs is an important mechanism underlying the pathophysiology of some cardiovascular diseases [5][6][7][8] and contributes to ventricular dysfunction [6] and atherosclerotic lesions [9]. Studies evaluating circulating levels of MMP-8 (neutrophil collagenase) in obese women without associated comorbidities have not yet been evaluated, although some studies have shown higher MMP-8 levels in subjects presenting with cardiovascular disorders [12][13][14][15].…”

The role of matrix metalloproteinases and polymorphisms of their genes in the development of coronary heart disease

“…У дослідженнях in vitro [38] було пока-зано, що ендотеліальні клітини, макрофаги, ГМК у ділянці атеросклеротичних уражень експресують ММР-8 після стимулювання прозапальними цитокінами: IL-1β, ФНП-α, CD40, її експресія зростає в разі швидкого прогресування ушкодження. Сироватковий вміст ММР-8 асоційований із наявністю атеросклерозу [39,40], розвитком нес-табільності АСБ [41,42], ГКС [43] та із несприятливим серцево-судинним прогнозом [44]. Виявлено, що в ММР-8-нокаутованих мишей знижені вміст ангіотензину-ІІ, кон-центрація та експресія молекул адгезії судинного ендотелію 1 типу, кількість лейкоцитів у стінці судин, і нижчий рівень артеріального тиску [45].…”