TIMP-1 expression in coronary thrombi associate with myocardial injury in ST-elevation myocardial infarction patients

Abstract

Background Matrix metalloproteinases (MMPs) and their inhibitors (TIMPs) are considered important both in atherosclerosis and remodeling after acute myocardial infarction (AMI). We aimed to study genetic expression and presence of MMP-2, MMP-9, TIMP-1, TIMP-2 and the extracellular MMP-inducer (EMMPRIN) in coronary thrombi. Circulating levels and genetic expression in circulating leukocytes were also assessed, and relations to degree of myocardial injury measured by troponin T and time from symptom to PCI were explored. Expression of cell markers were also analyzed, indicating relations to cell types.Methods Intracoronary thrombi were aspirated from 33 patients with ST-elevation myocardial infarction (STEMI). Blood samples with Pax-gene tubes were drawn at end of PCI and the next day. RNA was isolated from thrombi and leukocytes, and genes were relatively quantified by RT-PCR. Each thrombus was preserved for histology and immunohistochemistry analyzes. ResultsGenes coding for the five markers were present in 84-100% of thrombi and immunohistochemically stained in 96-100%. Expression of TIMP-1 in thrombi and in leukocytes correlated significantly to peak troponin T (r = 0.393 P = 0.026, r = 0.469 P = 0.006, respectively). No significant correlations between genes expressed in thrombi and time from symptom to PCI were observed. TIMP-1 was connected mainly to monocytes/ macrophages in the thrombi.Conclusion MMP-2, MMP-9, TIMP-1, TIMP-2 and EMMPRIN were highly expressed in human coronary thrombi. The correlation between troponin T and the expression of TIMP-1 both in thrombi and in leukocytes at time of PCI indicates that TIMP-1 plays a role in myocardial damage early post-MI.

TIMP-1 in the prognosis of patients who underwent coronary artery bypass surgery: a 12-year follow-up study

“…Opstad et al demonstrated that the quartiles of serum TIMP-1 levels after myocardial infarction in 243 patients contributed to cardiac remodeling, including a large infarct size, high NT-proBNP levels, and poor LVEF obtained at 3 months (36) Nordeng et al reported that TIMP-1 was highly expressed in intracoronary thrombi from 33 patients with ST-segment elevation myocardial infarction, mainly connected to monocytes and macrophages. Furthermore, both TIMP-1 in thrombi and leukocytes significantly correlated with peak troponin T levels, indicating its important role in early myocardial damage, remodeling, and inflammatory processes (37). Although the present study also showed that both hs-CRP and NT-proBNP were independently associated with TIMP-1, we further propose that NT-proBNP outweighs hs-CRP as a major determinant of TIMP-1.…”

Targeted and Infarcted Microenvironment‐Responsive Peptide Therapeutics to Reverse Cardiac Remodeling

“…MMP2 was three‐fold higher in the heart 24 h after MI compared to the sham group (Figure 3E,F), which was consistent with previous reports. [ 11,12 ] The result indicated that the MMP2 was abundant in the infarcted microenvironment after myocardial infarction, which may be conducive to the release of TNT.…”

“…We intravenously injected TNT to mice after AMI to reduce surgical trauma and TNT targeted the infarcted myocardium due to TA's strong affinity for cardiac ECM. The MMP2 level increased significantly 1 h after AMI [ 11 ] and TNT showed stimulated release of NPY in the presence of MMP2. The degradation of TIMP induced the influx of low pH and high ionic strength into the nanostructure in the myocardial infarction microenvironment and broke the hydrogen bonds and hydrophobic interactions between the TA and peptides.…”

“…Pro‐Leu‐Gly‐Leu‐Ala‐Gly (PLGLAG) (TIMP) peptide was a competitive substrate of MMP2, which can respond to MMP2. [ 11 ]…”

Combining WGCNA and machine learning to identify mechanisms and biomarkers of ischemic heart failure development after acute myocardial infarction

“…Because of this, the compensatory secretion of TIMP2 after AMI also makes it valuable for detection. Studies have shown that both MMP2 and TIMP2 are highly expressed in coronary artery thrombus [ 47 ]. In conclusion, MMPs increase after myocardial infarction, leading to degradation of extracellular matrix in the infarct area and LV remodeling [ 48 ].…”