Increased cardiac mRNA expression of matrix metalloproteinase-1 (MMP–1) and its inhibitor (TIMP–1) in DCM patients

Abstract

Left ventricular dilation and myocardial remodeling are hallmarks of dilated cardiomyopathy (DCM). It is assumed that left ventricular dilation is caused by the disintegration of the collagenous network by increased collagenolytic activity of matrix metalloproteinases (MMPs) and their adequate tissue inhibitors (TIMPs). In this study the myocardial MMP-1 and TIMP-1 mRNA expressions were investigated by using real-time quantitative PCR analysis from right septal endomyocardial biopsies of patients with dilated cardiomyopathy (n = 46) and control subjects (n = 11). The volume density (Vv%) of collagen was measured morphometrically. Classification was done according to LV diameters [left ventricular enddiastolic diameter (LVEDD, cm) calculated to body surface area (BSA, m(2))] into three DCM groups: group I (LVEDD-BSA > 2.7-3.0 cm/m(2)), group II ( > 3.0-3.6 cm/m(2)), group III ( > 3.6 cm/m(2)), controls (< 2.7 cm/m(2)). Compared with controls, the MMP-1 expression in patients with DCM was significantly increased (119.2 +/- 45.2 vs. 1.3 +/- 0.4; p < 0.001) as was TIMP-1 expression (9.6 +/- 1.2 vs. 1.3 +/- 0.4; p < 0.01). Moreover the MMP-1 and TIMP-1 expression varied according to LV diameter: group I (MMP-1: 8.7 +/- 3.5; p = 0.33; TIMP- 1: 4.5 +/- 1.2; p < 0.01); group II (MMP-1: 211.4 +/- 86.0; p < 0.001; TIMP-1: 12.5 +/- 1.9 ; p < 0.001); group III (MMP-1: 38.8 +/- 22.6; p < 0.01; TIMP-1: 8.1 +/- 1.7; p < 0.001). Compared with controls, the collagen level in DCMPt. was significantly increased: 5.0 +/- 0.6 vol% vs 1.2 +/- 0.2 vol% p < 0.001 and correlates with LV diameter. This study reveals that the overexpression of MMP-1, which is associated with an increased ratio of MMP-1/TIMP-1 in DCM, indicates an activated collagenolytic system while replacement fibrosis is accumulating. The MMP-1 overexpression is mainly found in moderately dilated DCM hearts (group II) indicating the dynamic process of LV dilation and the importance of collagenases in the early phase of LV remodeling.

Alteration of Matrix Metalloproteinases in Selective Left Ventricular Adriamycin-Induced Cardiomyopathy in the Pig

“…Felkin et al 25 Published reports on TIMP levels in DCM diverge. Decreasing 26,27 as well as increasing 14,23 levels are reported, yet again, the earlier studies tended to look at end-stage disease, whereas the latter observed earlier stages. Furthermore, mRNA levels in our study diverged to a high degree among the pigs.…”

Cardiomyocyte Specific Ablation of p53 Is Not Sufficient to Block Doxorubicin Induced Cardiac Fibrosis and Associated Cytoskeletal Changes

“…Further, upregulation of different matrix metalloproteases (MMPs 1, 2 and 9) has been reported in both short and long term settings of Dox treatment in animal and cell culture models [7], [59]–[61]. In the absence of sufficient quantities of tissue inhibitors of metalloproteases (TIMPs), activated MMPs can digest collagen matrix and ECM and trigger reparative fibrosis in Dox induced or dilated cardiomyopathy [59], [61], [62]. Although we have not measured MMP levels in our study, differences in the time course of MMP activation may also account for the early onset of fibrosis observed in our study compared to the absence of fibrosis in the acute setting of an earlier study [58].…”

Cardiac fibroblasts, fibrosis and extracellular matrix remodeling in heart disease

“…In patients with end-stage dilated cardiomyopathy, analysis of LV myocardial tissue showed decreased MMP1, increased MMP3, MMP9, TIMP1 and TIMP2, and no changes in MMP2 levels [106]. Picard and colleagues reported increased MMP1 and TIMP1 mRNA levels in right septal endomyocardial biopsies from patients with dilated cardiomyopathy that did not correlate with LV diameter, whereas collagen volume density correlated well with LV diameter in these patients [107]. Hypertensive patients with cardiac hypertrophy have been reported to have reduced plasma levels of MMP1 [97], MMP2 and MMP9 [108], while elevated plasma TIMP1 levels have been reported in hypertensive patients [97] that correlated with diastolic dysfunction and LV fibrosis [98].…”