Clin Res Cardiol (2022).

Matrix metalloproteinase 13 is upregulated after myocardial infarction and its depletion is beneficial for survival
H. Bräuninger1, S. Krüger1, P. M. Becher1, J. T. Neumann1, L. Bacmeister1, S. Voß1, V. Lang1, T. Zeller1, S. Lämmle2, A. El-Armouche2, P. Kirchhof1, S. Blankenberg1, D. Westermann1, D. Lindner1
1Klinik für Kardiologie, Universitäres Herz- und Gefäßzentrum Hamburg GmbH, Hamburg; 2Institut für Pharmakologie und Toxikologie, Medizinische Fakultät Carl Gustav Carus der TU Dresden, Dresden;
Cardiovascular diseases such as myocardial infarction (MI) remaining a leading cause of death in the world. Matrix metalloproteinases (MMPs) are not only essential for the cleavage of collagen but are also modifying inflammatory proteins and cytokines. Thus, MMPs are playing a substantial role in the context of inflammatory and fibrotic processes in tissue remodelling after MI.

Mmp13 the highest expressed collagenase in the murine left ventricle (LV). Previous results of our group revealed, highly elevated Mmp13 levels in the LV 5d as well as 28d post MI in mice. Therefore, the aim of this study was to characterize the role of MMP13 in MI and to evaluate its potential for treatment options. The functional homologue of Mmp13 in humans is MMP1. Single nucleotide polymorphisms (SNPs) in the promotor region of MMP1 can lead to alterations of gene expression levels. Therefore, we analysed the genotype of the BACC cohort containing approximately 2000 patients who presented with suspected myocardial infarction, to reveal associations with the development of MI and outcome after MI.

To determine the cellular origin of elevated Mmp13 in the LV after MI, Mmp13 expression in different cardiac cell types was accessed at a quiescent stage and under ischaemic conditions. Furthermore, MMP13-knockout (KO) mice were compared to wildtype (WT) littermates after induction of MI. Gene expression analysis and histological staining were performed 1, 5 and 28d post MI, to analyse fibrosis and inflammation. In addition, cardiac function of WT and MMP13-KO mice was accessed 28d post MI via hemodynamic measurements. For the human cohort study, two patient groups (non-MI and MI) were restricted out of the BACC cohort at the University Heart and Vascular Centre Hamburg. In these groups, genotypes for 3 SNPs were distinguished. Hazard ratios adjusted to age and male sex were assessed, to evaluate risk for MI and risk for death after MI in dependency of the allele.

At a quiescent stage, cardiac fibroblasts express more Mmp13 than cardiomyocytes or immune cells. After activation with ischeamic secretome of cardiomyocytes, the Mmp13 expression of macrophages (6.6-fold to control; p=0.0286) and fibroblasts (4.9-fold; p=0.0079) was significantly increased, while the Mmp13 expression of leucocytes was unaltered. Under stimulation with ischaemic secretome of fibroblasts, Mmp13 expression of macrophages (4.3-fold; p=0.0286) and leukocytes (2.3-fold; p=0.0260) was significantly elevated, while the Mmp13 expression of cardiomyocytes was again unaltered. Comparing MMP13-KO and WT mice after induction of MI, we found a striking difference in the survival rate of both groups. While the survival of WT mice was about 50%, very few KO mice died after MI (p=0.0107). Moreover, MMP13-KO-mice showed benefits in cardiac function compared to WT littermates 28d post MI. In the human cohort, risk for death was significantly altered between the genotypes in 2 of 3 investigated SNPs, indicating a role of MMP1 in the remodelling process after MI.

High levels of Mmp13 after MI originate mainly from activated macrophages and from activated fibroblasts. The KO of MMP13 protects mice from cardiac rupture after MI and KO mice showed improved cardiac function 28d post MI compared to WT controls. Analysis of SNPs of the human homologue of Mmp13 MMP1 – revealed an association of MMP1 with remodelling processes after MI.