Proceedings of The Physiological Society

Europhysiology 2018 (London, UK) (2018) Proc Physiol Soc 41, PCA029

Poster Communications

Matrix metalloproteinase 2 acts as repressor hypertrophic growth in ventricular cardiomyocytes of rat

G. Euler1, F. Locquet1, J. Kociszewska1, J. Heger1, P. Bencsik2,3, P. Ferdinandy2,3, R. Schulz1

1. Institute of Physiology, Justus Liebig University, Giessen, Deutschland, Germany. 2. Department of Biochemistry, University of Szeged, Szeged, Hungary. 3. Pharmahungary Group, Szeged, Hungary.

Matrix metalloproteinases (MMPs) are upregulated during the process of cardiac remodeling and were originally identified as modulators of the extracellular matrix during heart failure progression. However, intracellular functions of MMPs came in the focus of current research. They are found at nearly all intracellular locations, i.e. at the sarcomer, mitochondria, nuclei, and in the cytosol. This suggests multiple, not yet defined actions of MMPs in cardiomyocytes. Therefore, we conducted this study to determine expression levels of MMPs in isolated ventricular cardiomyocytes of rat and analysed the impact of MMPs on hypertrophic growth. Results: In ventricular cardiomyocytes from adult rats expression of MMP1, 2, 3, 9 and 14 mRNA was detected under baseline conditions. In western blots protein expression of MMP 2, 9 and 14 could be verified. Interestingly, stimulation of cardiomyocytes with hypertrophy inducing agents (10 µM PE, 1 ng/ml TGFβ1 or 100 nM AngII) decreased protein expression of MMPs. This indicates that MMP down regulation may be involved in hypertrophic growth. Indeed, inhibition of MMPs with TAP-0, MMP-inhibitor III or with ARP-100, an inhibitor specific for MMP2, enhanced hypertrophic growth, determined by an increase in the rate of protein synthesis and in cross sectional area. Also in the cardiomyogenic cell line H9c2 the MMP2-inhibitor ARP-100 provoked an increase in cross scetional area and in the rate of protein synthesis. Specific downregulation of MMP2 by siRNA in H9c2 cells as well as in adult cardiomyocytes enhanced the cross sectional area of cells within 48 h to 260 ± 129 % (n=6,) and 140 ± 10 % (n=4), respectively (each with p≤0.05 vs. untreated and scrambled siRNA controls). Hypertrophic growth effects of MMP inhibitors could be blocked by the ERK inhibitor, PD98059, and by the PI3K inhibitors, LY290042 or wortmannin, in adult cardiomyocytes. In conclusion, MMP2 acts as repressors of hypertrophic growth in cardiomyocytes via ERK and PI3K signaling. These findings define a new intracellular action of MMP2 in cardiomyocytes.

Where applicable, experiments conform with Society ethical requirements