(Higher Education Institutional Excellence Programme of the Ministry of Human Capacities
of Hungary, within the framework of the Therapeutic Development thematic programme
of the Semmelweis University)
Subjects:
Basic medicine
Pharmacology and pharmacy
Hypertension
Cardiovascular diseases
Matrix metalloproteinases (MMPs) are identified as modulators of the extracellular
matrix in heart failure progression. However, evidence for intracellular effects of
MMPs is emerging. Pro- and anti-hypertrophic cardiac effects are described. This may
be due to the various sources of different MMPs in the heart tissue. Therefore, the
aim of the present study was to determine the role of MMPs in hypertrophic growth
of isolated rat ventricular cardiac myocytes.Cardiomyocytes were isolated form ventricular
tissues of the rat hearts by collagenase perfusion. RT-qPCR, western blots, and zymography
were used for expression and MMP activity analysis. Cross-sectional area and the rate
of protein synthesis were determined as parameters for hypertrophic growth.MMP-1,
MMP-2, MMP-3, MMP-9 and MMP-14 mRNAs were detected in cardiomyocytes, and protein
expression of MMP-2, MMP-9, and MMP-14 was identified. Hypertrophic stimulation of
cardiomyocytes did not enhance, but interestingly decreased expression of MMPs, indicating
that downregulation of MMPs may promote hypertrophic growth. Indeed, the nonselective
MMP inhibitors TAPI-0 or TIMP2 and the MMP-2-selective ARP-100 enhanced hypertrophic
growth. Furthermore, TAPI-0 increased phosphorylation and thus activation of extracellular
signaling kinase (ERK) and Akt (protein kinase B), as well as inhibition of glycogen
synthase 3β (GSK3β). Abrogation of MEK/ERK- or phosphatidylinositol-3-kinase(PI3K)/Akt/GSK3β-signaling
with PD98059 or LY290042, respectively, inhibited hypertrophic growth under TAPI-0.MMPs'
inhibition promotes hypertrophic growth in cardiomyocytes in vitro. Therefore, MMPs
in the healthy heart may be important players to repress cardiac hypertrophy.
