Early induction of matrix metalloproteinase-9 transduces signaling in human heart end stage failure
Open accessAbstract
Extracellular matrix (ECM) turnover is regulated by matrix metalloproteinases (MMPs) and plays an important role in cardiac remodeling. Previous studies from our lab demonstrated an increase in gelatinolytic-MMP-2 and -9 activities in endocardial tissue from ischemic cardiomyopathic (ICM) and idiopathic dilated cardiomyopathic (DCM) hearts. The signaling mechanism responsible for the left ventricular (LV) remodeling, however, is unclear. Administration of cardiac specific inhibitor of metalloproteinase (CIMP) prevented the activation of MMP-2 and -9 in ailing to failing myocardium. Activation of MMP-2 and -9 leads to induction of proteinase activated receptor-1 (PAR-1). We hypothesize that the early induction of MMP-9 is a key regulator for modulating intracellular signaling through activation of PAR and various downstream events which are implicated in development of cardiac fibrosis in an extracellular receptor mediated kinase-1 (ERK-1) and focal adhesion kinase (FAK) dependent manner. To test this hypothesis, explanted human heart tissues from ICM and DCM patients were obtained at the time of orthotopic cardiac transplants. Quantitative analysis of MMP-2 and -9 gelatinolytic activities was made by real-time quantitative zymography. Gel phosphorylation staining for PAR-1 showed a significant increase in ICM hearts. Western blot and RT-PCR analysis and in-situ labeling, showed significant increased expression of PAR-1, ERK-1and FAK in ICM and DCM. These observations suggest that the enhanced expression and potentially increased activity of LV myocardial MMP-9 triggers the signal cascade instigating cardiac remodeling. This early mechanism for the initiation of LV remodeling appears to have a role in end-stage human heart failure.
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Elevated matrix metalloproteinase (MMP)-9 activity in the left ventricle of the human heart appears to be an early trigger of pathological remodeling leading to end-stage human heart failure.
“Although relatively little is known to date, Tyagi’s group (243) has suggested that elevated matrix metalloproteinase (MMP)-9 activity in the left ventricle of the human heart appears to be an early trigger of pathological remodeling leading to end-stage human heart failure.”
From Cardiac remodeling in obesity (2008) · cites this paper as [243]
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Wu, Y., Xia, Y., Li, P., Qu, H., Liu, Y., Yang, Y., Lin, J., Zheng, M., Tian, L., Wu, Z., et al. (2020) · Figshare · doi:10.6084/m9.figshare.12177489
Wu, Y., Xia, Y., Li, P., Qu, H., Liu, Y., Yang, Y., Lin, J., Zheng, M., Tian, L., Wu, Z., et al. (2020) · Figshare · doi:10.6084/m9.figshare.12177483
Cardiac Gαs and Gαi Modulate Sympathetic Versus Parasympathetic Mechanisms in Hyperhomocysteinemia
Vacek, T. P., Moshal, K. S., Metreveli, N. S., Tyagi, N., Sen, U., Rosenberger, D., & Tyagi, S. C. (2008) · Springer eBooks · doi:10.1007/978-0-387-09552-3_3
Self-citation
- Authors
- Moshal, K. S., Tyagi, N., Moss, V., Henderson, B., Steed, M., Ovechkin, A., Aru, G. M., & Tyagi, S. C.
- Affiliations
- University of Louisville (US)
- University of Mississippi Medical Center (US)
- Corresponding author
- Tyagi, Suresh C.
- Venue
- Journal of Cellular and Molecular Medicine
- Publisher
- Wiley
- Published
- 2005-07
- Volume
- 9
- Issue
- 3
- Pages
- 704-713
- ISSN
- 1582-1838 (ISSN-L)
- 1582-4934
- PMC
- PMC6741634
- OpenAlex
- W2055714965
- Cited by
- 61
- References
- 35
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 1 · 2023: 1 · 2022: 1 · 2020: 5 · 2019: 1 · 2017: 5 · 2016: 3 · 2015: 4 · 2014: 6 · 2013: 4 · 2012: 1
- FWCI
- 3.19
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Cellular and Molecular Medicine (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Heart, Lung, and Blood Institute (R01HL071010, HL 71010, R01HL074185, HL 74185)
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac Fibrosis and Remodeling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Protease and Inhibitor Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Signaling Pathways in Disease
- Keywords
- MMP-9, MMP-2, protease-activated receptor 1, cardiac remodeling, heart failure, ischemic cardiomyopathy, dilated cardiomyopathy, extracellular matrix turnover, ERK1, focal adhesion kinase, myocardial fibrosis, orthotopic heart transplantation
- MeSH terms
- Heart Failure, Humans, Myocardium, Phosphoproteins, Signal Transduction, Heart Transplantation, Ventricular Function, Left, In Situ Hybridization, Reverse Transcriptase Polymerase Chain Reaction, Matrix Metalloproteinase 9
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