Blockade of hypoxia-reoxygenation-mediated collagen type I expression and MMP activity by overexpression of TGF-beta1 delivered by AAV in mouse cardiomyocytes.
Transforming growth factor (TGF)-beta(1) is one of the most pleiotropic and multifunctional peptides known. While the cardioprotective effect of TGF-beta(1) during ischemia is well known, the specific role of TGF-beta(1) in altering the cardiac remodeling process remains unclear. This study was designed to examine the regulation of hypoxia-reoxygenation-mediated collagen type I expression and activity of matrix metalloproteinases (MMPs) by overexpression of TGF-beta(1) in cultured HL-1 mouse cardiomyocytes. TGF-beta(1) was overexpressed in cardiomyocytes by transfection with adeno-associated virus (AAV)/TGF-beta(1)(Latent) or with AAV/TGF-beta(1)(ACT) (active TGF-beta(1)). Twenty-four hours of hypoxia followed by 3 h of reoxygenation (H-R) markedly enhanced (pro)collagen type I expression and activity of MMPs concomitant with an increase in reactive oxygen species (ROS) release and LOX-1 expression. Overexpression of TGF-beta(1) reduced these alterations induced by H-R. TGF-beta(1) overexpression also blocked H-R-mediated p38 and p44/42 MAPK activation. Transfection with AAV/TGF-beta(1)(ACT) was superior to that with AAV/TGF-beta(1)(Latent). These data for the first time demonstrate that H-R induces signals for cardiac remodeling in cardiomyocytes and TGF-beta(1) can modulate, possibly via antioxidant mechanism, these signals. These findings contribute to further understanding of the role of TGF-beta(1) in the cardiac remodeling process.
Hu
Chang-Ping
CP
Division of Cardiovascular Medicine, Gene Therapy Program, Department of Internal Medicine, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
Dandapat
Abhijit
A
Liu
Yong
Y
Hermonat
Paul L
PL
Mehta
Jawahar L
JL
D000818:Animals; D002478:Cells, Cultured; D024042:Collagen Type I / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000229:Dependovirus / Q000235:genetics; D000860:Hypoxia / Q000378:metabolism*; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D015428:Myocardial Reperfusion Injury / Q000378:metabolism* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D017382:Reactive Oxygen Species / Q000378:metabolism; D051127:Scavenger Receptors, Class E / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D024042:Collagen Type I; D061965:Matrix Metalloproteinase Inhibitors; C495138:Olr1 protein, mouse; D017382:Reactive Oxygen Species; D051127:Scavenger Receptors, Class E; D053773:Transforming Growth Factor beta1; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases; D020782:Matrix Metalloproteinases