1. Placental growth factor regulates cardiac inflammation through the tissue inhibitor of metalloproteinases-3/tumor necrosis factor-α-converting enzyme axis: crucial role for adaptive cardiac remodeling during cardiac pressure overload.
- Author
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Carnevale D, Cifelli G, Mascio G, Madonna M, Sbroggiò M, Perrino C, Persico MG, Frati G, and Lembo G
- Subjects
- ADAM Proteins physiology, ADAM17 Protein, Adaptation, Physiological drug effects, Adaptation, Physiological physiology, Animals, Aorta physiopathology, Cardiomyopathy, Dilated drug therapy, Cardiomyopathy, Dilated physiopathology, Coronary Vessels physiopathology, Disease Models, Animal, Hypertrophy, Left Ventricular drug therapy, Male, Matrix Metalloproteinase 3 metabolism, Mice, Mice, Inbred C57BL, Mice, Knockout, Myocarditis drug therapy, Myocytes, Cardiac drug effects, Myocytes, Cardiac physiology, Placenta Growth Factor, Pregnancy Proteins genetics, Pregnancy Proteins pharmacology, Tissue Inhibitor of Metalloproteinase-3 physiology, Up-Regulation drug effects, Up-Regulation physiology, Ventricular Pressure drug effects, Ventricular Pressure physiology, Ventricular Remodeling drug effects, ADAM Proteins metabolism, Hypertrophy, Left Ventricular physiopathology, Myocarditis physiopathology, Pregnancy Proteins physiology, Tissue Inhibitor of Metalloproteinase-3 metabolism, Ventricular Remodeling physiology
- Abstract
Background: Heart failure is one of the leading causes of mortality and is primarily the final stage of several overload cardiomyopathies, preceded by an early adaptive hypertrophic response and characterized by coordinated cardiomyocyte growth, angiogenesis, and inflammation. Therefore, growth factors and cytokines have to be critically regulated during cardiac response to transverse aortic constriction. Interestingly, the dual properties of placental growth factor as an angiogenic factor and cytokine make it a candidate to participate in cardiac remodeling in response to hemodynamic overload., Methods and Results: After transverse aortic constriction, placental growth factor knockout mice displayed a dysregulation of cardiac remodeling, negatively affecting muscle growth. Molecular insights underscored that this effect was ascribable mainly to a failure in the establishment of adequate inflammatory response owing to an impaired activity of tumor necrosis factor-α-converting enzyme. Interestingly, after transverse aortic constriction, placental growth factor knockout mice had strongly increased levels of tissue inhibitor of metalloproteinases-3, the main natural TACE inhibitor, thus indicating an unbalance of the tissue inhibitor of metalloproteinases-3/tumor necrosis factor-α-converting enzyme axis. Strikingly, when we used an in vivo RNA interference approach to reduce tissue inhibitor of metalloproteinases-3 levels in placental growth factor knockout mice during transverse aortic constriction, we obtained a complete phenotype rescue of early dilated cardiomyopathy., Conclusions: Our results demonstrate that placental growth factor finely tunes a balanced regulation of the tissue inhibitor of metalloproteinases-3/tumor necrosis factor-α-converting enzyme axis and the consequent TNF-α activation in response to transverse aortic constriction, thus allowing the establishment of an inflammatory response necessary for adaptive cardiac remodeling.
- Published
- 2011
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