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      Hemodynamic regulation of tumor necrosis factor-alpha gene and protein expression in adult feline myocardium.

      Circulation Research

      physiology, Animals, Cats, Female, Gene Expression Regulation, Heart, Hemodynamics, In Vitro Techniques, Male, RNA, Messenger, analysis, Tumor Necrosis Factor-alpha

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          Tumor necrosis factor-alpha (TNF-alpha) mRNA and protein biosynthesis were examined in adult feline myocardium in the presence and absence of superimposed hemodynamic pressure overloading. A brief period of hemodynamic pressure overloading ex vivo resulted in de novo TNF-alpha mRNA expression within 30 minutes and de novo TNF-alpha protein production within 60 minutes; neither TNF-alpha mRNA nor protein was detected in hearts perfused at normal perfusion pressures. Moreover, TNF-alpha mRNA and protein biosynthesis were observed in myocyte and nonmyocyte cell types in the pressure-overloaded hearts. To determine whether a simple passive stretch of the myocardium was a sufficient stimulus for TNF-alpha biosynthesis, we examined TNF-alpha mRNA expression in stretched and unstretched papillary muscles. This study showed that myocardial stretch was a sufficient stimulus for the induction of TNF-alpha mRNA biosynthesis. The functional significance of the intramyocardial production of TNF-alpha was determined by examining cell motion in isolated contracting cardiac myocytes treated with superfusates from pressure-overloaded and control hearts. These studies showed that cell motion was depressed in myocytes treated with superfusates from the pressure-overloaded hearts but was normal with the superfusates from the control hearts. Finally, hemodynamic pressure overloading in vivo under physiological conditions was also shown to result in de novo intramyocardial TNF-alpha mRNA biosynthesis. In conclusion, this study constitutes the initial demonstration that the adult mammalian myocardium elaborates biologically active TNF-alpha, both ex vivo and in vivo, in response to hemodynamic pressure overloading.

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