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Am J Physiol Heart Circ Physiol 284: H960-H969, 2003. First published December 5, 2002; doi:10.1152/ajpheart.0718.2001
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Vol. 284, Issue 3, H960-H969, March 2003

Morphological and functional changes in cardiac myocytes isolated from mice overexpressing TNF-alpha

Andrzej M. Janczewski, Toshiaki Kadokami, Bonnie Lemster, Carole S. Frye, Charles F. McTiernan, and Arthur M. Feldman

Cardiovascular Institute, University of Pittsburgh Health System, Pittsburgh, Pennsylvania 15213

Transgenic (TG) TNF1.6 mice, which cardiac specifically overexpress tumor necrosis factor-alpha (TNF-alpha ), exhibit heart failure (HF) and increased mortality, which is markedly higher in young (<20 wk) males (TG-M) than females (TG-F). HF in this model may be partly caused by remodeling of the extracellular matrix and/or structure/function alterations at the single myocyte level. We studied left ventricular (LV) structure and function using echocardiography and LV myocyte morphometry, contractile function, and intracellular Ca2+ (Ca<UP><SUB>i</SUB><SUP>2+</SUP></UP>) handling using cell edge detection and fura 2 fluorescence, respectively, in 12-wk-old TG-M and TG-F mice and their wild-type (WT) littermates. TG-F mice showed LV hypertrophy without dilatation and only a small reduction of basal fractional shortening (FS) and response to isoproterenol (Iso). TG-M mice showed a large LV dilatation, higher mRNA levels of beta -myosin heavy chain and atrial natriuretic factor versus TG-F mice, reduced FS relative to both WT and TG-F mice, and minimal response to Iso. TG-F and TG-M myocytes were similarly elongated (by approx 20%). The amplitude of Ca<UP><SUB>i</SUB><SUP>2+</SUP></UP> transients and contractions and the response to Iso were comparable in WT and TG-F myocytes, whereas the time to 50% decline (TD50%) of the Ca<UP><SUB>i</SUB><SUP>2+</SUP></UP> transient, an index of the rate of sarcoplasmic reticulum Ca2+ uptake, was prolonged in TG-F myocytes. In TG-M myocytes, the amplitudes of Ca<UP><SUB>i</SUB><SUP>2+</SUP></UP> transients and contractions were reduced, TD50% of the Ca<UP><SUB>i</SUB><SUP>2+</SUP></UP> transient was prolonged, and the inotropic effect of Iso on Ca<UP><SUB>i</SUB><SUP>2+</SUP></UP> transients was reduced approximately twofold versus WT myocytes. Protein expression of sarco(endo)plasmic reticulum Ca2+-ATPase 2 and phospholamban was unaltered in TG versus WT hearts, suggesting functional origins of impaired Ca2+ handling in the former. These results indicate that cardiac-specific overexpression of TNF-alpha induces myocyte hypertrophy and gender-dependent alterations in Ca<UP><SUB>i</SUB><SUP>2+</SUP></UP> handling and contractile function, which may at least partly account for changes in LV geometry and in vivo cardiac function in this model.

transgenic mice; gender; heart failure; calcium; echocardiography


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