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This Article Full Text Full Text (PDF) All Versions of this Article: 296/4/H1089    most recent 01316.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Shen, J.-B. Articles by Liang, B. T. Search for Related Content PubMed PubMed Citation Articles by Shen, J.-B. Articles by Liang, B. T.

Reversal of cardiac myocyte dysfunction as a unique mechanism of rescue by P2X₄ receptors in cardiomyopathy

Pat and Jim Calhoun Cardiovascular Center, University of Connecticut School of Medicine, Farmington, Connecticut

Submitted 22 December 2008 ; accepted in final form 5 February 2009

Binary cardiac transgenic (Tg) overexpression of P2X₄ receptors (P2X₄R) improved the survival of the cardiomyopathic calsequestrin (CSQ) mice. Here we studied the mechanism of rescue using binary P2X₄R/CSQ Tg and CSQ Tg mice as models. Cellular and intact heart properties were determined by simultaneous sarcomere shortening (SS) and Ca²⁺ transients in vitro and echocardiography in vivo. Similar to a delay in death, binary mice exhibited a slowed heart failure progression with a greater left ventricular (LV) fractional shortening (FS) and thickness and a concomitant lesser degree of LV dilatation in both systole and diastole at 8 or 12 wk. By 16 wk, binary hearts showed similarly depressed FS and thinned out LV and equal enlargement of LV as did 12-wk-old CSQ hearts. Binary cardiac myocytes showed higher peak basal cell shortening (CS) and SS as well as greater basal rates of shortening and relaxation than did the CSQ myocytes at either 8 or 12 wk. Similar data were obtained in comparing the Ca²⁺ transient. At 16 wk, binary myocytes were like the 12-wk-old CSQ myocytes with equally depressed CS, SS, and Ca²⁺ transient. CSQ myocytes were longer than myocytes from wild-type and binary mice at 12 wk of age. At 16 wk, the binary myocyte length increased to that of the 12-wk-old CSQ myocyte, parallel to LV dilatation. The data suggest a unique mechanism, which involves a reversal of cardiac myocyte dysfunction and a delay in heart failure progression. It represents an example of targeting the abnormal failing myocyte in treating heart failure.

contractility; heart failure; hypertrophy