Submitted on December 22, 2008
Revised on January 23, 2009
Accepted on February 5, 2009
Reversal of Cardiac Myocyte Dysfunction as a Unique Mechanism of Rescue by P2X4 Receptors in Cardiomyopathy
Jian-Bing Shen1, Robin H. Shutt2, Mariela Agosto3, Achilles J. Pappano2, and Bruce T. Liang2*
1 University of Connecticut
2 University of Connecticut Health Center
3 University of Connecticut School of Medicine
* To whom correspondence should be addressed. E-mail: bliang{at}uchc.edu.
Binary cardiac transgenic (Tg) overexpression of P2X4 receptors (P2X4R) improved 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 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 LV fractional shortening (FS) and thickness and a concomitant lesser degree of LV dilatation in both systole and diastole at 8 or 12 weeks. By 16 weeks, binary hearts showed similarly depressed FS and thinned out LV, and equal enlargement of LV as did 12-week CSQ hearts. Binary cardiac myocytes showed higher peak basal cell shortening (CS) and sarcomere shortening (SS) as well as greater basal rates of shortening and relaxation than did the CSQ myocytes at either 8 or 12 weeks. Similar data were obtained in comparing the Ca2+ transient. At 16 weeks, binary myocytes were like the 12-week old CSQ myocytes with equally depressed CS, SS, Ca2+ transient. CSQ myocytes showed significant lengthening than did wild type myocytes but had length more than that of the binary myocytes at 12 weeks of age. At 16 weeks, the binary myocyte length increased to that of the 12-week 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.
