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1 Medicine, Boston University Medical Center, Boston, MA, USA
* To whom correspondence should be addressed. E-mail: douglas.sawyer{at}bmc.org.
The purpose of this study is to test the hypothesis that mechanical and electrical activity in adult rat ventricular myocytes (ARVM) alters responses to pro-apoptotic and pro-survival ligands. The effects of electrical stimulation on myocytes survival, stress signaling, response to 
-adrenergic receptor (-AR)stimulated apoptosis, and neuregulin-1(NRG) were examined. Electrical stimulation (6.6 V/cm, 0, 2, and 5 Hz, 2 msec duration, alternating polarity) of ARVM resulted in more than 70% capture. ARVM paced for 48 hours showed higher mitochondrial uptake of MTT (p < 0.05, 0Hz vs. 2 and 5 Hz). While cell viability (Trypan blue exclusion, CPK release) did not differ among 3 frequencies, the % TUNEL positive cells were decreased at low frequency stimulation (p < 0.05, 2Hz vs. 0 and 5 Hz). Chronic electrical stimulation for 24 hours did not induce stress response (HSP70,90) nor stress kinase (Erk, JNK, p38) activation. NRG stimulation of Erk and Akt was similar between paced and quiescent cells. Pacing sensitized myocytes to -AR stimulated JNK phosphorylation and cell death with 0.1 µM norepinephrine (NE) in paced myocytes causing equivalent cytotoxicity to 10 µM NE in quiescent cells. NRG suppressed -AR induced apoptosis through a PI3K-dependent pathway in both paced and quiescent cells. Thus myocyte contractility modulates both NE cytotoxicity as well as the cytoprotective effect of NRG. Moreover, this study demonstrates the feasibility and importance of using electrically paced cardiomyocytes in primary culture when examining the signaling pathways of cell survival.
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