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Nitric oxide signaling in stretch-induced apoptosis of neonatal rat cardiomyocytes

Xudong Liao^*,,1, Jun-Ming Liu, Lei Du^*, Aihui Tang, Yingli Shang^*, Shi Qiang Wang, Lan-Ying Chen^,2 and Quan Chen^*,2

^* State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences;

Cardiovascular Institute and Fu Wai Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences; and

State Key Laboratory of Biomembrane and Membrane Biotechnology, College of Life Sciences, Peking University, Beijing, China

²Correspondence: Q.C., State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, 25 Beisihuanxi Rd., Beijing 100080, P.R. China. E-mail: chenq{at}ioz.ac.cn; L.-Y.C., Cardiovascular Institute & Fu Wai Hospital, Peking Union Medical College & Chinese Academy of Medical Sciences, 167 Beilishi Rd., Beijing 100037, P.R. China. E-mail: lanyingchen{at}hotmail.com

ABSTRACT

Pressure overload associated with hypertension is an important pathological factor leading to heart remodeling and ultimately heart failure partially due to cardiomyocyte apoptosis. Here we show that endogenous NO signaling plays a critical role in mechanical stretch-induced cardiomyocyte apoptosis. Mechanical stretch induced elevated expression of both eNOS and inducible NO synthase (iNOS) and increased synthesis of NO. A sustained increase in iNOS expression was also found in hearts of hypertensive rats in vivo. Blockade of NO signaling by inhibitors of NOS (L-NAME and AMT) or downstream guanylyl cyclase (ODQ) strongly inhibited stretch-induced apoptosis, mitochondria depolarization, and cytochrome c release, suggesting that NO is required in stretch-induced cardiomyocyte apoptosis. The expression of iNOS, but not eNOS, was blocked by L-NAME and ODQ, indicating that the iNOS induction is NO dependent. The initial elevation of NO is likely due to Ca²⁺-dependent activation of eNOS because elimination of intracellular calcium by EGTA-AM inhibited both iNOS induction and NO elevation. Other calcium signaling inhibitors (nifedipine, ryanodine, thapsigargin, and ionic gadolinium) also attenuated the initial NO elevation. These data indicate that mechanical signals initiate Ca²⁺-dependent NO synthesis, which is further amplified by activation of NO-induced iNOS expression, to regulate cardiomyocyte apoptosis.—Liao, X., Liu, J-M., Du, Lei, Tang, A., Shang, Y., Wang, S. Q., Chen, L-Y, Chen, Q. Nitric oxide signaling in stretch-induced apoptosis of neonatal rat cardiomyocytes.

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