Lancel Steve, Zhang Jingmei, Evangelista Alicia, Trucillo Mario P, Tong Xiaoyong, Siwik Deborah A, Cohen Richard A, Colucci Wilson S
Cardiovascular Medicine Section, Boston University Medical Center, 88 E Newton St, Boston, MA 02118, USA.
Circ Res. 2009 Mar 27;104(6):720-3. doi: 10.1161/CIRCRESAHA.108.188441. Epub 2009 Mar 5.
Nitroxyl (HNO) exerts inotropic and lusitropic effects in myocardium, in part via activation of SERCA (sarcoplasmic reticulum calcium ATPase). To elucidate the molecular mechanism, adult rat ventricular myocytes were exposed to HNO derived from Angeli's salt. HNO increased the maximal rate of thapsigargin-sensitive Ca2+ uptake mediated by SERCA in sarcoplasmic vesicles and caused reversible oxidative modification of SERCA thiols. HNO increased the S-glutathiolation of SERCA, and adenoviral overexpression of glutaredoxin-1 prevented both the HNO-stimulated oxidative modification of SERCA and its activation, as did overexpression of a mutated SERCA in which cysteine 674 was replaced with serine. Thus, HNO increases the maximal activation of SERCA via S-glutathiolation at cysteine 674.
硝酰(HNO)对心肌发挥正性肌力和舒张性肌力作用,部分是通过激活肌浆网钙ATP酶(SERCA)来实现的。为阐明其分子机制,将成年大鼠心室肌细胞暴露于源自安吉利盐的HNO中。HNO增加了肌浆网囊泡中由SERCA介导的毒胡萝卜素敏感的Ca2+摄取的最大速率,并导致SERCA硫醇发生可逆的氧化修饰。HNO增加了SERCA的S-谷胱甘肽化,而腺病毒介导的谷氧还蛋白-1过表达可防止HNO刺激的SERCA氧化修饰及其激活,将半胱氨酸674替换为丝氨酸的突变型SERCA过表达也有同样效果。因此,HNO通过半胱氨酸674处的S-谷胱甘肽化增加SERCA的最大激活。