AT1 receptor antagonist restores cardiac ryanodine receptor function, rendering isoproterenol-induced failing heart less susceptible to Ca2+-leak induced by oxidative stress
AT1 receptor antagonist restores cardiac ryanodine receptor function, rendering isoproterenol-induced failing heart less susceptible to Ca2+-leak induced by oxidative stress
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DOI：
10.1253/circj.70.777
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发表时间：
2006-06-01
影响因子：
3.3
通讯作者：
Matsuzaki, Masunori
中科院分区：
文献类型：
--
作者：
Tokuhisa, Takahiro;Yano, Masafumi;Matsuzaki, Masunori
研究背景肌浆网（SR）中的钙调节蛋白在心力衰竭的病原体形成中起关键作用。在本研究中，慢性β-受体刺激对心脏和SR功能的影响进行了评估，有或没有血管紧张素-II受体拮抗剂治疗最近报道有抗β-adrenergic activity.Methods和结果大鼠异丙肾上腺素（+）或（-）坎地沙坦（CAN），然后SR囊泡分离出左心室肌。CAN（-）组心肌细胞Ca ~（2+）摄取量和肌浆网Ca ~（2+）-ATP酶活性明显低于假手术组，而CAN（+）组基本恢复正常。尽管在CAN（-）中，SR Ca 2+释放通道（称为ryanodine受体（RyR 2））的蛋白激酶A（PKA）磷酸化水平升高，但未检测到Ca 2+泄漏。然而，SIN-1（O-2（-）供体）在CAN（-）中以比假手术和CAN（+）低10倍的剂量诱导Ca 2+泄漏。在心肌细胞中，SIN-1在CAN（-）中减少了细胞缩短和Ca 2+峰值瞬时，并延长了从峰值到下降70%的时间，剂量也比假手术和CAN（+）低10倍。结论慢性β受体刺激不会诱导SR的任何Ca 2+泄漏，而当对PKA磷酸化RyR 2施加氧化应激时，很容易诱导Ca 2+泄漏。坎地沙坦不仅改善了钙摄取，而且还阻止了PKA磷酸化，使SR对钙渗漏不太敏感。
Background The Ca2+ regulatory proteins in the sarcoplasmic reticulum (SR) play a key role in the pathogen-1 esis of heart failure. In the present study the effect of chronic beta-receptor-stimulation on cardiac and SR functions was assessed, with or without angiotensin-II receptor antagonist treatment recently reported to have anti-beta-adrenergic activity.Methods and Results Rats were treated with isoproterenol with (+) or without (-) candesartan (CAN) and then SR vesicles were isolated from the left ventricular muscle. Both Ca2+-uptake and the amount of SR Ca2+- ATPase were significantly lower in the CAN(-) group than in the shams, but those were almost normally restored in the CAN(+). Although the level of the protein kinase A (PKA)-phosphorylation of the SR Ca2+ release channel, known as the ryanodine receptor (RyR2), was elevated in the CAN(-), no Ca2+-leak was detected. However, SIN-1 (O-2(-) donor) induced Ca2+-leak in the CAN(-) at a 10-fold lower dose than in the sham and CAN(+). In cardiomyocytes, SIN-1 decreased cell shortening and the peak Ca2+ transient and prolonged time from peak to 70% decline in CAN (-), again at 10-fold lower dose than in the sham and CAN(+).Conclusion Chronic beta-receptor-stimulation did not induce any Ca2+-leak from the SR, whereas Ca2+-leak was easily induced when oxidative stress was applied to the PKA-phosphorylated RyR2. Candesartan not only improved Ca2+-uptake, but also prevented PKA-phosphorylation, rendering the SR less susceptible to Ca2+-leak.