HNO/cGMP-dependent antihypertrophic actions of isopropylamine-NONOate in neonatal rat cardiomyocytes: potential therapeutic advantages of HNO over NO•
HNO/cGMP-dependent antihypertrophic actions of isopropylamine-NONOate in neonatal rat cardiomyocytes: potential therapeutic advantages of HNO over NO•
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DOI：
10.1152/ajpheart.00495.2012
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发表时间：
2013-08-01
影响因子：
4.8
通讯作者：
Ritchie, Rebecca H.
中科院分区：
文献类型：
--
作者：
Irvine, Jennifer C.;Cao, Nga;Ritchie, Rebecca H.
硝酰基（HNO）是NO中心点的氧化还原同系物。我们现在直接比较HNO和NO中心点供体在新生大鼠心肌细胞中的抗肥大功效，并比较它们在这种情况下的作用机制。异丙胺-NONOate（IPA-NO）引起浓度依赖性抑制内皮素-1（ET 1）诱导的心肌细胞大小增加，对肥大基因具有类似的抑制作用。L-半胱氨酸（HNO清除剂）、Rp-8-pCTP-cGMPS（cGMP依赖性蛋白激酶抑制剂）和1-H-（1，2，4）-oxodiazolo-quinxaline-1-one [ODQ;靶向可溶性鸟苷酸环化酶（sGC）]显著减弱了抗肥大IPA-NO作用，但不受羧基-PTIO（NO中心点清除剂）或CGRP（8-37）（降钙素基因相关肽拮抗剂）的影响。此外，IPA-NO显著增加心肌细胞cGMP 3.5倍（L-半胱氨酸敏感效应），刺激sGC活性3倍，没有检测到NO中心点释放。IPA-NO还抑制ET 1诱导的心肌细胞超氧化物的产生。纯NO中心点供体二乙胺-NONOate（DEA-NO）再现这些IPA-NO行动，但对羧基-PTIO而不是L-半胱氨酸敏感。虽然IPA-NO刺激纯化的sGC保存在邻苯三酚氧化应激下（与DEA-NO直接相反），心肌细胞sGC活性后，无论是捐助者减弱这种压力。令人兴奋的是，IPA-NO也表现出急性抗肥厚作用，在完整的心脏压力超负荷的反应。总之，这些数据有力地表明，IPA-NO对心肌细胞肥大的保护不依赖于NO中心点和CGRP，而是利用cGMP信号传导的新HNO激活。因此，HNO急性限制肥大独立于NO中心点，即使在超氧化物的条件下。因此，开发长效HNO供体可能是治疗心脏肥大的一种有吸引力的新策略，作为标准治疗的独立和/或添加治疗。
Nitroxyl (HNO) is a redox congener of NO center dot. We now directly compare the antihypertrophic efficacy of HNO and NO center dot donors in neonatal rat cardiomyocytes and compare their contributing mechanisms of actions in this setting. Isopropylamine-NONOate (IPA-NO) elicited concentration-dependent inhibition of endothelin-1 (ET1)-induced increases in cardiomyocyte size, with similar suppression of hypertrophic genes. Antihypertrophic IPA-NO actions were significantly attenuated by L-cysteine (HNO scavenger), Rp-8-pCTP-cGMPS (cGMP-dependent protein kinase inhibitor), and 1-H-(1,2,4)-oxodiazolo-quinxaline-1-one [ODQ; to target soluble guanylyl cyclase (sGC)] but were unaffected by carboxy-PTIO (NO center dot scavenger) or CGRP(8-37) (calcitonin gene-related peptide antagonist). Furthermore, IPA-NO significantly increased cardiomyocyte cGMP 3.5-fold (an L-cysteine-sensitive effect) and stimulated sGC activity threefold, without detectable NO center dot release. IPA-NO also suppressed ET1-induced cardiomyocyte superoxide generation. The pure NO center dot donor diethylamine-NONOate (DEA-NO) reproduced these IPA-NO actions but was sensitive to carboxy-PTIO rather than L-cysteine. Although IPA-NO stimulation of purified sGC was preserved under pyrogallol oxidant stress (in direct contrast to DEA-NO), cardiomyocyte sGC activity after either donor was attenuated by this stress. Excitingly IPA-NO also exhibited acute antihypertrophic actions in response to pressure overload in the intact heart. Together these data strongly suggest that IPA-NO protection against cardiomyocyte hypertrophy is independent of both NO center dot and CGRP but rather utilizes novel HNO activation of cGMP signaling. Thus HNO acutely limits hypertrophy independently of NO center dot, even under conditions of elevated superoxide. Development of longer-acting HNO donors may thus represent an attractive new strategy for the treatment of cardiac hypertrophy, as stand-alone and/or add-on therapy to standard care.