Targeting the heme-oxidized nitric oxide receptor for selective vasodilatation of diseased blood vessels
Targeting the heme-oxidized nitric oxide receptor for selective vasodilatation of diseased blood vessels
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DOI：
10.1172/jci28371
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发表时间：
2006-09-01
影响因子：
15.9
通讯作者：
Schmidt, Harald H. H. W.
中科院分区：
文献类型：
--
作者：
Stasch, Johannes-Peter;Schmidt, Peter M.;Schmidt, Harald H. H. W.
ROS是几种心血管疾病的危险因素，并通过清除NO和形成强氧化剂过氧亚硝酸盐来干扰NO/可溶性鸟苷酸环化酶/环GMP（NO/sGC/cGMP）信号传导：增加的氧化应激通过降低其表达水平和损害NO诱导的活化来影响含血红素的NO受体sGC，使得用NO供体进行的血管扩张治疗不太有效。在这里，我们在体内显示，氧化应激和相关的血管疾病状态，包括人类糖尿病，导致sGC是无法区分的体外氧化/血红素自由酶。这种sGC变体代表了我们认为是一种新的cGMP信号传导实体，其对NO无反应且易于降解。而sGC的未被占据的血红素口袋的高亲和力配体，如锌-原卟啉IX和新型NO-非依赖性sGC激活剂4-[（（4-羧基丁基）{2-[（4-苯乙基苄基）氧基]苯乙基}氨基）甲基[苯甲酸]（BAY 58-2667）稳定了酶，只有后者激活了NO-不敏感的sGC变体。重要的是，在分离的细胞、血管和体内，BAY 58-2667在病理生理学和氧化应激条件下更有效和增强。这种治疗原理优先扩张病变血管而不是正常血管，并且可能对目前研究的BAY 58-2667作为独特诊断工具和高度创新的血管治疗的临床用途具有深远的影响。
ROS are a risk factor of several cardiovascular disorders and interfere with NO/soluble guanylyl cyclase/cyclic GMP (NO/sGC/cGMP) signaling through scavenging of NO and formation of the strong oxidant peroxynitrite: Increased oxidative stress affects the heme-containing NO receptor sGC by both decreasing its expression levels and impairing NO-induced activation, making vasodilator therapy with NO donors less effective. Here we show in vivo that oxidative stress and related vascular disease states, including human diabetes mellitus, led to an sGC that was indistinguishable from the in vitro oxidized/heme-free enzyme. This sGC variant represents what we believe to be a novel cGMP signaling entity that is unresponsive to NO and prone to degradation. Whereas high-affinity ligands for the unoccupied heme pocket of sGC such as zinc-protoporphyrin IX and the novel NO-independent sGC activator 4-[((4-carboxybutyl){2-[(4-pheneth ylbenzyl)oxy]phenethyl}amino) methyl [benzoic]acid (BAY 58-2667) stabilized the enzyme, only the latter activated the NO-insensitive sGC variant. Importantly, in isolated cells, in blood vessels, and in vivo, BAY 58-2667 was more effective and potentiated under pathophysiological and oxidative stress conditions. This therapeutic principle preferentially dilates diseased versus normal blood vessels and may have far-reaching implications for the currently investigated clinical use of BAY 58-2667 as a unique diagnostic tool and highly innovative vascular therapy.