Department of Physiology and Pharmacology, Biomedicum, Karolinska Institutet, Solna, Sweden.
Freiberg Instruments GmbH, Freiberg, Germany.
Nat Chem Biol. 2023 Oct;19(10):1267-1275. doi: 10.1038/s41589-023-01411-5. Epub 2023 Sep 14.
Despite wide appreciation of the biological role of nitric oxide (NO) synthase (NOS) signaling, questions remain about the chemical nature of NOS-derived bioactivity. Here we show that NO-like bioactivity can be efficiently transduced by mobile NO-ferroheme species, which can transfer between proteins, partition into a hydrophobic phase and directly activate the sGC-cGMP-PKG pathway without intermediacy of free NO. The NO-ferroheme species (with or without a protein carrier) efficiently relax isolated blood vessels and induce hypotension in rodents, which is greatly potentiated after the blockade of NOS activity. While free NO-induced relaxations are abolished by an NO scavenger and in the presence of red blood cells or blood plasma, a model compound, NO-ferroheme-myoglobin preserves its vasoactivity suggesting the physiological relevance of NO-ferroheme species. We conclude that NO-ferroheme behaves as a signaling entity in the vasculature.
尽管人们广泛认识到一氧化氮合酶 (NOS) 信号在生物学中的作用，但关于 NOS 衍生生物活性的化学性质仍存在疑问。在这里，我们表明，类似一氧化氮的生物活性可以被可移动的一氧化氮-亚铁血红素物种有效地转导，这些物种可以在蛋白质之间转移、分配到疏水区，并直接激活 sGC-cGMP-PKG 途径，而无需游离一氧化氮的中介。一氧化氮-亚铁血红素物种（有或没有蛋白质载体）可以有效地使分离的血管松弛，并在啮齿动物中引起低血压，而在阻断 NOS 活性后，其作用大大增强。虽然游离一氧化氮诱导的松弛作用被一氧化氮清除剂和在存在红细胞或血浆时被消除，但模型化合物一氧化氮-亚铁血红素-肌红蛋白保留其血管活性，表明一氧化氮-亚铁血红素物种具有生理相关性。我们的结论是，一氧化氮-亚铁血红素在血管中充当信号实体。
