What are the molecular mechanisms for the antiproliferative effects of nitric oxide and cGMP in vascular smooth muscle?
What are the molecular mechanisms for the antiproliferative effects of nitric oxide and cGMP in vascular smooth muscle?
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一氧化氮和cGMP抗血管平滑肌增殖作用的分子机制是什么？
作者：
F. Murad
虽然血管制剂中一氧化氮和cGMP的平滑肌抗增殖作用已经知道了几年，这些作用的精确分子机制仍然未知。据推测，这些作用参与几个血管过程，包括动脉粥样硬化形成、再灌注损伤、血管生成、炎症、肿瘤生长、伤口愈合和组织移植。对这些影响的分子理解无疑将为这些重要的疾病和过程提供额外的治疗干预。虽然在过去的二十年中，一氧化氮和cGMP领域的信息和出版物呈几何级数增长，但仍有许多重要问题有待回答和解决。预计1996年将有4500多篇涉及这些信使的出版物，可能比任何其他研究课题都多。尽管如此，仍有许多重要的实验要做。读者可以参考最近几篇综述，这些综述总结了一氧化氮和cGMP的作用（参考文献1-3）。Yu及其同事在本期《循环》中阐述了这些信使的血管平滑肌抗增殖作用。
作者发现，SNP（一种硝基血管扩张剂和一氧化氮供体或前药）和A-02131-1（一种cGMP磷酸二酯酶的选择性抑制剂）可降低大鼠血管平滑肌细胞原代培养物的增殖，这些细胞已被几种生长因子之一刺激，如表皮生长因子、血小板衍生生长因子、佛波醇肉豆蔻酸酯或冈田酸。作者发现，cGMP类似物8-Br-cGMP也可以模拟这种作用，8-Br-cGMP可以激活cGMP依赖性蛋白激酶（PKG），但对磷酸二酯酶的水解更有抵抗力。SNP或8-Br-cGMP的抗增殖作用可被选择性cGMP依赖性蛋白激酶抑制剂KT 5823阻断，但不被腺苷酸腺苷（2′，5 ′-dideoxydoadenosine，ADAP）阻断。
Although the smooth muscle antiproliferative effects of nitric oxide and cGMP in vascular preparations have been known for several years, the precise molecular mechanisms for these effects remain unknown. Presumably these effects participate in several vascular processes, including atherogenesis, reperfusion injury, angiogenesis, inflammation, tumor growth, wound healing, and tissue grafts. A molecular understanding of these effects would no doubt provide additional therapeutic interventions for these important disorders and processes. Although the information and publications in the field of nitric oxide and cGMP have grown logarithmically in the past two decades, many important questions remain to be answered and resolved. More than 4500 publications addressing these messengers were expected in 1996, probably more than for any other research topic. Nevertheless, many important experiments remain to be done. Readers are referred to several recent reviews summarizing the effects of nitric oxide and cGMP (References 1-3). Yu and colleagues4 address the vascular smooth muscle antiproliferative effects of these messengers in this issue of Circulation .
The authors find that SNP, a nitrovasodilator and nitric oxide donor or prodrug, and A-02131-1, a selective inhibitor of cGMP phosphodiesterase, decrease the proliferation of primary cultures of rat vascular smooth muscle cells that have been stimulated with one of several growth factors, such as epidermal growth factor, platelet-derived growth factor, phorbol myristate, or okadaic acid. The authors find that the effects are also mimicked by a cGMP analogue, 8-Br-cGMP, which can activate cGMP-dependent protein kinase (PKG) but is more resistant to hydrolysis by phosphodiesterase. The antiproliferative effects of SNP or 8-Br-cGMP were blocked by KT5823, presumably a selective inhibitor of cGMP-dependent protein kinase, but not by 2′,5′-dideoxyadenosine (an adenylyl …