Cerra M C, Pellegrino D
Department of Pharmaco-Biology, University of Calabria, 87030 Arcavacata di Rende (CS), Italy.
Curr Med Chem. 2007;14(5):585-99. doi: 10.2174/092986707780059715.
The intracellular messenger cyclic GMP (cGMP) represents the key signal in several transduction pathways throughout the animal world. In the heart cGMP signaling contributes to functional interaction of different cell types. Nitric oxide (NO) and natriuretic peptides (NPs), major autocrine-paracrine cardiovascular regulators, increment intracellular cGMP through guanylate cyclases (GCs). NO and NPs interact with two GC types: cytosolic (soluble: sGC) and membrane bound [particulate: pGC (NP receptor types A and B)], respectively. Depending on sub-cellular localization and regulation of the enzymes, cGMP produced by either pGC or sGC exerts different complementary effects. The two pathways are reciprocally regulated. NPs-depending pGC is modulated by NO-cGMP signaling, and the activity of NO is influenced by cellular concentrations of both NO itself and NPs. This heterologous feedback regulates GCs, linking cardiovascular autocrine-paracrine activities of NPs and NO. Importance of these cGMP converging routes goes far beyond their role under normal conditions. They are of relevance especially in disease states when tissue and circulating levels of NPs, and local NO production are altered. An example is the endothelial dysfunction associated with deficient NO production and uncoupled endothelium-myocardium communications. In this case, NPs-pGC-cGMP could supplement the reduced activity of NO-scGC-cGMP pathway. In addition, these systems regulate cell growth and apoptosis, playing a role in myocardial pathological morpho-functional remodeling. Here we will review recent concepts on NO/NPs dependent control of heart function in vertebrates, also focusing on cGMP-activated downstream signaling and its role in health and disease conditions.
细胞内信使环磷酸鸟苷（cGMP）是整个动物界多种转导途径中的关键信号。在心脏中，cGMP信号传导有助于不同细胞类型之间的功能相互作用。一氧化氮（NO）和利钠肽（NPs）是主要的自分泌-旁分泌心血管调节因子，它们通过鸟苷酸环化酶（GCs）增加细胞内cGMP。NO和NPs分别与两种类型的GC相互作用：胞质型（可溶性：sGC）和膜结合型[颗粒型：pGC（NP受体A和B型）]。根据酶的亚细胞定位和调节，pGC或sGC产生的cGMP发挥不同的互补作用。这两条途径相互调节。依赖NPs的pGC受NO-cGMP信号传导调节，而NO的活性受NO自身和NPs细胞浓度的影响。这种异源反馈调节GCs，将NPs和NO的心血管自分泌-旁分泌活性联系起来。这些cGMP汇聚途径的重要性远远超出了它们在正常条件下的作用。它们尤其在疾病状态下具有相关性，此时NPs的组织和循环水平以及局部NO生成发生改变。一个例子是与NO生成不足和内皮-心肌通讯解偶联相关的内皮功能障碍。在这种情况下，NPs-pGC-cGMP可以补充NO-sGC-cGMP途径降低的活性。此外，这些系统调节细胞生长和凋亡，在心肌病理形态功能重塑中发挥作用。在这里，我们将综述脊椎动物中NO/NPs依赖的心脏功能控制的最新概念，同时关注cGMP激活的下游信号传导及其在健康和疾病状态中的作用。
