Rengo Giuseppe, Lymperopoulos Anastasios, Koch Walter J
Division of Cardiology, Fondazione Salvatore Maugeri-IRCCS-Istituto di Telese (BN), Italy.
Curr Treat Options Cardiovasc Med. 2009 Aug;11(4):328-38. doi: 10.1007/s11936-009-0033-5.
Heart failure (HF) still poses an enormous clinical challenge, as its incidence, morbidity, and mortality rates are continuously rising. G protein-coupled receptors (GPCRs) constitute the most ubiquitous superfamily of plasma membrane receptors and represent the single most important type of therapeutic drug target. Because there is overstimulation of the failing heart by various endogenous ligands, such as catecholamines and angiotensin II--which by activating their cognate GPCRs in cardiac muscle induce detrimental effects--therapeutic targeting of these receptors has been pursued. This research has led to the development of successful and useful drug classes, such as angiotensin-converting enzyme inhibitors and beta-adrenergic receptor blockers. However, there still is a need to develop innovative treatments that might be more effective at reversing compromised myocyte function. Over the past several years, much evidence has accumulated indicating that a single GPCR, activated by the same endogenous ligand, can elicit several different signaling pathways with quite different, and often opposite, cellular effects. Because the aforementioned ligands, currently used for HF, target these receptors on their extracellular interface, thus merely preventing the endogenous agonists from binding the receptor, they inhibit all the signaling pathways elicited by the receptor indiscriminately. Importantly, several of these pathways emanating from the same GPCR can actually be beneficial for therapy, so their enhancement rather than their blockade is desirable for HF therapy. This highlights the need for selective targeting of GPCR-induced signaling pathways on the intracellular interface of the receptor, which might produce new and innovative therapies for cardiovascular disease.
心力衰竭（HF）仍然是一个巨大的临床挑战，因为其发病率、致残率和死亡率持续上升。G蛋白偶联受体（GPCRs）构成了最普遍存在的质膜受体超家族，是最重要的一类治疗药物靶点。由于衰竭心脏受到各种内源性配体的过度刺激，如儿茶酚胺和血管紧张素II（它们通过激活心肌中的同源GPCRs产生有害作用），因此人们一直在寻求针对这些受体的治疗方法。这项研究已经促成了一些成功且有用的药物类别，如血管紧张素转换酶抑制剂和β-肾上腺素能受体阻滞剂的开发。然而，仍然需要开发可能在逆转受损心肌细胞功能方面更有效的创新治疗方法。在过去几年中，积累了大量证据表明，由相同内源性配体激活的单个GPCR可以引发几种不同的信号通路，这些通路具有截然不同且往往相反的细胞效应。由于目前用于HF的上述配体在细胞外界面靶向这些受体，仅仅阻止内源性激动剂与受体结合，它们会不加区分地抑制受体引发的所有信号通路。重要的是，来自同一GPCR的这些通路中有几条实际上可能对治疗有益，因此对于HF治疗来说，增强这些通路而非阻断它们是可取的。这凸显了在受体的细胞内界面选择性靶向GPCR诱导的信号通路的必要性，这可能会为心血管疾病带来新的创新治疗方法。
