University of Otago, Christchurch Cardioendocrine Research Group , PO Box 4345, Christchurch , New Zealand +64 3 3640543 ; +64 3 3640525 ;
Expert Opin Drug Discov. 2011 Jun;6(6):633-44. doi: 10.1517/17460441.2011.571251. Epub 2011 Mar 24.
The physiological importance of GPCR/ligand pathways is highlighted by the fact that numerous pathologies are attributed to their signaling dysfunction. Over 50% of the pharmaceutical drugs currently used to treat human disease are based on compounds that interact with GPCRs. Apelin/APJ constitutes a novel endogenous peptide/GPCR system proposed to be involved in a wide range of physiological functions. Early evidence suggests that apelin/APJ may hold promise as a target for development of novel therapeutic agents which may counteract a number of pathologies including cardiovascular disease. Despite advances in treatment of cardiovascular disease, incidence, prevalence, morbidity and economic costs remain high necessitating the development of new treatment paradigms.
This review summarizes apelin/APJ structure, distribution and regulation; presents evidence for a role of apelin in pressure/volume homeostasis and in the pathophysiology of cardiovascular disease; summarizes data on beneficial effects of apelin in preclinical, animal models of cardiovascular disease and measurement of plasma levels of apelin across the full spectrum of cardiovascular disease in humans; and notes the first studies describing bioactivity of apelin peptides in human healthy volunteers and patients with heart failure.
More clarity is needed on the precise physiological/pathophysiological role of the apelin/APJ system in human health and disease. Nonetheless, preclinical studies and initial studies in humans show that APJ antagonism may represent a novel therapeutic target for patients with cardiovascular disease. Development of appropriately validated assays for apelin will clarify circulating levels of the peptide in health and disease. Development of suitable agonists/antagonists will pave the way for much needed future studies essential for advancing this promising field of drug discovery.
GPCR/配体途径的生理重要性突出表现在许多病理学都归因于其信号功能障碍。目前用于治疗人类疾病的 50%以上的药物都是基于与 GPCR 相互作用的化合物。Apelin/APJ 构成了一种新型的内源性肽/GPCR 系统，据推测该系统参与广泛的生理功能。早期证据表明，Apelin/APJ 可能作为开发新型治疗药物的靶点具有很大的潜力，这些药物可能对抗包括心血管疾病在内的多种病理学。尽管心血管疾病的治疗取得了进展，但发病率、患病率、发病率和经济成本仍然很高，这需要开发新的治疗模式。
本文综述了 Apelin/APJ 的结构、分布和调节；提出了 Apelin 在压力/容积平衡和心血管疾病病理生理学中的作用的证据；总结了 Apelin 在心血管疾病的临床前、动物模型中的有益作用的数据，以及在人类心血管疾病的全谱中测量 Apelin 的血浆水平；并注意到首次描述 Apelin 肽在健康志愿者和心力衰竭患者中的生物活性的研究。
在 Apelin/APJ 系统在人类健康和疾病中的精确生理/病理生理作用方面，还需要更明确的认识。尽管如此，临床前研究和初步的人类研究表明，APJ 拮抗剂可能代表了心血管疾病患者的一个新的治疗靶点。适当验证的 Apelin 检测方法的开发将阐明肽在健康和疾病中的循环水平。合适的激动剂/拮抗剂的开发将为这一急需的未来研究铺平道路，这些研究对于推进这一有前途的药物发现领域至关重要。
