Cardiorenal Research Laboratory, Department of Cardiovascular Medicine, Mayo Clinic, 200 1st Street SW, Rochester, MN 55905, USA.
Department of Physiology and Biomedical Engineering, Mayo Clinic 200 1st St SW, Rochester MN 55905, USA.
Cardiovasc Res. 2023 Feb 3;118(18):3416-3433. doi: 10.1093/cvr/cvac125.
The discovery of the heart as an endocrine organ resulted in a remarkable recognition of the natriuretic peptide system (NPS). Specifically, research has established the production of atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) from the heart, which exert pleiotropic cardiovascular, endocrine, renal, and metabolic actions via the particulate guanylyl cyclase A receptor (GC-A) and the second messenger, cGMP. C-type natriuretic peptide (CNP) is produced in the endothelium and kidney and mediates important protective auto/paracrine actions via GC-B and cGMP. These actions, in part, participate in the efficacy of sacubitril/valsartan in heart failure (HF) due to the augmentation of the NPS. Here, we will review important insights into the biology of the NPS, the role of precision medicine, and focus on the phenotypes of human genetic variants of ANP and BNP in the general population and the relevance to HF. We will also provide an update of the existence of NP deficiency states, including in HF, which provide the rationale for further therapeutics for the NPS. Finally, we will review the field of peptide engineering and the development of novel designer NPs for the treatment of HF. Notably, the recent discovery of a first-in-class small molecule GC-A enhancer, which is orally deliverable, will be highlighted. These innovative designer NPs and small molecule possess enhanced and novel properties for the treatment of HF and cardiovascular diseases.
心脏作为内分泌器官的发现，使得人们对利钠肽系统（NPS）有了显著的认识。具体而言，研究已经证实，心钠肽（ANP）和 B 型利钠肽（BNP）由心脏产生，通过颗粒型鸟苷酸环化酶 A 受体（GC-A）和第二信使 cGMP，发挥心血管、内分泌、肾脏和代谢的多效作用。C 型利钠肽（CNP）在内皮细胞和肾脏中产生，并通过 GC-B 和 cGMP 介导重要的保护自分泌/旁分泌作用。这些作用部分参与了沙库巴曲缬沙坦在心力衰竭（HF）中的疗效，因为 NPS 得到了增强。在这里，我们将回顾 NPS 生物学的重要见解、精准医学的作用，并重点关注人群中 ANP 和 BNP 的人类遗传变异的表型与 HF 的相关性。我们还将提供 NP 缺乏症状态（包括 HF）的最新研究进展，这为 NPS 的进一步治疗提供了依据。最后，我们将回顾肽工程领域和新型设计肽治疗 HF 的开发。值得注意的是，将重点介绍最近发现的一种新型口服可递的第一类小分子 GC-A 增强剂。这些创新性的设计肽和小分子具有增强的、新颖的特性，可用于治疗 HF 和心血管疾病。
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