Scott Nicola J A, Prickett Timothy C R, Charles Christopher J, Espiner Eric A, Richards A Mark, Rademaker Miriam T
Department of Medicine, Christchurch Heart Institute, University of Otago Christchurch, Christchurch, New Zealand.
Cardiovascular Research Institute, National University Health Systems, Centre for Translational Medicine, Singapore, Singapore.
Exp Physiol. 2024 Aug;109(8):1305-1316. doi: 10.1113/EP091826. Epub 2024 Jun 18.
Osteocrin (OSTN) is an endogenous protein sharing structural similarities with the natriuretic peptides [NPs; atrial (ANP), B-type (BNP) and C-type (CNP) NP], which are hormones known for their crucial role in maintaining pressure/volume homeostasis. Osteocrin competes with the NPs for binding to the receptor involved in their clearance (NPR-C). In the present study, having identified, for the first time, the major circulating form of OSTN in human and ovine plasma, we examined the integrated haemodynamic, endocrine and renal effects of vehicle-controlled incremental infusions of ovine proOSTN (83-133) and its metabolism in eight conscious normal sheep. Incremental i.v. doses of OSTN produced stepwise increases in circulating concentrations of the peptide, and its metabolic clearance rate was inversely proportional to the dose. Osteocrin increased plasma levels of ANP, BNP and CNP in a dose-dependent manner, together with concentrations of their intracellular second messenger, cGMP. Increases in plasma cGMP were associated with progressive reductions in arterial pressure and central venous pressure. Plasma cAMP, renin and aldosterone were unchanged. Despite significant increases in urinary cGMP levels, OSTN administration was not associated with natriuresis or diuresis in normal sheep. These results support OSTN as an endogenous ligand for NPR-C in regulating plasma concentrations of NPs and associated cGMP-mediated bioactivity. Collectively, our findings support a role for OSTN in maintaining cardiovascular homeostasis.
骨调节素（OSTN）是一种内源性蛋白质，与利钠肽[NP；心房利钠肽（ANP）、B型利钠肽（BNP）和C型利钠肽（CNP）]在结构上有相似之处，这些激素以其在维持压力/容量稳态中的关键作用而闻名。骨调节素与利钠肽竞争结合参与其清除的受体（NPR-C）。在本研究中，我们首次鉴定了人和羊血浆中骨调节素的主要循环形式，然后在八只清醒的正常绵羊中研究了载体对照递增输注羊proOSTN（83-133）的综合血流动力学、内分泌和肾脏效应及其代谢情况。递增静脉注射骨调节素剂量导致该肽的循环浓度逐步升高，其代谢清除率与剂量成反比。骨调节素以剂量依赖性方式增加ANP、BNP和CNP的血浆水平，以及它们细胞内第二信使cGMP的浓度。血浆cGMP的增加与动脉压和中心静脉压的逐渐降低相关。血浆cAMP、肾素和醛固酮未发生变化。尽管尿cGMP水平显著升高，但在正常绵羊中给予骨调节素与利钠或利尿无关。这些结果支持骨调节素作为NPR-C的内源性配体，在调节NP的血浆浓度和相关cGMP介导的生物活性方面发挥作用。总体而言，我们的研究结果支持骨调节素在维持心血管稳态中的作用。
