Departments of Medicine, University of Otago, Christchurch, PO Box 4345, Christchurch, 8140, New Zealand.
Biostatistics and Computational Biology Unit, University of Otago, Christchurch, New Zealand.
Sci Rep. 2024 Apr 30;14(1):9919. doi: 10.1038/s41598-024-60677-4.
Natriuretic peptides (NP) have multiple actions benefitting cardiovascular and metabolic health. Although many of these are mediated by Guanylyl Cyclase (GC) receptors NPR1 and NPR2, their role and relative importance in vivo is unclear. The intracellular mediator of NPR1 and NPR2, cGMP, circulates in plasma and can be used to examine relationships between receptor activity and tissue responses targeted by NPs. Plasma cGMP was measured in 348 participants previously recruited in a multidisciplinary community study (CHALICE) at age 50 years at a single centre. Associations between bio-active NPs and bio-inactive aminoterminal products with cGMP, and of cGMP with tissue response, were analysed using linear regression. Mediation of associations by NPs was assessed by Causal Mediation Analysis (CMA). ANP's contribution to cGMP far exceed those of other NPs. Modelling across three components (demographics, NPs and cardiovascular function) shows that ANP and CNP are independent and positive predictors of cGMP. Counter intuitively, findings from CMA imply that in specific tissues, NPR1 responds more to BNP stimulation than ANP. Collectively these findings align with longer tissue half-life of BNP, and direct further therapeutic interventions towards extending tissue activity of ANP and CNP.
利钠肽（NP）具有多种有益于心血管和代谢健康的作用。尽管其中许多作用是由鸟苷酸环化酶（GC）受体 NPR1 和 NPR2 介导的，但它们在体内的作用和相对重要性尚不清楚。NPR1 和 NPR2 的细胞内介质 cGMP 存在于血浆中，可用于研究受体活性与 NP 靶向的组织反应之间的关系。在一个单一中心，对之前在多学科社区研究（CHALICE）中招募的 348 名参与者在 50 岁时测量了血浆 cGMP。使用线性回归分析生物活性 NP 和生物非活性氨基末端产物与 cGMP 之间的关联，以及 cGMP 与组织反应之间的关联。通过因果中介分析（CMA）评估 NP 对关联的中介作用。ANP 对 cGMP 的贡献远远超过其他 NP。通过三个组成部分（人口统计学、NP 和心血管功能）进行建模表明，ANP 和 CNP 是 cGMP 的独立和积极预测因子。与直觉相反的是，CMA 的结果表明，在特定组织中，NPR1 对 BNP 的刺激比 ANP 更敏感。这些发现共同表明 BNP 的组织半衰期更长，并进一步针对延长 ANP 和 CNP 的组织活性进行了治疗干预。
