Cargando…

Evidence for Angiotensin II as a Naturally Existing Suppressor for the Guanylyl Cyclase A Receptor and Cyclic GMP Generation

The natriuretic peptide system (NPS) and renin-angiotensin-aldosterone system (RAAS) function oppositely at multiple levels. While it has long been suspected that angiotensin II (ANGII) may directly suppress NPS activity, no clear evidence to date supports this notion. This study was designed to sys...

Descripción completa

Detalles Bibliográficos
Autores principales: Ma, Xiao, Iyer, Seethalakshmi R., Ma, Xiaoyu, Reginauld, Shawn H., Chen, Yang, Pan, Shuchong, Zheng, Ye, Moroni, Dante G., Yu, Yue, Zhang, Lianwen, Cannone, Valentina, Chen, Horng H., Ferrario, Carlos M., Sangaralingham, S. Jeson, Burnett, John C.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10218449/
https://www.ncbi.nlm.nih.gov/pubmed/37239899
http://dx.doi.org/10.3390/ijms24108547
_version_ 1785048776190197760
author Ma, Xiao
Iyer, Seethalakshmi R.
Ma, Xiaoyu
Reginauld, Shawn H.
Chen, Yang
Pan, Shuchong
Zheng, Ye
Moroni, Dante G.
Yu, Yue
Zhang, Lianwen
Cannone, Valentina
Chen, Horng H.
Ferrario, Carlos M.
Sangaralingham, S. Jeson
Burnett, John C.
author_facet Ma, Xiao
Iyer, Seethalakshmi R.
Ma, Xiaoyu
Reginauld, Shawn H.
Chen, Yang
Pan, Shuchong
Zheng, Ye
Moroni, Dante G.
Yu, Yue
Zhang, Lianwen
Cannone, Valentina
Chen, Horng H.
Ferrario, Carlos M.
Sangaralingham, S. Jeson
Burnett, John C.
author_sort Ma, Xiao
collection PubMed
description The natriuretic peptide system (NPS) and renin-angiotensin-aldosterone system (RAAS) function oppositely at multiple levels. While it has long been suspected that angiotensin II (ANGII) may directly suppress NPS activity, no clear evidence to date supports this notion. This study was designed to systematically investigate ANGII–NPS interaction in humans, in vivo, and in vitro. Circulating atrial, b-type, and c-type natriuretic peptides (ANP, BNP, CNP), cyclic guanosine monophosphate (cGMP), and ANGII were simultaneously investigated in 128 human subjects. Prompted hypothesis was validated in vivo to determine the influence of ANGII on ANP actions. The underlying mechanisms were further explored via in vitro approaches. In humans, ANGII demonstrated an inverse relationship with ANP, BNP, and cGMP. In regression models predicting cGMP, adding ANGII levels and the interaction term between ANGII and natriuretic peptides increased the predictive accuracy of the base models constructed with either ANP or BNP, but not CNP. Importantly, stratified correlation analysis further revealed a positive association between cGMP and ANP or BNP only in subjects with low, but not high, ANGII levels. In rats, co-infusion of ANGII even at a physiological dose attenuated cGMP generation mediated by ANP infusion. In vitro, we found the suppressive effect of ANGII on ANP-stimulated cGMP requires the presence of ANGII type-1 (AT(1)) receptor and mechanistically involves protein kinase C (PKC), as this suppression can be substantially rescued by either valsartan (AT(1) blocker) or Go6983 (PKC inhibitor). Using surface plasmon resonance (SPR), we showed ANGII has low binding affinity to the guanylyl cyclase A (GC-A) receptor compared to ANP or BNP. Our study reveals ANGII is a natural suppressor for the cGMP-generating action of GC-A via AT(1)/PKC dependent manner and highlights the importance of dual-targeting RAAS and NPS in maximizing beneficial properties of natriuretic peptides in cardiovascular protection.
format Online
Article
Text
id pubmed-10218449
institution National Center for Biotechnology Information
language English
publishDate 2023
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-102184492023-05-27 Evidence for Angiotensin II as a Naturally Existing Suppressor for the Guanylyl Cyclase A Receptor and Cyclic GMP Generation Ma, Xiao Iyer, Seethalakshmi R. Ma, Xiaoyu Reginauld, Shawn H. Chen, Yang Pan, Shuchong Zheng, Ye Moroni, Dante G. Yu, Yue Zhang, Lianwen Cannone, Valentina Chen, Horng H. Ferrario, Carlos M. Sangaralingham, S. Jeson Burnett, John C. Int J Mol Sci Article The natriuretic peptide system (NPS) and renin-angiotensin-aldosterone system (RAAS) function oppositely at multiple levels. While it has long been suspected that angiotensin II (ANGII) may directly suppress NPS activity, no clear evidence to date supports this notion. This study was designed to systematically investigate ANGII–NPS interaction in humans, in vivo, and in vitro. Circulating atrial, b-type, and c-type natriuretic peptides (ANP, BNP, CNP), cyclic guanosine monophosphate (cGMP), and ANGII were simultaneously investigated in 128 human subjects. Prompted hypothesis was validated in vivo to determine the influence of ANGII on ANP actions. The underlying mechanisms were further explored via in vitro approaches. In humans, ANGII demonstrated an inverse relationship with ANP, BNP, and cGMP. In regression models predicting cGMP, adding ANGII levels and the interaction term between ANGII and natriuretic peptides increased the predictive accuracy of the base models constructed with either ANP or BNP, but not CNP. Importantly, stratified correlation analysis further revealed a positive association between cGMP and ANP or BNP only in subjects with low, but not high, ANGII levels. In rats, co-infusion of ANGII even at a physiological dose attenuated cGMP generation mediated by ANP infusion. In vitro, we found the suppressive effect of ANGII on ANP-stimulated cGMP requires the presence of ANGII type-1 (AT(1)) receptor and mechanistically involves protein kinase C (PKC), as this suppression can be substantially rescued by either valsartan (AT(1) blocker) or Go6983 (PKC inhibitor). Using surface plasmon resonance (SPR), we showed ANGII has low binding affinity to the guanylyl cyclase A (GC-A) receptor compared to ANP or BNP. Our study reveals ANGII is a natural suppressor for the cGMP-generating action of GC-A via AT(1)/PKC dependent manner and highlights the importance of dual-targeting RAAS and NPS in maximizing beneficial properties of natriuretic peptides in cardiovascular protection. MDPI 2023-05-10 /pmc/articles/PMC10218449/ /pubmed/37239899 http://dx.doi.org/10.3390/ijms24108547 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Ma, Xiao
Iyer, Seethalakshmi R.
Ma, Xiaoyu
Reginauld, Shawn H.
Chen, Yang
Pan, Shuchong
Zheng, Ye
Moroni, Dante G.
Yu, Yue
Zhang, Lianwen
Cannone, Valentina
Chen, Horng H.
Ferrario, Carlos M.
Sangaralingham, S. Jeson
Burnett, John C.
Evidence for Angiotensin II as a Naturally Existing Suppressor for the Guanylyl Cyclase A Receptor and Cyclic GMP Generation
title Evidence for Angiotensin II as a Naturally Existing Suppressor for the Guanylyl Cyclase A Receptor and Cyclic GMP Generation
title_full Evidence for Angiotensin II as a Naturally Existing Suppressor for the Guanylyl Cyclase A Receptor and Cyclic GMP Generation
title_fullStr Evidence for Angiotensin II as a Naturally Existing Suppressor for the Guanylyl Cyclase A Receptor and Cyclic GMP Generation
title_full_unstemmed Evidence for Angiotensin II as a Naturally Existing Suppressor for the Guanylyl Cyclase A Receptor and Cyclic GMP Generation
title_short Evidence for Angiotensin II as a Naturally Existing Suppressor for the Guanylyl Cyclase A Receptor and Cyclic GMP Generation
title_sort evidence for angiotensin ii as a naturally existing suppressor for the guanylyl cyclase a receptor and cyclic gmp generation
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10218449/
https://www.ncbi.nlm.nih.gov/pubmed/37239899
http://dx.doi.org/10.3390/ijms24108547
work_keys_str_mv AT maxiao evidenceforangiotensiniiasanaturallyexistingsuppressorfortheguanylylcyclaseareceptorandcyclicgmpgeneration
AT iyerseethalakshmir evidenceforangiotensiniiasanaturallyexistingsuppressorfortheguanylylcyclaseareceptorandcyclicgmpgeneration
AT maxiaoyu evidenceforangiotensiniiasanaturallyexistingsuppressorfortheguanylylcyclaseareceptorandcyclicgmpgeneration
AT reginauldshawnh evidenceforangiotensiniiasanaturallyexistingsuppressorfortheguanylylcyclaseareceptorandcyclicgmpgeneration
AT chenyang evidenceforangiotensiniiasanaturallyexistingsuppressorfortheguanylylcyclaseareceptorandcyclicgmpgeneration
AT panshuchong evidenceforangiotensiniiasanaturallyexistingsuppressorfortheguanylylcyclaseareceptorandcyclicgmpgeneration
AT zhengye evidenceforangiotensiniiasanaturallyexistingsuppressorfortheguanylylcyclaseareceptorandcyclicgmpgeneration
AT moronidanteg evidenceforangiotensiniiasanaturallyexistingsuppressorfortheguanylylcyclaseareceptorandcyclicgmpgeneration
AT yuyue evidenceforangiotensiniiasanaturallyexistingsuppressorfortheguanylylcyclaseareceptorandcyclicgmpgeneration
AT zhanglianwen evidenceforangiotensiniiasanaturallyexistingsuppressorfortheguanylylcyclaseareceptorandcyclicgmpgeneration
AT cannonevalentina evidenceforangiotensiniiasanaturallyexistingsuppressorfortheguanylylcyclaseareceptorandcyclicgmpgeneration
AT chenhorngh evidenceforangiotensiniiasanaturallyexistingsuppressorfortheguanylylcyclaseareceptorandcyclicgmpgeneration
AT ferrariocarlosm evidenceforangiotensiniiasanaturallyexistingsuppressorfortheguanylylcyclaseareceptorandcyclicgmpgeneration
AT sangaralinghamsjeson evidenceforangiotensiniiasanaturallyexistingsuppressorfortheguanylylcyclaseareceptorandcyclicgmpgeneration
AT burnettjohnc evidenceforangiotensiniiasanaturallyexistingsuppressorfortheguanylylcyclaseareceptorandcyclicgmpgeneration