Evidence for Angiotensin II as a Naturally Existing Suppressor for the Guanylyl Cyclase A Receptor and Cyclic GMP Generation.
Evidence for Angiotensin II as a Naturally Existing Suppressor for the Guanylyl Cyclase A Receptor and Cyclic GMP Generation.
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血管紧张素II作为Guanylyl环化酶A受体和环状GMP生成的自然现有抑制剂的证据。
DOI：
10.3390/ijms24108547
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发表时间：
2023-05-10
影响因子：
5.6
通讯作者：
Burnett Jr, John C.
中科院分区：
文献类型：
--
作者：
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 Jr, John C.
关键词：
利钠肽系统(NPS)和肾素-血管紧张素-醛固酮系统(RAAS)在多个水平上起着相反的作用。虽然长期以来一直怀疑血管紧张素II(AngII)可能直接抑制NPS的活性，但到目前为止还没有明确的证据支持这一观点。本研究旨在系统地研究Angii-NPS在人体、体内和体外的相互作用。同时测定了128例受试者的循环心钠素、b型和c型利钠肽(ANP、BNP、CNP)、环鸟苷(CGMP)和血管紧张素转换酶(AngII)。在体内验证提示假说以确定血管紧张素转换酶对心钠素作用的影响。通过体外实验进一步探讨了其潜在的机制。在人类中，Angii与ANP、BNP和cGMP呈负相关。在预测cGMP的回归模型中，增加AngII水平和AngII与利钠肽之间的相互作用项可以提高ANP或BNP构建的基础模型的预测准确性，但不能提高CNP的预测精度。重要的是，分层相关分析进一步显示，cGMP与ANP或BNP之间只在Angii水平低但不高的受试者中呈正相关。在大鼠中，即使在生理剂量下共同输注血管紧张素Ⅱ也能减少ANP输注介导的cGMP的产生。在体外，我们发现Angii对ANP刺激的cGMP的抑制作用需要Angi1(AT1)受体的存在，并且机制上涉及蛋白激酶C(PKC)，因为这种抑制可以被Valsartan(AT1阻滞剂)或Go6983(PKC抑制剂)所挽救。通过表面等离子体共振(SPR)，我们发现与ANP或BNP相比，AngII与鸟苷酸环化酶A(GC-A)受体的结合亲和力较低。我们的研究表明，Angii是通过AT1/PKC依赖的方式天然抑制GC-A产生cGMP的作用，并强调了双靶向RAAS和NPS在最大化利钠肽在心血管保护中的有益特性的重要性。
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 (AT1) receptor and mechanistically involves protein kinase C (PKC), as this suppression can be substantially rescued by either valsartan (AT1 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 AT1/PKC dependent manner and highlights the importance of dual-targeting RAAS and NPS in maximizing beneficial properties of natriuretic peptides in cardiovascular protection.
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影响因子：
4
作者：
Ding J;Yu M;Jiang J;Luo Y;Zhang Q;Wang S;Yang F;Wang A;Wang L;Zhuang M;Wu S;Zhang Q;Xia Y;Lu D
通讯作者：
Lu D
影响因子：
4.6
作者：
Arise, Kiran K.;Kumar, Prerna;Pandey, Kailash N.
通讯作者：
Pandey, Kailash N.
影响因子：
56.9
作者：
BURNETT, JC;KAO, PC;REEDER, GS
通讯作者：
REEDER, GS
影响因子：
9.3
作者：
Kawai T;Forrester SJ;O'Brien S;Baggett A;Rizzo V;Eguchi S
通讯作者：
Eguchi S
影响因子：
39.3
作者：
Jackson AM;Jhund PS;Anand IS;Düngen HD;Lam CSP;Lefkowitz MP;Linssen G;Lund LH;Maggioni AP;Pfeffer MA;Rouleau JL;Saraiva JFK;Senni M;Vardeny O;Wijkman MO;Yilmaz MB;Saito Y;Zile MR;Solomon SD;McMurray JJV
通讯作者：
McMurray JJV