Cardiorenal Research Laboratory, Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN 55905, USA.
Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN 55902, USA.
Int J Mol Sci. 2023 May 10;24(10):8547. doi: 10.3390/ijms24108547.
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) receptor and mechanistically involves protein kinase C (PKC), as this suppression can be substantially rescued by either valsartan (AT 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/PKC dependent manner and highlights the importance of dual-targeting RAAS and NPS in maximizing beneficial properties of natriuretic peptides in cardiovascular protection.
利钠肽系统（NPS）和肾素-血管紧张素-醛固酮系统（RAAS）在多个层面上发挥相反的作用。虽然长期以来一直怀疑血管紧张素 II（ANGII）可能直接抑制 NPS 活性，但迄今为止尚无明确证据支持这一观点。本研究旨在系统地研究体内和体外的 ANGII-NPS 相互作用。同时在 128 名人类受试者中研究了循环心房钠尿肽（ANP）、B 型利钠肽（BNP）、C 型利钠肽（CNP）、环鸟苷单磷酸（cGMP）和 ANGII。体内验证了假设，以确定 ANGII 对 ANP 作用的影响。进一步通过体外方法探索了潜在机制。在人类中，ANGII 与 ANP、BNP 和 cGMP 呈负相关。在预测 cGMP 的回归模型中，添加 ANGII 水平和 ANGII 与利钠肽之间的相互作用项增加了仅用 ANP 或 BNP 构建的基础模型的预测准确性，但 CNP 则不然。重要的是，分层相关分析进一步表明，仅在 ANGII 水平较低的受试者中，cGMP 与 ANP 或 BNP 呈正相关。在大鼠中，即使在生理剂量下共同输注 ANGII 也会减弱由 ANP 输注介导的 cGMP 产生。在体外，我们发现 ANGII 对 ANP 刺激的 cGMP 的抑制作用需要存在血管紧张素 II 型 1（AT）受体，并且在机制上涉及蛋白激酶 C（PKC），因为这种抑制作用可以通过缬沙坦（AT 阻断剂）或 Go6983（PKC 抑制剂）得到极大挽救。使用表面等离子体共振（SPR），我们表明与 ANP 或 BNP 相比，ANGII 对鸟苷酸环化酶 A（GC-A）受体的结合亲和力较低。我们的研究揭示了 ANGII 通过 AT/PKC 依赖性方式成为 GC-A 产生 cGMP 作用的天然抑制剂，并强调了在心血管保护中最大限度地发挥利钠肽有益特性的双重靶向 RAAS 和 NPS 的重要性。
