Angiotensin II Inhibits DDAH1‐nNOS Signaling through AT1R and μOR Dimerization in the Central Nervous System to Modulate Central Control of Blood Pressure

다국어 초록 (Multilingual Abstract)

G protein‐coupled receptors (GPCRs) play an important role in drug therapy, and represent one of the largest families of drug targets. Blockade of angiotensin II type 1 receptor (AT1R) signaling has been shown to alleviate hypertension and improve outcomes in patients with heart failure. GPCRs formations or desensitization and trafficking can lead to pathophysiological processes. The aim of the present study was to investigate that may Ang II through induce AT1R and μOR dimerization in the NTS leads to the progress of hypertension.
Formation of heterodimers was assessed with proximity ligation assays. Microinjections of μOR or α2A‐AR agonists into the NTS and measured changes in BP of WKY rats. Real‐time PCR and immunoblotting analyses were used to quantify RNA and protein expression levels.
The levels of μOR and α2A‐AR heterodimer were increased and the extracellular signal–regulated kinases 1/2T202/Y204, ribosomal protein S6 kinaseT359/S363, nNOSS1416 phosphorylation; DDAH1expression were abolished in the NTS of adult spontaneously hypertensive rats (SHRs), however, the overexpressed endomorphins‐2 in the NTS of SHR when compared with young SHR. Microinjection of μOR agonist into NTS induced persist presser effect of WKY rats, decreased NO production and DDAH1. Immunoblotting analysis showed that μOR agonist significantly reduced the DDAH1 activity and decreased the expression of nNOS phosphorylation. Additionally, Ang II inhibitors (losartan) significantly decreased the BP and abolished AT1R‐induced both formation of AT1R and μOR heterodimers and α2A‐AR and μOR heterodimers. Besides, also has the same founding, losartan significantly enhanced nNOSS1416 phosphorylation and DDAH1 expression. In summary, these results represent a novel finding that Ang‐II induces endomorphins‐2 and abolished DDAH1 through enhancing the formation of AT1R and μOR heterodimers formation in the NTS to progress hypertension.
Support or Funding Information
This work was supported by funding from the Ministry of Science and Technology (MOST106‐2314‐B‐037‐022‐MY2, MOST107‐2320‐B‐075B‐001) and Kaohsiung Veterans General Hospital (VGHKS107‐175) (to P.‐W. C). The authors declare that they have no competing interests.
This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.