Telmisartan Inhibits Nitric Oxide Production and Vessel Relaxation via Protein Phosphatase 2A-mediated Endothelial NO Synthase-Ser¹¹⁷⁹ Dephosphorylation
10.3346/jkms.2019.34.e266
- Author:
Du Hyong CHO
1
Author Information
1. Department of Pharmacology, Yeungnam University College of Medicine, Daegu, Korea. biohyong@hanmail.net
- Publication Type:Original Article
- Keywords:
Telmisartan;
Nitric Oxide;
Endothelial Nitric Oxide Synthase;
Protein Phosphatase 2A;
Vessel Relaxation;
Phosphorylation
- MeSH:
Acetylcholine;
Animals;
Aorta;
Blotting, Western;
Catalytic Domain;
Endothelial Cells;
In Vitro Techniques;
Losartan;
Mice;
Mice, Obese;
Nitric Oxide Synthase Type III;
Nitric Oxide;
Okadaic Acid;
Peroxisomes;
Phosphorylation;
Protein Phosphatase 2;
Rats;
Receptor, Angiotensin, Type 1;
Relaxation;
Renin-Angiotensin System;
Vascular Diseases
- From:Journal of Korean Medical Science
2019;34(42):e266-
- CountryRepublic of Korea
- Language:English
-
Abstract:
BACKGROUND: Apart from its blood pressure-lowering effect by blocking the renin-angiotensin-aldosterone system, telmisartan, an angiotensin II type 1 receptor blocker (ARB), exhibits various ancillary effects including cardiovascular protective effects in vitro. Nonetheless, the protective effects of telmisartan in cerebrocardiovascular diseases are somewhat variable in large-scale clinical trials. Dysregulation of endothelial nitric oxide (NO) synthase (eNOS)-derived NO contributes to the developments of various vascular diseases. Nevertheless, the direct effects of telmisartan on endothelial functions including NO production and vessel relaxation, and its action mechanism have not been fully elucidated. Here, we investigated the mechanism by which telmisartan regulates NO production and vessel relaxation in vitro and in vivo. METHODS: We measured nitrite levels in culture medium and mouse serum, and performed inhibitor studies and western blot analyses using bovine aortic endothelial cells (BAECs) and a hyperglycemic mouse model. To assess vessel reactivity, we performed acetylcholine (ACh)-induced vessel relaxation assay on isolated rat aortas. RESULTS: Telmisartan decreased NO production in normoglycemic and hyperglycemic BAECs, which was accompanied by reduced phosphorylation of eNOS at Ser¹¹⁷⁹ (p-eNOS-Ser¹¹⁷⁹). Telmisartan increased the expression of protein phosphatase 2A catalytic subunit (PP2Ac) and co-treatment with okadaic acid completely restored telmisartan-inhibited NO production and p-eNOS-Ser¹¹⁷⁹ levels. Of the ARBs tested (including losartan and fimasartan), only telmisartan decreased NO production and p-eNOS-Ser¹¹⁷⁹ levels, and enhanced PP2Ac expression. Co-treatment with GW9662 had no effect on telmisartan-induced changes. In line with in vitro observations, telmisartan reduced serum nitrite and p-eNOS-Ser¹¹⁷⁹ levels, and increased PP2Ac expression in high fat diet-fed mice. Furthermore, telmisartan attenuated ACh-induced rat aorta relaxation. CONCLUSION: We demonstrated that telmisartan inhibited NO production and vessel relaxation at least in part by PP2A-mediated eNOS-Ser¹¹⁷⁹ dephosphorylation in a peroxisome proliferator-activated receptor γ-independent manner. These results may provide a mechanism that explains the inconsistent cerebrocardiovascular protective effects of telmisartan.
