2. Academic Validation
  3. 3'-Oxo-tabernaelegantine A (OTNA) selectively relaxes pulmonary arteries by inhibiting AhR

3'-Oxo-tabernaelegantine A (OTNA) selectively relaxes pulmonary arteries by inhibiting AhR

  • Phytomedicine. 2021 Nov:92:153751. doi: 10.1016/j.phymed.2021.153751.
Pei Long 1,  Yong Li 2,  Qing Wen 1,  Maohua Huang 1,  Songtao Li 1,  Yuning Lin 1,  Xiaojun Huang 1,  Minfeng Chen 1,  Jie Ouyang 1,  Yunlin Ao 1,  Qi Qi 3,  Haipeng Zhang 3,  Wencai Ye 1,  Guohua Cheng 4,  Xiaoqi Zhang 5,  Dongmei Zhang 6
Affiliations

Affiliations

  • 1 College of Pharmacy, Jinan University, Guangzhou 510632, China; Guangdong Province Key Laboratory of Pharmacodynamic Constituents of Traditional Chinese Medicine and New Drugs Research, Jinan University, Guangzhou 510632, China.
  • 2 College of Pharmacy, Jinan University, Guangzhou 510632, China; Guangdong Province Key Laboratory of Pharmacodynamic Constituents of Traditional Chinese Medicine and New Drugs Research, Jinan University, Guangzhou 510632, China; School of Pharmacy, North Sichuan Medical College, Nanchong 637100, China.
  • 3 Department of Pharmacology, School of Medicine, Jinan University, Guangzhou 510632, China.
  • 4 College of Pharmacy, Jinan University, Guangzhou 510632, China. Electronic address: [email protected].
  • 5 College of Pharmacy, Jinan University, Guangzhou 510632, China; Guangdong Province Key Laboratory of Pharmacodynamic Constituents of Traditional Chinese Medicine and New Drugs Research, Jinan University, Guangzhou 510632, China. Electronic address: [email protected].
  • 6 College of Pharmacy, Jinan University, Guangzhou 510632, China; Guangdong Province Key Laboratory of Pharmacodynamic Constituents of Traditional Chinese Medicine and New Drugs Research, Jinan University, Guangzhou 510632, China. Electronic address: [email protected].
PMID: 34563984 DOI: 10.1016/j.phymed.2021.153751
Abstract

Background: Pulmonary arterial hypertension (PAH), characterized by pulmonary artery constriction and vascular remodeling, has a high mortality rate. New drugs for the treatment of PAH urgently need to be developed.

Purpose: This study was designed to investigate the vasorelaxant activity of OTNA in isolated pulmonary arteries, and explore its molecular mechanism.

Methods: Pulmonary arteries and thoracic aortas were isolated from mice, and vascular tone was tested with a Wire Myograph System. Nitric oxide levels were determined with DAF-FM DA and DAX-J2™ Red. Cellular thermal shift assays, microscale thermophoresis, and molecular docking were used to identify the interaction between OTNA and Aryl Hydrocarbon Receptor (AhR). The levels of PI3K, p-PI3K, Akt, p-Akt, eNOS, p-eNOS, and AhR were analyzed by Western blotting.

Results: OTNA selectively relaxed the isolated pulmonary artery rings in an endothelium-dependent manner. Mechanistic study showed that OTNA induced NO production through activation of the PI3K/Akt/eNOS pathway in endothelial cells. Furthermore, we also found that OTNA directly bound to AhR and activated the PI3K/Akt/eNOS pathway to dilate pulmonary arteries by inhibiting AhR.

Conclusions: OTNA relaxes pulmonary arteries by antagonizing AhR. This study provides a new natural antagonist of AhR as a promising lead compound for PAH treatment.

Keywords

3′-oxo-tabernaelegantine A; Aryl hydrocarbon receptor; Endothelial cells; Endothelial nitric oxide synthase; Nitric oxide; Pulmonary arterial hypertension.

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