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
  • 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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