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  3. Targeting the smooth muscle cell KEAP1-Nrf2-STING axis with pterostilbene attenuates abdominal aortic aneurysm

Targeting the smooth muscle cell KEAP1-Nrf2-STING axis with pterostilbene attenuates abdominal aortic aneurysm

  • Phytomedicine. 2024 May 10:130:155696. doi: 10.1016/j.phymed.2024.155696.
Jiami Zou 1,  Zhihua Zheng 1,  Weile Ye 1,  Mei Jin 1,  Pinglian Yang 1,  Peter J Little 2,  Jiaojiao Wang 3,  Zhiping Liu 4
Affiliations

Affiliations

  • 1 State Key Laboratory of Bioactive Molecules and Druggability Assessment, Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Discovery of Chinese Ministry of Education (MOE), College of Pharmacy, Jinan University, Guangzhou 510632, China.
  • 2 School of Pharmacy, Pharmacy Australia Centre of Excellence, The University of Queensland, Woolloongabba, QLD 4102, Australia; Department of Pharmacy, Guangzhou Xinhua University, Guangzhou 510520, China.
  • 3 Key Laboratory of Big Data Mining and Precision Drug Design of Guangdong Medical University, Key Laboratory for Research and Development of Natural Drugs of Guangdong Province, School of Pharmacy, Guangdong Medical University, Dongguan, Guangdong, 523808, China. Electronic address: jjwang89@163.com.
  • 4 State Key Laboratory of Bioactive Molecules and Druggability Assessment, Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Discovery of Chinese Ministry of Education (MOE), College of Pharmacy, Jinan University, Guangzhou 510632, China. Electronic address: liuzhiping@jnu.edu.cn.
PMID: 38763007 DOI: 10.1016/j.phymed.2024.155696
Abstract

Background: Abdominal aortic aneurysm (AAA) is a life-threatening aortic disease, and to date, there are currently no effective pharmacological treatments to address this condition. Activation of cytosolic DNA sensing adaptor stimulator of interferon genes (STING) signaling is a crucial mechanism in AAA formation.

Purpose: This study investigated pterostilbene (Pt), a naturally occurring polyphenol and resveratrol analogue, as a STING Inhibitor for preventing AAA.

Methods: We evaluated the effect of Pt on AAA formation in angiotensin II (AngII)-infused apolipoprotein E-deficient (ApoE-/-) mice. We used histological analysis, MMP activity measurement, western blot, and immunohistochemistry to detect AAA formation and development. We applied RNA Sequencing, molecular docking, cellular thermal shift assay (CETSA) and functional studies to dissect the molecular mechanism of Pt-regulating KEAP1-Nrf2-STING signaling. We conditionally knocked down Nrf2 in vascular smooth muscle cells (VSMCs) in vivo to investigate its role in Pt-mediated protective effects on AAA.

Results: Pt effectively blocked the formation of AAA in AngII-infused ApoE-/- mice. Whole transcriptome Sequencing analysis revealed that nuclear factor erythroid 2-related factor 2 (Nrf2) and STING pathway in VSMCs were linked to the anti-AAA effects of pterostilbene. Mechanistically, Pt upregulated Nrf2 target genes (e.g., HO-1 and NQO1) through activation of the KEAP1/Nrf2 signaling, which restricted the immunostimulatory axis of mtDNA-STING-TBK1-NF-κB, thereby alleviating VSMC inflammation and preserving the VSMC contractile phenotype. Subsequently, molecular docking and CETSA revealed a binding mode between Pt and KEAP1/Nrf2. Intriguingly, the inhibitory effect of Pt on STING signaling and the protective role of Pt in AAA were largely abrogated by VSMC-specific Nrf2 knockdown in mice.

Conclusion: Collectively, naturally derived Pt shows promising efficacy for the treatment of AAA by targeting the KEAP1-Nrf2-STING axis in VSMCs.

Keywords

Abdominal aortic aneurysm; Nrf2; Pterostilbene; STING; Smooth muscle cell; mtDNA.

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