Deficiency of 5-HT2B receptors alleviates atherosclerosis by regulating macrophage phenotype through inhibiting interferon signalling

Yahan Liu; Zhipeng Wang; Li Fang; Yaohua Xu; Beilei Zhao; Xuya Kang; Yanqing Zhao; Jintao Han; Yan Zhang; Erdan Dong; Nanping Wang

doi:10.1111/bph.17315

Deficiency of 5-HT_2B receptors alleviates atherosclerosis by regulating macrophage phenotype through inhibiting interferon signalling

Br J Pharmacol. 2024 Sep 4. doi: 10.1111/bph.17315. Online ahead of print.

Authors

Yahan Liu¹, Zhipeng Wang¹, Li Fang¹, Yaohua Xu¹, Beilei Zhao¹, Xuya Kang¹, Yanqing Zhao², Jintao Han², Yan Zhang^{1

3}, Erdan Dong^{1

4

5}, Nanping Wang^{6

7}

Affiliations

¹ Institute of Cardiovascular Sciences, School of Basic Medical Sciences, Peking University Health Science Center; State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing, China.
² Department of Interventional Radiology and Vascular Surgery, Peking University Third Hospital, Beijing, China.
³ Institute of Cardiovascular Diseases, The first affiliated Hospital of Dalian Medical University, Dalian, China.
⁴ Department of Cardiology and Institute of Vascular Medicine, Peking University Third Hospital; Research Unit of Medical Science Research Management/Basic and Clinical Research of Metabolic Cardiovascular Diseases, Chinese Academy of Medical Sciences, Beijing, China.
⁵ Research Center for Cardiopulmonary Rehabilitation, University of Health and Rehabilitation Sciences Qingdao Hospital (Qingdao Municipal Hospital); School of Health and Life Sciences, University of Health and Rehabilitation Sciences, Qingdao, China.
⁶ Wuhu Hospital, East China Normal University (ECNU), Wuhu, China.
⁷ East China Normal University Health Science Center, Shanghai, China.

PMID: 39232850
DOI: 10.1111/bph.17315

Abstract

Background and purpose: Elevated levels of 5-HT have been correlated with coronary artery disease and cardiac events, suggesting 5-HT is a potential novel factor in the development of atherosclerotic cardiovascular disease. However, the underlying pathological mechanisms of the 5-HT system in atherosclerosis remain unclear. The 5-HT_2B receptor (5-HT2BR), which establishes a positive feedback loop with 5-HT, has been identified as a contributor to pathophysiological processes in various vascular disorders. In this study, we investigated the immunological impact of 5-HT2BR in atherosclerosis-prone apolipoprotein E-deficient (ApoE^-/-) mice.

Experimental approach: Plasma levels of 5-HT were measured in mice using an ELISA kit. Atherosclerotic plaque formation, macrophage infiltration and inflammatory signalling were assessed in ApoE^-/- mice by employing both pharmacological inhibition and genetic deficiency of 5-HT2BR. Inflammasome activation was elucidated using peritoneal macrophages isolated from 5-HT2BR-deficient mice.

Key results: An upregulation of 5-HT2BR expression was observed in the aortas of ApoE^-/- mice, exhibiting a strong correlation with the presence of macrophages in plaques. Atherosclerosis was attenuated in mice through pharmacological inhibition and genetic deficiency of 5-HT2BR. Additionally, a significant reduction in atherosclerotic plaque size was achieved through bone marrow reconstitution with 5-HT2BR-deficient cells. 5-HT2BR-deficient macrophages showed attenuated interferon (IFN) signalling, NLRP3 inflammasome activation, and interleukin-1β release. Moreover, macrophages primed with 5-HT2BR deficiency displayed an anti-inflammatory phenotype.

Conclusion and implications: These findings support the hypothesis that 5-HT2BR in macrophages plays a causal role in the development of atherosclerosis, revealing a novel perspective for potential therapeutic strategies in atherosclerosis-related diseases.

Keywords: 5‐HT2B; atherosclerosis; inflammasome; interferon signalling; macrophage.

Abstract

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