Role of peripheral CB1 cannabinoid receptors in atherosclerosis and metabolism

Chen, Bingni (2024): Role of peripheral CB1 cannabinoid receptors in atherosclerosis and metabolism. Dissertation, LMU München: Medizinische Fakultät

Abstract

Atherosclerosis is a chronic immune disease fueled by a complex interplay of lipid, inflammatory, and biomechanical factors. Previous studies demonstrated that the cannabinoid CB1 receptor plays a detrimental role in metabolic and cardiovascular diseases. While the development of peripherally restricted CB1 antagonists, which are devoid of central side effects, hold promise in treating metabolic disorders such as diabetes and obesity, their potential benefit in atherosclerosis is unknown. The aim of this thesis was to clarify the endothelial cell-specific effects of CB1 and underlying mechanisms in the pathophysiology of atherosclerosis. It was found that endothelial Cnr1 expression was upregulated upon oscillatory shear stress (OSS) in human aortic endothelial cells (HAoECs) and preferentially expressed in atheroprone areas of mouse aortic endothelium. Endothelial Cnr1 deficiency (Cnr1EC-KO) in female mice on atherogenic apolipoprotein E (Apoe) deficiency background reduced plaque formation, particularly in atheroprone sites. Only moderate effects were observed in male mice, which may hint to a sex-specific difference in endothelial CB1 signalling. Moreover, aortic endothelial cells of female Cnr1EC-KO mice exhibited a less pro-inflammatory phenotype with decreased adhesion molecule ICAM1 and VCAM1 expression. Interestingly, ex vivo imaging of carotid arteries via two-photon microscopy revealed less endothelial DIL-LDL uptake in female Cnr1EC-KO mice endothelial cells along with a significantly reduced aortic endothelial expression of caveolin-1 (CAV1), a key structural protein involved in lipid transcytosis. RNA sequencing of aortic endothelial cells further supported the role of CB1 in regulating caveolar signalling. In vitro, pharmacological blocking with CB1 antagonist AM281 in HAoECs under OSS resulted in a decreased LDL uptake, which was mediated through a cAMP-PKA-dependent regulation of CAV1 expression. Vice versa, the stimulation of HAoECs with the CB1 agonist ACEA increased DIL-LDL uptake and enhanced CAV1 expression. Notably, endothelial CB1 deficiency protected against metabolic dysfunction in adipose tissue and liver, while improving insulin sensitivity. Finally, treating mice with the peripherally active CB1 antagonist JD5037 reduced plaque progression, CAV1 expression, and endothelial adhesion molecule expression, which was only observed in females. Collectively, impaired CB1 signalling in endothelial cells inhibits endothelial LDL uptake, attenuates vascular inflammation, and improves metabolic function, leading to protection against atherosclerosis.

• Dokumententyp: Dissertationen (Dissertation, LMU München)
• Keywords: autoimmune disease, atherosclerosis, metabolism, lipid uptake, inflammation
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften ; 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• Fakultäten: Medizinische Fakultät
• Sprache der Hochschulschrift: Englisch
• Datum der mündlichen Prüfung: 7. Mai 2024
• 1. Bericht­erstatter:in: Marten-Steffens, Sabine