Role of macrophage CB1 in atherosclerosis

Wang, Yong (2024): Role of macrophage CB1 in atherosclerosis. Dissertation, LMU München: Faculty of Medicine

Abstract

Although the potential connection between the cannabinoid CB1 receptor and atherosclerosis has been suggested, the specific influence it exerts on the various cell types involved in the disease remains unclear. Here, we investigated its role in myeloid cells, which are key cellular effectors in atherosclerosis. Male mice with myeloid-specific knockout of the CB1-encoding gene (Cnr1) on an atherogenic apolipoprotein E (Apoe) deficiency background exhibited notably smaller lesions and necrotic cores compared to the control group. However, in females, only moderate effects were observed, and primarily at an advanced stage of the disease. The atheroprotective effects in male mice were attributed to reduced recruitment of arterial monocytes, decreased proliferation of plaque macrophages, and a less inflammatory polarization state. Interestingly, the sex-specific variances in CB1 signaling within murine macrophages were reproducible in vitro and mitigated by estradiol treatment. Detailed analysis of kinase activity profiling revealed the involvement of p53 signaling and cyclin dependent kinases in mediating the effects of CB1. Unbiased transcriptomic profiling further confirmed the role of CB1 in regulating macrophage oxidative metabolism, which was subsequently validated by metabolic flux assays. Notably, CB1 deficiency or antagonism led to an improvement in oxidative energy metabolism. Additionally, the peripherally acting CB1 antagonist JD5037 halted early plaque formation in male mice. To summarize, impaired CB1 signaling in macrophages reduces their recruitment to arteries, local proliferation, and inflammatory reprogramming, leading to protection against atherosclerosis, especially during the early disease stages. The phenotype was only observed in male mice, which may hint to a sex-specific difference of macrophage CB1 signaling.

• Item Type: Theses (Dissertation, LMU Munich)
• Keywords: myeloid CB1, atherosclerosis, macrophage proliferation, sex-specific variances
• Subjects: 600 Technology, Medicine; 600 Technology, Medicine > 610 Medical sciences and medicine
• Faculties: Faculty of Medicine
• Language: English
• Date of oral examination: 13. March 2024
• 1. Referee: Marten-Steffens, Sabine
• Signature of the printed copy: 0700/UMD 21669