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Wang, Y.* ; Li, G.* ; Chen, B.* ; Shakir, G.* ; Volz, M.* ; van der Vorst, E.P.C.* ; Maas, S.L.* ; Geiger, M.* ; Jethwa, C.* ; Bartelt, A. ; Li, Z.* ; Wettich, J.* ; Sachs, N.* ; Maegdefessel, L.* ; Nazari Jahantigh, M.* ; Hristov, M.* ; Lacy, M.* ; Lutz, B.* ; Weber, C.* ; Herzig, S. ; Guillamat Prats, R.* ; Steffens, S.*

Myeloid cannabinoid CB1 receptor deletion confers atheroprotection in male mice by reducing macrophage proliferation in a sex-dependent manner.

Cardiovasc. Res. 120, 1411-1426 (2024)
Verlagsversion DOI PMC
Open Access Gold (Paid Option)
Creative Commons Lizenzvertrag
AIMS: Although the cannabinoid CB1 receptor has been implicated in atherosclerosis, its cell-specific effects in this disease are not well understood. To address this, we generated a transgenic mouse model to study the role of myeloid CB1 signaling in atherosclerosis. METHODS AND RESULTS: Here, we report that male mice with myeloid-specific Cnr1 deficiency on atherogenic background developed smaller lesions and necrotic cores than controls, while only minor genotype differences were observed in females. Male Cnr1 deficient mice showed reduced arterial monocyte recruitment and macrophage proliferation with less inflammatory phenotype. The sex-specific differences in proliferation were dependent on estrogen receptor (ER)α-estradiol signaling. Kinase activity profiling identified a CB1-dependent regulation of p53 and cyclin-dependent kinases. Transcriptomic profiling further revealed chromatin modifications, mRNA processing and mitochondrial respiration among the key processes affected by CB1 signaling, which was supported by metabolic flux assays. Chronic administration of the peripherally-restricted CB1 antagonist JD5037 inhibited plaque progression and macrophage proliferation, but only in male mice. Finally, CNR1 expression was detectable in human carotid endarterectomy plaques and inversely correlated with proliferation, oxidative metabolism and inflammatory markers, suggesting a possible implication of CB1-dependent regulation in human pathophysiology. CONCLUSION: Impaired macrophage CB1 signaling is atheroprotective by limiting their arterial recruitment, proliferation and inflammatory reprogramming in male mice. The importance of macrophage CB1 signaling appears to be sex-dependent.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
Schlagwörter Cannabinoid CB1 receptor; Macrophage; Proliferation; p53; Oestrogen receptor alpha; Activated Endocannabinoid System; Muscle-cell-proliferation; Atherosclerosis; P53; Accumulation; Dysfunction; Blockade
ISSN (print) / ISBN 0008-6363
e-ISSN 1755-3245
Zeitschrift Cardiovascular Research
Quellenangaben Band: 120, Heft: 12, Seiten: 1411-1426 Artikelnummer: , Supplement: ,
Verlag Oxford University Press
Verlagsort Great Clarendon St, Oxford Ox2 6dp, England
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Diabetes and Cancer (IDC)
Förderungen Chinese Scholar Council
Federal Ministry of Education and Research (BMBF)
LMU Medical Faculty FoeFoLe program
Interdisciplinary Center for Clinical Research within the faculty of Medicine at the RWTH Aachen University
Fritz Thyssen Stiftung
Deutsche Forschungsgemeinschaft