CETP Expression in Bone-Marrow-Derived Cells Reduces the Inflammatory Features of Atherosclerosis in Hypercholesterolemic Mice

Author:

Rentz Thiago1ORCID,Dorighello Gabriel G.1ORCID,dos Santos Renata R.2,Barreto Lohanna M.1,Freitas Israelle N.1,Lazaro Carolina M.1,Razolli Daniela S.3ORCID,Cazita Patricia M.4,Oliveira Helena C. F.13ORCID

Affiliation:

1. Department of Structural and Functional Biology, Institute of Biology, State University of Campinas, Campinas 13083-862, SP, Brazil

2. Division of Radiotherapy, Medical School Hospital, Faculty of Medical Sciences, State University of Campinas, Campinas 13083-887, SP, Brazil

3. Obesity and Comorbidities Research Center, State University of Campinas, Campinas 13083-864, SP, Brazil

4. Laboratório de Lípides (LIM10), Hospital das Clínicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo 01246-903, SP, Brazil

Abstract

CETP activity reduces plasma HDL-cholesterol concentrations, a correlate of an increased risk of atherosclerotic events. However, our recent findings suggest that CETP expression in macrophages promotes an intracellular antioxidant state, reduces free cholesterol accumulation and phagocytosis, and attenuates pro-inflammatory gene expression. To determine whether CETP expression in macrophages affects atherosclerosis development, we transplanted bone marrow from transgenic mice expressing simian CETP or non-expressing littermates into hypercholesterolemic LDL-receptor-deficient mice. The CETP expression did not change the lipid-stained lesion areas but decreased the macrophage content (CD68), neutrophil accumulation (LY6G), and TNF-α aorta content of young male transplanted mice and decreased LY6G, TNF-α, iNOS, and nitrotyrosine (3-NT) in aged female transplanted mice. These findings suggest that CETP expression in bone-marrow-derived cells reduces the inflammatory features of atherosclerosis. These novel mechanistic observations may help to explain the failure of CETP inhibitors in reducing atherosclerotic events in humans.

Funder

Fundação de Amparo à Pesquisa do Estado de São Paulo

CAPES (Coordenação de Aperfeiçoamento de Pessoal de Nível Superior) fellowship

FAPESP fellowships

Publisher

MDPI AG

Subject

Molecular Biology,Biochemistry

Reference52 articles.

1. (2023, May 23). Cardiovascular Diseases (CVDs). Available online: https://www.who.int/news-room/fact-sheets/detail/cardiovascular-diseases-(cvds).

2. From Focal Lipid Storage to Systemic Inflammation: JACC Review Topic of the Week;Libby;J. Am. Coll. Cardiol.,2019

3. Macrophages in Atherosclerosis: A Dynamic Balance;Moore;Nat. Rev. Immunol.,2013

4. Mitochondrial Bioenergetics and Redox Dysfunctions in Hypercholesterolemia and Atherosclerosis;Oliveira;Mol. Asp. Med.,2020

5. Cholesterol Efflux Pathways Regulate Myelopoiesis: A Potential Link to Altered Macrophage Function in Atherosclerosis;Murphy;Front. Immunol.,2014

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