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Emerging roles of calpain proteolytic systems in macrophage cholesterol handling

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Abstract

Calpains are Ca2+-dependent intracellular proteases that play central roles in the post-translational processing of functional proteins. In mammals, calpain proteolytic systems comprise the endogenous inhibitor calpastatin as well as 15 homologues of the catalytic subunits and two homologues of the regulatory subunits. Recent pharmacological and gene targeting studies in experimental animal models have revealed the contribution of conventional calpains, which consist of the calpain-1 and -2 isozymes, to atherosclerotic diseases. During atherogenesis, conventional calpains facilitate the CD36-dependent uptake of oxidized low-density lipoprotein (LDL), and block cholesterol efflux through ATP-binding cassette transporters in lesional macrophages, allowing the expansion of lipid-enriched atherosclerotic plaques. In addition, calpain-6, an unconventional non-proteolytic calpain, in macrophages reportedly potentiates pinocytotic uptake of native LDL, and attenuates the efferocytic clearance of apoptotic and necrotic cell corpses from the lesions. Herein, we discuss the recent progress that has been made in our understanding of how calpain contributes to atherosclerosis, in particular focusing on macrophage cholesterol handling.

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Abbreviations

ABCA1:

ATP-binding cassette transporter A1

ABCA7:

ATP-binding cassette transporter A7

ABCG1:

ATP-binding cassette transporter G1

ACAT1:

Acyl-coenzyme A: cholesterol acyltransferase 1

ApoE:

Apolipoprotein E

Capn:

Calpain

EC:

Endothelial cell

EJC:

Exon junction complex

Gas6:

Growth arrest specific 6

HDL:

High-density lipoprotein

ICAM-1:

Intercellular adhesion molecule-1

LDL:

Low-density lipoprotein

LDLR:

LDL receptor

LGMD2A:

Limb-girdle muscular dystrophy type 2A

LOX-1:

Lectin-like oxidized low-density lipoprotein receptor-1

LXRα:

Liver X receptor α

MCP-1:

Monocyte chemoattractant protein-1

M-CSF:

Macrophage colony-stimulating factor

MertK:

C-mer proto-oncogene tyrosine kinase

PPARγ:

Peroxisome proliferator-activated receptor γ

RANKL:

Receptor activator of nuclear factor kappa-B ligand

SOCS3:

Suppressor of cytokine signaling-3

SR-A:

Class A scavenger receptor

TNF-α:

Tumor necrosis factor-α

VCAM-1:

Vascular cell adhesion molecule-1

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Acknowledgements

This study was supported in part by Japan Society for the Promotion of Science KAKENHI Grant Number 26461368 (to A.M.), Japan Society for the Promotion of Science KAKENHI Grant Number 15K09418 (to T.M.), a research grant from Takeda Science Foundation, a research grant from Banyu Life Science Foundation International, a research grant from NOVARTIS Foundation, a research grant from Ono Medical Research Foundation, and the Japan Heart Foundation and Astellas Grant for Research on Atherosclerosis Update, and a research grant from SENSHIN Medical Research Foundation (all to T.M.).

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  1. Department of Biochemistry, Showa University School of Medicine, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo, 142-8555, Japan

    Takuro Miyazaki & Akira Miyazaki

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  1. Takuro Miyazaki
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  2. Akira Miyazaki
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Correspondence to Takuro Miyazaki.

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Miyazaki, T., Miyazaki, A. Emerging roles of calpain proteolytic systems in macrophage cholesterol handling. Cell. Mol. Life Sci. 74, 3011–3021 (2017). https://doi.org/10.1007/s00018-017-2528-7

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  • DOI: https://doi.org/10.1007/s00018-017-2528-7

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