Calpain-6 confers atherogenicity to macrophages by dysregulating pre-mRNA splicing

Miyazaki, Takuro; Tonami, Kazuo; Hata, Shoji; Aiuchi, Toshihiro; Ohnishi, Koji; Liu, Xiao; Kim-Kaneyama, Joo Ri; Takeya, Motohiro; Itabe, Hiroyuki; Sorimachi, Hiroyuki; Kurihara, Hiroki; Miyazaki, Akira

doi:10.1172/jci85880

Cited by 30 publications

(44 citation statements)

References 38 publications

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“…Importantly, ablation of calpain-6 substantially decreases pinocytotic activity in macrophages in murine atherosclerotic lesions [52]. Immunohistochemistry in human aortic atheromas showed that the nuclear localization of CWC22 is diminished in macrophages in advanced atheromas but not in the cells in mild atherosclerotic lesions, while calpain-6 is upregulated in macrophages in the advanced atheromas [52]. Thus, the calpain-6-induced disruption of the CWC22/EJC complex in macrophages translates into human atherosclerotic lesions.…”

Section: Pinocytotic Uptake Of Native Ldlmentioning

confidence: 99%

“…We have recently described the contribution of unconventional calpains to the pathogenesis of atherosclerosis [52]. Among calpain family members, Capn2, Capn6 and Capn9 are induced in pro-atherogenic aortae of high cholesterol diet-fed Ldlr -/-mice.…”

Section: Calpain and Atherogenesismentioning

confidence: 99%

“…In addition to those molecules, contributions of Rho GTPases to this phenomenon have been documented [86,87]. Pinocytotic LDL uptake in cultured macrophages is mediated through calpain-6, whereas the uptake of oxidized LDL through scavenger receptors is independent of this molecule [52]. In atherosclerotic lesions, calpain-6 is induced in macrophages in response to inflammatory cytokines such as TNF-a, and directly binds to CWC22, an essential loading factor for the exon-junction complex (EJC).…”

Section: Pinocytotic Uptake Of Native Ldlmentioning

confidence: 99%

“…It is noteworthy that Rac1 is a negative regulator of pinocytosis; thus, the impaired nuclear translocation of CWC22 by calpain-6 augments the pinocytotic uptake of native LDL in macrophages. Importantly, ablation of calpain-6 substantially decreases pinocytotic activity in macrophages in murine atherosclerotic lesions [52]. Immunohistochemistry in human aortic atheromas showed that the nuclear localization of CWC22 is diminished in macrophages in advanced atheromas but not in the cells in mild atherosclerotic lesions, while calpain-6 is upregulated in macrophages in the advanced atheromas [52].…”

Section: Pinocytotic Uptake Of Native Ldlmentioning

confidence: 99%

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Emerging roles of calpain proteolytic systems in macrophage cholesterol handling

Miyazaki

2017

Cell. Mol. Life Sci.

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Calpains are Ca-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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Section: Pinocytotic Uptake Of Native Ldlmentioning

confidence: 99%

Section: Calpain and Atherogenesismentioning

confidence: 99%

Section: Pinocytotic Uptake Of Native Ldlmentioning

confidence: 99%

Section: Pinocytotic Uptake Of Native Ldlmentioning

confidence: 99%

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Emerging roles of calpain proteolytic systems in macrophage cholesterol handling

Miyazaki

2017

Cell. Mol. Life Sci.

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“…We previously reported that calpain-1 gets involved in the atherogenesis by up-regulating the scavenger receptor CD36 expression (Yang et al 2016). In addition to conventional calpain, one of unconventional calpain isozyme, calpain-6, appears to be induced in macrophages during atherogenesis, thereby facilitating form cell formation (Miyazaki et al 2016). Calpains D r a f t have also been implicated to play a critical deleterious role in endothelial dysfunction (Stalker et al 2003).…”

Section: Introductionmentioning

confidence: 99%

Calpain inhibitor I attenuates atherosclerosis and inflammation in atherosclerotic rats through eNOS/NO/NF-κB pathway

Yin

Yang³

et al. 2018

Can. J. Physiol. Pharmacol.

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We previously reported that calpain, the Ca2+-sensitive cysteine protease, gets involved in atherogenesis. This study aimed to investigate the effects of calpain inhibitor I (CAI, 5 mg/kg per day) with or without NG-nitro-l-arginine-methyl ester (l-NAME) (100 mg/kg per day), the inhibitor of nitric oxide synthase (NOS), on atherosclerosis and inflammation in a rat model induced by high-cholesterol diet (HCD). The results demonstrated HCD increased protein expression of calpain-1 but not calpain-2 in aortic tissue. In addition, CAI reduced the thickness of atherosclerotic intima compared with HCD group, which was weakened by the l-NAME combination. CAI with or without l-NAME decreased the activity of calpain in the aorta. Also, CAI decreased the expressions of vascular cell adhesion molecule-1 (VCAM-1), intracellular cell adhesion molecule-1 (ICAM-1), and monocyte chemoattractant protein-1 (MCP-1) in the aorta at the levels of both mRNA and protein. Furthermore, CAI increased the activity and the protein expression of endothelial NOS (eNOS) accompanied by increased content of NO and downregulated the protein expression of nuclear factor κB (NF-κB) of the nucleus in the aorta. However, the abovementioned effects were at least partly cancelled by l-NAME except for the protein expression of eNOS. The results suggested that CAI attenuated atherosclerosis and inflammation through eNOS/NO/NF-κB pathway.

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Effects of functionally diverse calpain system on immune cells

Chen

Liu

2021

Immunol Res

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Calpain-6 confers atherogenicity to macrophages by dysregulating pre-mRNA splicing

Cited by 30 publications

References 38 publications

Emerging roles of calpain proteolytic systems in macrophage cholesterol handling

Emerging roles of calpain proteolytic systems in macrophage cholesterol handling

Calpain inhibitor I attenuates atherosclerosis and inflammation in atherosclerotic rats through eNOS/NO/NF-κB pathway

Effects of functionally diverse calpain system on immune cells

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