Calpain and Atherosclerosis

Miyazaki, Takuro; Koya, Takayuki; Kigawa, Yasuyoshi; Oguchi, Tamio; Lei, Xiaofeng; Kim‐Kaneyama, Joo‐ri; Miyazaki, Akira

doi:10.5551/jat.14787

Cited by 37 publications

(33 citation statements)

References 74 publications

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“…Well-established ubiquitous isozymes, μ-and m-calpain, which require micromolar and millimolar levels of Ca 2+ for half-maximal activation, respectively, are normally kept inactive because an endogenous inhibitor, calpastatin (CAST), colocalizes and robustly downregulates their enzymatic activity intracellularly. 12,13 A previous investigation suggested that pharmacological intervention against systemic calpain systems ameliorates pathological angiogenesis in a mouse OIR model 14 ; nevertheless, EC-specific roles of calpain system contribution to pathological angiogenesis are still unclear. Calpain reportedly proteolyzes various signal transducers in a site-specific fashion, thereby modifying the functions of their substrates 12,13 ; hence, we hypothesized that calpain/CAST systems in ECs proteolytically modulate the JAK/STAT/SOCS signals and disturb pathological angiogenesis.…”

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confidence: 99%

Calpastatin Counteracts Pathological Angiogenesis by Inhibiting Suppressor of Cytokine Signaling 3 Degradation in Vascular Endothelial Cells

Miyazaki

Taketomi

Saito

et al. 2015

Circulation Research

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Rationale: Janus kinase/signal transducer and activator of transcription (JAK/STAT) signals and their endogenous inhibitor, suppressor of cytokine signaling 3 (SOCS3), in vascular endothelial cells (ECs) reportedly dominate the pathological angiogenesis. However, how these inflammatory signals are potentiated during pathological angiogenesis has not been fully elucidated. We suspected that an intracellular protease calpain, which composes the multifunctional proteolytic systems together with its endogenous inhibitor calpastatin (CAST), contributes to the JAK/STAT regulations. Objective: To specify the effect of EC calpain/CAST systems on JAK/STAT signals and their relationship with pathological angiogenesis. Methods and Results: The loss of CAST, which is ensured by several growth factor classes, was detectable in neovessels in murine allograft tumors, some human malignant tissues, and oxygen-induced retinopathy lesions in mice. EC-specific transgenic introduction of CAST caused downregulation of JAK/STAT signals, upregulation of SOCS3 expression, and depletion of vascular endothelial growth factor (VEGF)-C, thereby counteracting unstable pathological neovessels and disease progression in tumors and oxygen-induced retinopathy lesions in mice. Neutralizing antibody against VEGF-C ameliorated pathological angiogenesis in oxygen-induced retinopathy lesions. Small interfering RNA–based silencing of endogenous CAST in cultured ECs facilitated μ-calpain–induced proteolytic degradation of SOCS3, leading to VEGF-C production through amplified interleukin-6–driven STAT3 signals. Interleukin-6–induced angiogenic tube formation in cultured ECs was accelerated by CAST silencing, which is suppressible by pharmacological inhibition of JAK/STAT signals, antibody-based blockage of VEGF-C, and transfection of calpain-resistant SOCS3, whereas transfection of wild-type SOCS3 exhibited modest angiostatic effects. Conclusions: Loss of CAST in angiogenic ECs facilitates μ-calpain–induced SOCS3 degradation, which amplifies pathological angiogenesis through interleukin-6/STAT3/VEGF-C axis.

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confidence: 99%

Calpastatin Counteracts Pathological Angiogenesis by Inhibiting Suppressor of Cytokine Signaling 3 Degradation in Vascular Endothelial Cells

Miyazaki

Taketomi

Saito

et al. 2015

Circulation Research

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“…41 Calpain induces proteolytic degradation of ABCA1 and disrupts the biogenesis of HDL in hepatocytes. 42 The work reported here showed that tBHQ stimulated nuclear translocation of Nrf2 and subsequently increased the expression of the ARE-dependent gene, HO-1, inhibited calpain activity and then upregulated the ABCA1 protein level. Calpains have more than 10 isoforms; the μ-and m-calpains, the most characterized isoforms, are ubiquitously expressed in mammalian tissues, and tightly regulate functional molecules through limited proteolytic cleavage.…”

Section: Increased Abca1 Protein Expression and Cholesterol Effluxmentioning

confidence: 88%

Tertiary-Butylhydroquinone Upregulates Expression of ATP-Binding Cassette Transporter A1 via Nuclear Factor E2-Related Factor 2/Heme Oxygenase-1 Signaling in THP-1 Macrophage-Derived Foam Cells

Lü¹,

Tang

Liu³

et al. 2013

Circ J

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“…By using pharmacological inhibitors or mice deficient in calpain-1 or calpain-2 or mice over-expressing calpastatin, the endogenous inhibitor, many studies demonstrated that inactivation of calpain inhibited the atherosclerosis, suggesting that calpains gets involved in the pathogenesis of atherosclerosis (Clinkinbeard et al 2013;Hua and Nair 2015;Miyazaki et al 2013;Ruetten and Thiemermann 1997;Takeshita et al 2013). …”

Section: Discussionmentioning

confidence: 99%

“…Among the superfamily, Calpain-1 and calpain-2 are categorized as "conventional calpain" (Daugherty et al 2000). By using pharmacological inhibitors or mice deficient in calpain-1 or calpain-2 or mice over-expressing calpastatin, the endogenous inhibitor, many studies demonstrated that inactivation of calpain inhibited atherosclerosis, suggesting the involvement of calpains in the development of atherosclerosis (Clinkinbeard et al 2013;Hua and Nair 2015;Miyazaki et al 2013;Ruetten and Thiemermann 1997;Takeshita et al 2013). We previously reported that calpain-1 gets involved in the atherogenesis by up-regulating the scavenger receptor CD36 expression (Yang et al 2016).…”

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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Calpain and Atherosclerosis

Cited by 37 publications

References 74 publications

Calpastatin Counteracts Pathological Angiogenesis by Inhibiting Suppressor of Cytokine Signaling 3 Degradation in Vascular Endothelial Cells

Calpastatin Counteracts Pathological Angiogenesis by Inhibiting Suppressor of Cytokine Signaling 3 Degradation in Vascular Endothelial Cells

Tertiary-Butylhydroquinone Upregulates Expression of ATP-Binding Cassette Transporter A1 via Nuclear Factor E2-Related Factor 2/Heme Oxygenase-1 Signaling in THP-1 Macrophage-Derived Foam Cells

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

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