Cytosolic Hsp60 orchestrates the survival and inflammatory responses of vascular smooth muscle cells in injured aortic vessels

Choi, Boae; Choi, Myung-Un; Park, Charny; Lee, Eun Kyung; Kang, Dong Hoon; Lee, Dong Hoon; Yeom, Jae Yoon; Jung, Yeonjoo; Kim, Jaesang; Lee, Sanghyuk; Kang, Sang Won

doi:10.1093/cvr/cvv130

Cited by 20 publications

(11 citation statements)

References 37 publications

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“…Additionally, OSMR-β −/− ApoE −/− mice exhibited a dramatic increase in the content of collagen and SMCs, but a decrease in macrophage infiltration and lipid accumulation. It has been demonstrated that the inflammation induced by TNF-α or IL-1β can promote matrix-degrading metalloproteinase expression and promote tissue remodeling (34, 35), and TNF-α facilitates oxidative stress in SMCs and accelerates vascular SMC apoptosis (36, 37). Correspondingly, previous studies have demonstrated that advanced lesions are characterized by the apoptosis and necrosis of macrophages or other cell types, which results in the release of lipids and inflammatory mediators and the formation of the necrotic core.…”

Section: Discussionmentioning

confidence: 99%

Oncostatin M receptor β deficiency attenuates atherogenesis by inhibiting JAK2/STAT3 signaling in macrophages

Zhang

Qin

et al. 2017

Journal of Lipid Research

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Oncostatin M (OSM) is a secreted cytokine mainly involved in chronic inflammatory and cardiovascular diseases through binding to OSM receptor β (OSMR-β). Recent studies demonstrated that the presence of OSM contributed to the destabilization of atherosclerotic plaque. To investigate whether OSMR-β deficiency affects atherosclerosis, male OSMR-β−/−ApoE−/− mice were generated and utilized. Here we observed that OSMR-β expression was remarkably upregulated in both human and mouse atherosclerotic lesions, which were mainly located in macrophages. We found that OSMR-β deficiency significantly ameliorated atherosclerotic burden in aorta and aortic root relative to ApoE-deficient littermates and enhanced the stability of atherosclerotic plaques by increasing collagen and smooth muscle cell content, while decreasing macrophage infiltration and lipid accumulation. Moreover, bone marrow transplantation of OSMR-β−/− hematopoietic cells to atherosclerosis-prone mice displayed a consistent phenotype. Additionally, we observed a relatively reduced level of JAK2 and signal transducer and activator of transcription (STAT)3 in vivo and under Ox-LDL stimulation in vitro. Our findings suggest that OSMR-β deficiency in macrophages improved high-fat diet-induced atherogenesis and plaque vulnerability. Mechanistically, the protective effect of OSMR-β deficiency on atherosclerosis may be partially attributed to the inhibition of the JAK2/STAT3 activation in macrophages, whereas OSM stimulation can activate the signaling pathway.

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Section: Discussionmentioning

confidence: 99%

Oncostatin M receptor β deficiency attenuates atherogenesis by inhibiting JAK2/STAT3 signaling in macrophages

Zhang

Qin

et al. 2017

Journal of Lipid Research

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“…Hsp60 activation of the IKK/NF-κB pathway for survival can be seen in vascular smooth muscle cells where it can prevent apoptosis as well as promote neointimal thickening of the damaged vessels. However, persistent activation of the pathway has been linked to various chronic inflammatory diseases such as cancer and atherosclerosis ( Choi et al, 2015 ). From the cytosol, Hsp60 can leave the inside of the cell and attach itself to the cell’s surface or enter the extracellular space through secretory vesicles ( Campanella et al, 2012 ).…”

Section: Chaperonopathies and The Role Of Mthsp60 In Diseasementioning

confidence: 99%

“…The mtHsp60 encoding gene HSPD1 is a nuclear gene that is translated in the cytosol and imported into the mitochondria due to the presence of an N-terminal mitochondrial targeting sequence that is cleaved upon translocation across the mitochondrial membrane ( Cheng et al, 1989 , 1990 ; Reading et al, 1989 ; Singh et al, 1990 ). A small fraction of Hsp60 resides in the cytosol and also at the cell surface but the function outside of the mitochondria has not been well established ( Soltys and Radhey, 1997 ; Chun et al, 2010 ; Choi et al, 2015 ; Kalderon et al, 2015 ). Chaperonins carry out protein folding cycles in an ATP-dependent manner.…”

Section: Introductionmentioning

confidence: 99%

Complex Destabilization in the Mitochondrial Chaperonin Hsp60 Leads to Disease

Rodrı́guez

Salzen

Holguin

et al. 2020

Front. Mol. Biosci.

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Several neurological disorders have been linked to mutations in chaperonin genes and more specifically to the HSPD1 gene. In humans, HSPD1 encodes the mitochondrial Heat Shock Protein 60 (mtHsp60) chaperonin, which carries out essential protein folding reactions that help maintain mitochondrial and cellular homeostasis. It functions as a macromolecular complex that provides client proteins an environment that favors proper folding in an ATP-dependent manner. It has been established that mtHsp60 plays a crucial role in the proper folding of mitochondrial proteins involved in ATP producing pathways. Recently, various single-point mutations in the mtHsp60 encoding gene have been directly linked to neuropathies and paraplegias. Individuals who harbor mtHsp60 mutations that negatively impact its folding ability display phenotypes with highly compromised muscle and neuron cells. Carriers of these mutations usually develop neuropathies and paraplegias at different stages of their lives mainly characterized by leg stiffness and weakness as well as degeneration of spinal cord nerves. These phenotypes are likely due to hindered energy producing pathways involved in cellular respiration resulting in ATP deprived cells. Although the complete protein folding mechanism of mtHsp60 is not well understood, recent work suggests that several of these mutations act by destabilizing the oligomeric stability of mtHsp60. Here, we discuss recent studies that highlight key aspects of the mtHsp60 mechanism with a focus on some of the known disease-causing point mutations, D29G and V98I, and their effect on the protein folding reaction cycle.

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“…Both TNF‐α and IL‐1β, for example, induce matrix‐degrading metalloproteinase expression and promote tissue remodeling . In addition, TNF‐α facilitates increases in oxidative stress in VSMCs and facilitates VSMC apoptosis . In contrast to these proinflammatory cytokines, IL‐10 is a potent anti‐inflammatory cytokine with the ability to deactivate macrophages .…”

Section: Discussionmentioning

confidence: 99%

“…34,35 In addition, TNF-a facilitates increases in oxidative stress in VSMCs and facilitates VSMC apoptosis. 36,37 In contrast to these proinflammatory cytokines, IL-10 is a potent anti-inflammatory cytokine with the ability to deactivate macrophages. 38 Consistent with these studies, we found that vinexin b À/À apo E À/À mice exhibited more stable lesions characterized by diminished necrotic cores and increased collagen and VSMC content.…”

Section: Discussionmentioning

confidence: 99%

Vinexin β Ablation Inhibits Atherosclerosis in Apolipoprotein E–Deficient Mice by Inactivating the Akt–Nuclear Factor κB Inflammatory Axis

Guan

Cheng

Guo

et al. 2017

JAHA

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BackgroundVinexin β is a novel adaptor protein that regulates cellular adhesion, cytoskeletal reorganization, signal transduction, and transcription; however, the exact role that vinexin β plays in atherosclerosis remains unknown.Methods and ResultsImmunoblot analysis showed that vinexin β expression is upregulated in the atherosclerotic lesions of both patients with coronary heart disease and hyperlipemic apolipoprotein E–deficient mice and is primarily localized in macrophages indicated by immunofluorescence staining. The high‐fat diet–induced double‐knockout mice exhibited lower aortic plaque burdens than apolipoprotein E−/− littermates and decreased macrophage content. Vinexin β deficiency improved plaque stability by attenuating lipid accumulation and increasing smooth muscle cell content and collagen. Moreover, the bone marrow transplant experiment demonstrated that vinexin β deficiency exerts atheroprotective effects in hematopoietic cells. Consistent with these changes, the mRNA expression of proinflammatory cytokines were downregulated in vinexin β−/− apolipoprotein E−/− mice, whereas the anti‐inflammatory M2 macrophage markers were upregulated. The immunohistochemical staining and in vitro experiments showed that deficiency of vinexin β inhibited the accumulation of monocytes and the migration of macrophages induced by tumor necrosis factor α–stimulated human umbilical vein endothelial cells as well as macrophage proliferation. Finally, the inhibitory effects exerted by vinexin β deficiency on foam cell formation, nuclear factor κB activation, and inflammatory cytokine expression were largely reversed by constitutive Akt activation, whereas the increased expression of the nuclear factor κB subset promoted by adenoviral vinexin β was dramatically suppressed by inhibition of AKT.ConclusionsVinexin β deficiency attenuates atherogenesis primarily by suppressing vascular inflammation and inactivating Akt–nuclear factor κB signaling. Our data suggest that vinexin β could be a therapeutic target for the treatment of atherosclerosis.

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Cytosolic Hsp60 orchestrates the survival and inflammatory responses of vascular smooth muscle cells in injured aortic vessels

Abstract: This study provides the first evidence that cytosolic Hsp60 could be a therapeutic target for preventing VSMC hyperplasia and inflammatory response in the injured vessels.

Cited by 20 publications

References 37 publications

Oncostatin M receptor β deficiency attenuates atherogenesis by inhibiting JAK2/STAT3 signaling in macrophages

Oncostatin M receptor β deficiency attenuates atherogenesis by inhibiting JAK2/STAT3 signaling in macrophages

Complex Destabilization in the Mitochondrial Chaperonin Hsp60 Leads to Disease

Vinexin β Ablation Inhibits Atherosclerosis in Apolipoprotein E–Deficient Mice by Inactivating the Akt–Nuclear Factor κB Inflammatory Axis

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