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Lawrence Steinman - One of the best experts on this subject based on the ideXlab platform.

  • phosphorylation of αb crystallin supports reactive astrogliosis in demyelination
    Proceedings of the National Academy of Sciences of the United States of America, 2017
    Co-Authors: Hedwich F Kuipers, Jane Yoon, Jack Van Horssen, May H Han, Paul L Bollyky, Theo D Palmer, Lawrence Steinman
    Abstract:

    The small heat shock protein αB-crystallin (CRYAB) has been implicated in multiple sclerosis (MS) pathogenesis. Earlier studies have indicated that CRYAB inhibits inflammation and attenuates clinical disease when administered in the experimental autoimmune encephalomyelitis model of MS. In this study, we evaluated the role of CRYAB in primary demyelinating events. Using the cuprizone model of demyelination, a noninflammatory model that allows the analysis of glial responses in MS, we show that endogenous CRYAB expression is associated with increased severity of demyelination. Moreover, we demonstrate a strong correlation between the expression of CRYAB and the extent of reactive astrogliosis in demyelinating areas and in in vitro assays. In addition, we reveal that CRYAB is differentially phosphorylated in astrocytes in active demyelinating MS lesions, as well as in cuprizone-induced lesions, and that this phosphorylation is required for the reactive astrocyte response associated with demyelination. Furthermore, taking a proteomics approach to identify proteins that are bound by the phosphorylated forms of CRYAB in primary cultured astrocytes, we show that there is clear differential binding of protein targets due to the specific phosphorylation of CRYAB. Subsequent Ingenuity Pathway Analysis of these targets reveals implications for intracellular pathways and biological processes that could be affected by these modifications. Together, these findings demonstrate that astrocytes play a pivotal role in demyelination, making them a potential target for therapeutic intervention, and that phosphorylation of CRYAB is a key factor supporting the pathogenic response of astrocytes to oligodendrocyte injury.

  • CRYAB modulates the activation of CD4+ T cells from relapsing–remitting multiple sclerosis patients
    Multiple sclerosis (Houndmills Basingstoke England), 2013
    Co-Authors: Que Lan Quach, Lawrence Steinman, Jonathan B Rothbard, Luanne M. Metz, Jenna C. Thomas, Shalina S Ousman
    Abstract:

    Background:Suppression of activation of pathogenic CD4+ T cells is a potential therapeutic intervention in multiple sclerosis (MS). We previously showed that a small heat shock protein, CRYAB, reduced T cell proliferation, pro-inflammatory cytokine production and clinical signs of experimental allergic encephalomyelitis, a model of MS.Objective:We assessed whether the ability of CRYAB to reduce the activation of T cells translated to the human disease.Methods:CD4+ T cells from healthy controls and volunteers with MS were activated in vitro in the presence or absence of a CRYAB peptide (residues 73–92). Parameters of activation (proliferation rate, cytokine secretion) and tolerance (anergy, activation-induced cell death, microRNAs) were evaluated.Results:The secretion of pro-inflammatory cytokines by CD4+ T cells was decreased in the presence of CRYAB in a subset of relapsing–remitting multiple sclerosis (RRMS) participants with mild disease severity while no changes were observed in healthy controls. Furt...

  • CRYAB modulates the activation of cd4 t cells from relapsing remitting multiple sclerosis patients
    Multiple Sclerosis Journal, 2013
    Co-Authors: Que Lan Quach, Lawrence Steinman, Jonathan B Rothbard, Luanne M. Metz, Jenna C. Thomas, Shalina S Ousman
    Abstract:

    Background:Suppression of activation of pathogenic CD4+ T cells is a potential therapeutic intervention in multiple sclerosis (MS). We previously showed that a small heat shock protein, CRYAB, reduced T cell proliferation, pro-inflammatory cytokine production and clinical signs of experimental allergic encephalomyelitis, a model of MS.Objective:We assessed whether the ability of CRYAB to reduce the activation of T cells translated to the human disease.Methods:CD4+ T cells from healthy controls and volunteers with MS were activated in vitro in the presence or absence of a CRYAB peptide (residues 73–92). Parameters of activation (proliferation rate, cytokine secretion) and tolerance (anergy, activation-induced cell death, microRNAs) were evaluated.Results:The secretion of pro-inflammatory cytokines by CD4+ T cells was decreased in the presence of CRYAB in a subset of relapsing–remitting multiple sclerosis (RRMS) participants with mild disease severity while no changes were observed in healthy controls. Furt...

  • systemic augmentation of αb crystallin provides therapeutic benefit twelve hours post stroke onset via immune modulation
    Proceedings of the National Academy of Sciences of the United States of America, 2011
    Co-Authors: Ahmet Arac, Lawrence Steinman, Sara E Brownell, Jonathan B Rothbard, Charlene Chen, Marta P Pereira, Gregory W Albers, Gary K Steinberg
    Abstract:

    Tissue plasminogen activator is the only treatment option for stroke victims; however, it has to be administered within 4.5 h after symptom onset, making its use very limited. This report describes a unique target for effective treatment of stroke, even 12 h after onset, by the administration of αB-crystallin (CRYAB), an endogenous immunomodulatory neuroprotectant. In CRYAB−/− mice, there was increased lesion size and diminished neurologic function after stroke compared with wild-type mice. Increased plasma CRYAB was detected after experimental stroke in mice and after stroke in human patients. Administration of CRYAB even 12 h after experimental stroke reduced both stroke volume and inflammatory cytokines associated with stroke pathology. CRYAB is an endogenous anti-inflammatory and neuroprotectant molecule produced after stroke, whose beneficial properties can be augmented when administered therapeutically after stroke.

  • αb crystallin improves murine cardiac function and attenuates apoptosis in human endothelial cells exposed to ischemia reperfusion
    The Annals of Thoracic Surgery, 2011
    Co-Authors: Jeffrey B Velotta, Lawrence Steinman, Jonathan B Rothbard, Naoyuki Kimura, Stephanie H Chang, Jaehoon Chung, Satoshi Itoh, Philip C Yang, Robert C Robbins, Michael P Fischbein
    Abstract:

    Background This study investigates the protective effect of exogenous αB-crystallin (CRYAB) on myocardial function after ischemia-reperfusion injury. Methods Mice underwent temporary left anterior descending artery occlusion for 30 minutes. Either CRYAB (50 μg) or phosphate-buffered saline (100 μL [n = 6, each group]) were injected in the intramyocardial medial and lateral perinfarct zone 15 minutes before reperfusion. Intraperitoneal injections were administered every other day. Left ventricular ejection fraction was evaluated on postoperative day 40 with magnetic resonance imaging. To investigate the effect of CRYAB on apoptosis after hypoxia/reoxygenation in vitro, murine atrial cardiomyocytes (HL-1 cells) or human microvascular endothelial cells (HMEC-1) were incubated with either 50 μg CRYAB (500 μg /10 mL) or phosphate-buffered saline in a hypoxia chamber for 6, 12, and 24 hours, followed by 30 minutes of reoxygenation at room air. Apoptosis was then assessed by western blot (Bcl-2, free bax, cleaved caspases-3, 9, PARP) and enzyme-linked immunosorbent assay analyses (cytoplasmic histone-associated DNA fragments and caspase-3 activity). Results On postoperative day 40, CRYAB-treated mice had a 1.8-fold increase in left ventricular ejection fraction versus control mice (27% ± 6% versus 15% ± 4% SD, p p p Conclusions Exogenous CRYAB administration significantly improves cardiac function after ischemia-reperfusion injury, in vivo. The protective anti-apoptotic affects of CRYAB may target the endothelial cell.

Shalina S Ousman - One of the best experts on this subject based on the ideXlab platform.

  • Presence and activation of pro-inflammatory macrophages are associated with CRYAB expression in vitro and after peripheral nerve injury.
    Journal of neuroinflammation, 2021
    Co-Authors: Erin-mai F Lim, Trisha M Finlay, Vahid Hoghooghi, Kathleen M Hagen, Kunal Kapoor, Ariana Frederick, Shalina S Ousman
    Abstract:

    Inflammation constitutes both positive and negative aspects to recovery following peripheral nerve injury. Following damage to the peripheral nervous system (PNS), immune cells such as macrophages play a beneficial role in creating a supportive environment for regrowing axons by phagocytosing myelin and axonal debris. However, a prolonged inflammatory response after peripheral nerve injury has been implicated in the pathogenesis of negative symptoms like neuropathic pain. Therefore, the post-injury inflammation must be carefully controlled to prevent secondary damage while allowing for regeneration. CRYAB (also known as alphaB-crystallin/HSPB5) is a small heat shock protein that has many protective functions including an immunomodulatory role in mouse models of multiple sclerosis, spinal cord injury, and stroke. Because its expression wanes and rebounds in the early and late periods respectively after PNS damage, and CRYAB null mice with sciatic nerve crush injury display symptoms of pain, we investigated whether CRYAB is involved in the immune response following PNS injury. Sciatic nerve crush injuries were performed in age-matched CRYAB knockout (CRYAB-/-) and wildtype (WT) female mice. Nerve segments distal to the injury site were processed by immunohistochemistry for macrophages and myelin while protein lysates of the nerves were analyzed for cytokines and chemokines using Luminex and enzyme-linked immunosorbent assay (ELISA). Peritoneal macrophages from the two genotypes were also cultured and polarized into pro-inflammatory or anti-inflammatory phenotypes where their supernatants were analyzed for cytokines and chemokines by ELISA and protein lysates for macrophage antigen presenting markers using western blotting. We report that (1) more pro-inflammatory CD16/32+ macrophages are present in the nerves of CRYAB-/- mice at days 14 and 21 after sciatic nerve crush-injury compared to WT counterparts, and (2) CRYAB has an immunosuppressive effect on cytokine secretion [interleukin (IL)-β, IL-6, IL-12p40, tumor necrosis factor (TNF)-α] from pro-inflammatory macrophages in vitro. CRYAB may play a role in curbing the potentially detrimental pro-inflammatory macrophage response during the late stages of peripheral nerve regeneration.

  • presence and activation of pro inflammatory macrophages are associated with CRYAB expression in vitro and after peripheral nerve injury
    Journal of Neuroinflammation, 2021
    Co-Authors: Erin-mai F Lim, Trisha M Finlay, Vahid Hoghooghi, Kathleen M Hagen, Kunal Kapoor, Ariana Frederick, Shalina S Ousman
    Abstract:

    BACKGROUND Inflammation constitutes both positive and negative aspects to recovery following peripheral nerve injury. Following damage to the peripheral nervous system (PNS), immune cells such as macrophages play a beneficial role in creating a supportive environment for regrowing axons by phagocytosing myelin and axonal debris. However, a prolonged inflammatory response after peripheral nerve injury has been implicated in the pathogenesis of negative symptoms like neuropathic pain. Therefore, the post-injury inflammation must be carefully controlled to prevent secondary damage while allowing for regeneration. CRYAB (also known as alphaB-crystallin/HSPB5) is a small heat shock protein that has many protective functions including an immunomodulatory role in mouse models of multiple sclerosis, spinal cord injury, and stroke. Because its expression wanes and rebounds in the early and late periods respectively after PNS damage, and CRYAB null mice with sciatic nerve crush injury display symptoms of pain, we investigated whether CRYAB is involved in the immune response following PNS injury. METHODS Sciatic nerve crush injuries were performed in age-matched CRYAB knockout (CRYAB-/-) and wildtype (WT) female mice. Nerve segments distal to the injury site were processed by immunohistochemistry for macrophages and myelin while protein lysates of the nerves were analyzed for cytokines and chemokines using Luminex and enzyme-linked immunosorbent assay (ELISA). Peritoneal macrophages from the two genotypes were also cultured and polarized into pro-inflammatory or anti-inflammatory phenotypes where their supernatants were analyzed for cytokines and chemokines by ELISA and protein lysates for macrophage antigen presenting markers using western blotting. RESULTS We report that (1) more pro-inflammatory CD16/32+ macrophages are present in the nerves of CRYAB-/- mice at days 14 and 21 after sciatic nerve crush-injury compared to WT counterparts, and (2) CRYAB has an immunosuppressive effect on cytokine secretion [interleukin (IL)-β, IL-6, IL-12p40, tumor necrosis factor (TNF)-α] from pro-inflammatory macrophages in vitro. CONCLUSIONS CRYAB may play a role in curbing the potentially detrimental pro-inflammatory macrophage response during the late stages of peripheral nerve regeneration.

  • CRYAB modulates the activation of CD4+ T cells from relapsing–remitting multiple sclerosis patients
    Multiple sclerosis (Houndmills Basingstoke England), 2013
    Co-Authors: Que Lan Quach, Lawrence Steinman, Jonathan B Rothbard, Luanne M. Metz, Jenna C. Thomas, Shalina S Ousman
    Abstract:

    Background:Suppression of activation of pathogenic CD4+ T cells is a potential therapeutic intervention in multiple sclerosis (MS). We previously showed that a small heat shock protein, CRYAB, reduced T cell proliferation, pro-inflammatory cytokine production and clinical signs of experimental allergic encephalomyelitis, a model of MS.Objective:We assessed whether the ability of CRYAB to reduce the activation of T cells translated to the human disease.Methods:CD4+ T cells from healthy controls and volunteers with MS were activated in vitro in the presence or absence of a CRYAB peptide (residues 73–92). Parameters of activation (proliferation rate, cytokine secretion) and tolerance (anergy, activation-induced cell death, microRNAs) were evaluated.Results:The secretion of pro-inflammatory cytokines by CD4+ T cells was decreased in the presence of CRYAB in a subset of relapsing–remitting multiple sclerosis (RRMS) participants with mild disease severity while no changes were observed in healthy controls. Furt...

  • CRYAB modulates the activation of cd4 t cells from relapsing remitting multiple sclerosis patients
    Multiple Sclerosis Journal, 2013
    Co-Authors: Que Lan Quach, Lawrence Steinman, Jonathan B Rothbard, Luanne M. Metz, Jenna C. Thomas, Shalina S Ousman
    Abstract:

    Background:Suppression of activation of pathogenic CD4+ T cells is a potential therapeutic intervention in multiple sclerosis (MS). We previously showed that a small heat shock protein, CRYAB, reduced T cell proliferation, pro-inflammatory cytokine production and clinical signs of experimental allergic encephalomyelitis, a model of MS.Objective:We assessed whether the ability of CRYAB to reduce the activation of T cells translated to the human disease.Methods:CD4+ T cells from healthy controls and volunteers with MS were activated in vitro in the presence or absence of a CRYAB peptide (residues 73–92). Parameters of activation (proliferation rate, cytokine secretion) and tolerance (anergy, activation-induced cell death, microRNAs) were evaluated.Results:The secretion of pro-inflammatory cytokines by CD4+ T cells was decreased in the presence of CRYAB in a subset of relapsing–remitting multiple sclerosis (RRMS) participants with mild disease severity while no changes were observed in healthy controls. Furt...

  • Characterization of migration parameters on peripheral and central nervous system T cells following treatment of experimental allergic encephalomyelitis with CRYAB.
    Journal of neuroimmunology, 2013
    Co-Authors: Adeola I Oyebamiji, Trisha M Finlay, Rachael M Hough, Vahid Hoghooghi, Erin-mai F Lim, Connie H Y Wong, Shalina S Ousman
    Abstract:

    CRYAB, a small heat shock protein, was previously shown to decrease neuroinflammation in experimental allergic encephalomyelitis (EAE). We investigated whether the expression of cell adhesion molecules and chemokine receptors on peripheral and spinal cord T cells, that could possibly affect their migration to the central nervous system, was altered following EAE CRYAB treatment. Less LFA-1+ lymphocytes and lower levels of iTAC, MCP-5 and MIG were observed in spinal cords of CRYAB-injected EAE animals. In addition, fewer blood T cells expressed CCR6, CXCR4 and CCR7 and in vivo-derived CRYAB EAE CD4+ lymphocytes were less migratory towards a MIP-3alpha gradient in vitro.

Kleber G. Franchini - One of the best experts on this subject based on the ideXlab platform.

  • αB‐Crystallin interacts and attenuates the tyrosine phosphatase activity of Shp2 in cardiomyocytes under mechanical stress
    FEBS letters, 2016
    Co-Authors: Danieli C. Gonçalves, Talita M. Marin, Michelle B. M. Pereira, Aline M. Santos, Adriana Franco Paes Leme, Kleber G. Franchini
    Abstract:

    The small heat shock protein αB-Crystallin (CRYAB, HspB5) and SH2 domain-containing tyrosine phosphatase 2 (Shp2) are important molecules in heart response to pathophysiological stress. Here we show that CRYAB interacts with and potentially regulates Shp2 catalytic activity in stretched cardiomyocytes. Such an interaction requires CRYAB oligomer to attenuate Shp2 activation. Stretched cardiomyocytes show a robust CRYAB/Shp2 association accompanied by a reduction in the Shp2 phosphatase activity. Accordingly, CRYAB knock-down in cardiomyocytes enhances Shp2 activity induced by mechanical stress. These results revealed a new role for CRYAB, as a modulator of Shp2 phosphatase activity during a functionally relevant stimulus in cardiomyocytes.

Hong Lok Lung - One of the best experts on this subject based on the ideXlab platform.

  • tumor suppressor alpha b crystallin CRYAB associates with the cadherin catenin adherens junction and impairs npc progression associated properties
    Oncogene, 2012
    Co-Authors: Z Huang, Yue Cheng, Pui Man Chiu, Florence M F Cheung, John M Nicholls, Lw D Kwong, Eugene R Zabarovsky, Eric J Stanbridge, Hong Lok Lung
    Abstract:

    Alpha B-crystallin (CRYAB) maps within the nasopharyngeal carcinoma (NPC) tumor-suppressive critical region 11q22-23 and its downregulation is significantly associated with the progression of NPC. However, little is known about the functional impact of CRYAB on NPC progression. In this study we evaluated the NPC tumor-suppressive and progression-associated functions of CRYAB. Activation of CRYAB suppressed NPC tumor formation in nude mice. Overexpression of CRYAB affected NPC progression-associated phenotypes such as loss of cell adhesion, invasion, interaction with the tumor microenvironment, invasive protrusion formation in three dimensional Matrigel culture, as well as expression of epithelial–mesenchymal transition-associated markers. CRYAB mediates this ability to suppress cancer progression by inhibition of E-cadherin cytoplasmic internalization and maintenance of β-catenin in the membrane that subsequently reduces the levels of expression of critical downstream targets such as cyclin-D1 and c-myc. Both ectopically expressed and recombinant CRYAB proteins were associated with endogenous E-cadherin and β-catenin, and, thus, the cadherin/catenin adherens junction. The CRYAB α-crystallin core domain is responsible for the interaction of CRYAB with both E-cadherin and β-catenin. Taken together, these results indicate that CRYAB functions to suppress NPC progression by associating with the cadherin/catenin adherens junction and modulating the β-catenin function.

  • Tumor suppressor Alpha B-crystallin ( CRYAB ) associates with the cadherin/catenin adherens junction and impairs NPC progression-associated properties
    Oncogene, 2011
    Co-Authors: Z Huang, Yue Cheng, Pui Man Chiu, Florence M F Cheung, John M Nicholls, Eugene R Zabarovsky, Eric J Stanbridge, D L-w Kwong, Anne Wing Mui Lee, Hong Lok Lung
    Abstract:

    Alpha B-crystallin (CRYAB) maps within the nasopharyngeal carcinoma (NPC) tumor-suppressive critical region 11q22-23 and its downregulation is significantly associated with the progression of NPC. However, little is known about the functional impact of CRYAB on NPC progression. In this study we evaluated the NPC tumor-suppressive and progression-associated functions of CRYAB. Activation of CRYAB suppressed NPC tumor formation in nude mice. Overexpression of CRYAB affected NPC progression-associated phenotypes such as loss of cell adhesion, invasion, interaction with the tumor microenvironment, invasive protrusion formation in three dimensional Matrigel culture, as well as expression of epithelial-mesenchymal transition-associated markers. CRYAB mediates this ability to suppress cancer progression by inhibition of E-cadherin cytoplasmic internalization and maintenance of β-catenin in the membrane that subsequently reduces the levels of expression of critical downstream targets such as cyclin-D1 and c-myc. Both ectopically expressed and recombinant CRYAB proteins were associated with endogenous E-cadherin and β-catenin, and, thus, the cadherin/catenin adherens junction. The CRYAB α-crystallin core domain is responsible for the interaction of CRYAB with both E-cadherin and β-catenin. Taken together, these results indicate that CRYAB functions to suppress NPC progression by associating with the cadherin/catenin adherens junction and modulating the β-catenin function.

Xuejun Wang - One of the best experts on this subject based on the ideXlab platform.

  • tfeb activation protects against cardiac proteotoxicity via increasing autophagic flux
    Journal of Molecular and Cellular Cardiology, 2017
    Co-Authors: Hanming Zhang, Xuejun Wang
    Abstract:

    Abstract Insufficient lysosomal removal of autophagic cargoes in cardiomyocytes has been suggested as a main cause for the impairment of the autophagic-lysosomal pathway (ALP) in many forms of heart disease including cardiac proteinopathy and may play an important pathogenic role; however, the molecular basis and the correcting strategy for the cardiac ALP insufficiency require further investigation. The present study was sought to determine whether myocardial expression and activity of TFEB, the recently identified ALP master regulator, are impaired in a cardiac proteinopathy mouse model and to determine the effect of genetic manipulation of TFEB expression on autophagy and proteotoxicity in a cardiomyocyte model of proteinopathy. We found that increased myocardial TFEB mRNA levels and a TFEB protein isoform switch were associated with marked decreases in the mRNA levels of representative TFEB target genes and increased mTORC1 activation, in mice with cardiac transgenic expression of a missense (R120G) mutant αB-crystallin (CRYAB R120G ), a well-established model of cardiac proteinopathy. Using neonatal rat ventricular cardiomyocyte cultures, we demonstrated that downregulation of TFEB decreased autophagic flux in cardiomyocytes both at baseline and during CRYAB R120G overexpression and increased CRYAB R120G protein aggregates. Conversely, forced TFEB overexpression increased autophagic flux and remarkably attenuated the CRYABR 120G overexpression-induced accumulation of ubiquitinated proteins, caspase 3 cleavage, LDH leakage, and decreases in cell viability. Moreover, these protective effects of TFEB were dramatically diminished by inhibiting autophagy. We conclude that myocardial TFEB signaling is impaired in cardiac proteinopathy and forced TFEB overexpression protects against proteotoxicity in cardiomyocytes through improving ALP activity.

  • Protein quality control in protection against systolic overload cardiomyopathy: the long term role of small heat shock proteins
    American journal of translational research, 2010
    Co-Authors: Asangi R. Kumarapeli, Kathleen M. Horak, Xuejun Wang
    Abstract:

    Molecular chaperones represent the first line of defense of intracellular protein quality control. As a major constituent of molecular chaperones, heat shock proteins (HSP) are known to confer cardiomyocyte short-term protection against various insults and injuries. Previously, we reported that the small HSP αB-crystallin (CRYAB) attenuates cardiac hypertrophic response in mice subjected to 2 weeks of severe pressure overload. However, the long-term role of small HSPs in cardiac hypertrophy and failure has rarely been studied. The present study investigates the cardiac responses to chronic severe pressure overload in CRYAB/HSPB2 germ line ablated (KO) and cardiac-specific CRYAB overexpressingtransgenic (TG) mice. Pressure overload was induced by transverse aortic constriction in KO, TG, and non-transgenic wild type (NTG) control mice and 10 weeks later molecular, cellular, and whole organ level hypertrophic responses were analyzed. As we previously described, CRYAB/HSPB2 KO mice showed abnormal baseline cardiac physiology that worsened into a restrictive cardiomyopathic phenotype with aging. Severe pressure overload in these mice led to rapid deterioration of heart function and development of congestive cardiac failure. Contrary to their short term protective phenotype, CRYAB TG mice showed no significant effects on cardiac hypertrophic responses and very modest improvement of hemodynamics during chronic systolic overload. These findings indicate that small HSPs CRYAB and/or HSPB2 are essential to maintain cardiac structure and function but overex-pression of CRYAB is not sufficient to confer a sustained protection against chronic systolic overload.

  • αB-Crystallin Suppresses Pressure Overload Cardiac Hypertrophy
    Circulation research, 2008
    Co-Authors: Asangi R. Kumarapeli, Wei Huang, Mingxin Tang, Hanqiao Zheng, Kathleen M. Horak, Xuejun Wang
    Abstract:

    αB-Crystallin (CRYAB) is the most abundant small heat shock protein (HSP) constitutively expressed in cardiomyocytes. Gain- and loss-of-function studies demonstrated that CRYAB can protect against myocardial ischemia/reperfusion injury. However, the role of CRYAB or any HSPs in cardiac responses to mechanical overload is unknown. This study addresses this issue. Nontransgenic mice and mice with cardiomyocyte-restricted transgenic overexpression of CRYAB or with germ-line ablation of the CRYAB/HSPB2 genes were subjected to transverse aortic constriction or sham surgery. Two weeks later, cardiac responses were analyzed by fetal gene expression profiling, cardiac function analyses, and morphometry. Comparison among the 3 sham surgery groups reveals that CRYAB overexpression is benign, whereas the knockout is detrimental to the heart as reflected by cardiac hypertrophy and malfunction at 10 weeks of age. Compared to nontransgenic mice, transgenic mouse hearts showed significantly reduced NFAT transactivation ...

  • αB-Crystallin Modulates Protein Aggregation of Abnormal Desmin
    Circulation research, 2003
    Co-Authors: Xuejun Wang, Raisa Klevitsky, Wei Huang, Joseph W. Glasford, Jeffrey Robbins
    Abstract:

    αB-crystallin (CRYAB) is the most abundant small heat shock protein in the heart. Upregulation of CRYAB in desmin-related myopathy and its downregulation in end-stage congestive heart failure have both been reported. We previously demonstrated via cardiac-specific transgenesis that modest increases in normal CRYAB are not detrimental to the heart, whereas expression of the R120G mutation of CRYAB caused a desminopathy. It is generally believed that CRYAB plays an important role in protecting the intermediate filaments, but the underlying mechanism is unclear. We hypothesized that CRYAB protects the desmin filaments via preventing abnormal desmin protein from aggregating adversely. To test this hypothesis in vivo, mice expressing a desmin mutation that causes a desmin-related cardiomyopathy (D7) were bred into the R120G-CRYAB transgenic (TG) background to examine the accumulation and aberrant aggregation of desmin protein. Despite lower mRNA expression of D7-des than in the D7-des TG hearts, the double-TG myocardium exhibited significantly higher desmin protein levels and dramatically more aberrant desmin aggregates than the D7-des TG hearts. The double-TG mice displayed a significantly stronger cardiac hypertrophic response, with the mice dying of congestive heart failure before 7 weeks. To explore the ability of wild-type (WT) CRYAB to protect against mutant desmin, a desmin mutant was expressed in both the conventional and WT-CRYAB stably transfected HEK cells. Significantly less aberrant desmin aggregation was observed in the WT-CRYAB–overexpressing cells than in the HEK cells. The results suggest that CRYAB modulates abnormal desmin aggregation and can serve a cardioprotective role.

  • expression of r120g αb crystallin causes aberrant desmin and αb crystallin aggregation and cardiomyopathy in mice
    Circulation Research, 2001
    Co-Authors: Xuejun Wang, Raisa Klevitsky, Hanna Osinska, Martin A Gerdes, Michelle L Nieman, John N Lorenz, Timothy E Hewett, Jeffrey Robbins
    Abstract:

    Abstract—Upregulation of αB-crystallin (CRYAB), a small heat shock protein, is associated with a variety of diseases, including the desmin-related myopathies. CRYAB, which binds to both desmin and cytoplasmic actin, may participate as a chaperone in intermediate filament formation and maintenance, but the physiological consequences of CRYAB upregulation are unknown. A mutation in CRYAB, R120G, has been linked to a familial desminopathy. However, it is unclear whether the mutation is directly causative. We created multiple transgenic mouse lines that overexpressed either murine wild-type CRYAB or the R120G mutation in cardiomyocytes. Overexpression of wild-type CRYAB was relatively benign, with no increases in mortality and no induction of desmin-related cardiomyopathy even in a line in which CRYAB mRNA expression was increased ≈104-fold and the protein level increased by 11-fold. In contrast, lines expressing the R120G mutation were compromised, with a high-expressing line exhibiting 100% mortality by ear...