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  • Ovid Technologies (Wolters Kluwer Health)  (8)
  • Ogata, Takehiro  (8)
  • 1
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    Maternal High-Fat Diet Exaggerates Atherosclerosis in Adult Offspring by Augmenting Periaortic Adipose Tissue-Specific Proinflammatory Response
    Ovid Technologies (Wolters Kluwer Health) ; 2015
    In:  Arteriosclerosis, Thrombosis, and Vascular Biology Vol. 35, No. 3 ( 2015-03), p. 558-569
    Details
    In: Arteriosclerosis, Thrombosis, and Vascular Biology, Ovid Technologies (Wolters Kluwer Health), Vol. 35, No. 3 ( 2015-03), p. 558-569
    Abstract: Maternal obesity elicits offspring’s metabolic disorders via developmental modifications of visceral adipose tissue; however, its effect on atherogenesis remains undefined. Perivascular adipose tissue has recently been implicated in vascular remodeling and vasoreactivity. We hypothesize that developmental modifications of perivascular adipose tissue by maternal high-fat diet (HFD) exposure promotes atherosclerosis in adult offspring. Approach and Results— Eight-week-old female apolipoprotein E-deficient mice were fed an HFD or normal diet (ND) during gestation and lactation. Offspring were fed a high-cholesterol diet from 8 weeks of age. Twenty-week-old male offspring of HFD-fed dams (O-HFD) showed a 2.1-fold increase in atherosclerotic lesion of the entire aorta compared with those of ND-fed dams (O-ND). Although mRNA expressions of interleukin-6, tumor necrosis factor, and monocyte chemotactic protein-1 and accumulation of macrophages in epididymal white adipose tissue were less in O-HFD than in O-ND, thoracic periaortic adipose tissue (tPAT) showed an exaggerated inflammatory response in O-HFD. Intra-abdominal transplantation of tPAT from 8-week-old O-HFD alongside the distal abdominal aorta exaggerated atherosclerosis development of the infrarenal aorta in recipient apolipoprotein E-deficient mice compared with tPAT from O-ND (210%, P 〈 0.01). Although macrophage accumulation was rarely detected in tPAT of 8-week-old offspring, mRNA expression and protein levels of macrophage colony–stimulating factor were markedly elevated in O-HFD (2.3-fold, 3.3-fold, respectively, P 〈 0.05), suggesting that increased macrophage colony–stimulating factor expression contributes to the augmented accumulation of macrophages, followed by the enhanced proinflammatory response. Conclusions— Our findings demonstrate that maternal HFD exaggerates atherosclerosis development in offspring by augmenting tPAT-specific inflammatory response proceeded by an increased expression of macrophage colony–stimulating factor.
    Type of Medium: Online Resource
    ISSN: 1079-5642 , 1524-4636
    URL: Article
    DOI: 10.1161/ATVBAHA.114.305122
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2015
    detail.hit.zdb_id: 1494427-3
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  • 2
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    Abstract 12861: Adjoining Myofibroblasts Disrupt Impulse Propagation of Myocardial Tissue via Connexin 43-Mediated Heterocellular Gap Junctional Coupling
    Ovid Technologies (Wolters Kluwer Health) ; 2021
    In:  Circulation Vol. 144, No. Suppl_1 ( 2021-11-16)
    Details
    In: Circulation, Ovid Technologies (Wolters Kluwer Health), Vol. 144, No. Suppl_1 ( 2021-11-16)
    Abstract: Introduction: The composite population of myofibroblasts (MFBs) and cardiomyocytes (CMCs) is known to alter impulse conduction in the heart. A previous study reported that structural disruption between cardiomyocytes by fibrosis or myofibroblast proliferation causes conduction delay due to insulating or reducing the intercellular current. However, it is unknown whether and how the conduction is altered when the myocardial tissue faces adjoining with MFB-rich granulation tissue, like, e.g. , the border zone of myocardial infarcts during infarct healing. Objectives: To clarify the influence of heterocellular gap-junctional coupling between CMCs and MFBs by calcium imaging in an injured myocardial tissue-mimicking model in which CMCs connect with MFBs via microporous membranes. Methods: Fluo-8 fluorescence patterns of impulse propagation were spatiotemporally imaged (27 x 18.9 mm, 333 frames/s, 32 °C) in neonatal rat CMC monolayers cultured on the upper sides of the Boyden chamber (pore diameter, 8 μm) of which MFB monolayer was co-cultured on the reverse sides (CMC-MFB group). For comparison, CMC monolayers were cultured on both membrane sides (CMC-CMC group). Results: During consecutive pacing at 1 - 4 Hz, CMC monolayers showed concentric propagation from the pacing site with slower conduction velocity (CV) and more irregular wavefronts in a frequency-dependent manner. The conduction slowing and its non-uniformity were more remarkable in the CMC-MFB group than in the CMC-CMC group. We confirmed the gap junction coupling between the upper CMC and lower MFB layers using co-immunostaining and calcein staining. Heptanol, gap junction inhibiter, inhibited calcein dye transfer from the upper CMC layer to the lower MFB layer. The knockdown of Cx43 in MFBs on the reverse layer improved the delay of CV and non-uniformity in the CMC-MFB group. Conclusions: In this study, we clarified the electric association between adjoining MFBs and CMCs. Our observations suggest that adjoining MFBs slow down conduction velocity and disrupt conduction uniformity on CMCs via Cx43-mediated heterocellular gap-junctional coupling between CMCs and MFBs.
    Type of Medium: Online Resource
    ISSN: 0009-7322 , 1524-4539
    URL: Article
    DOI: 10.1161/circ.144.suppl_1.12861
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2021
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  • 3
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    Systems Network Genomic Analysis Reveals Cardioprotective Effect of MURC/Cavin‐4 Deletion Against Ischemia/Reperfusion Injury
    Ovid Technologies (Wolters Kluwer Health) ; 2019
    In:  Journal of the American Heart Association Vol. 8, No. 15 ( 2019-08-06)
    Details
    In: Journal of the American Heart Association, Ovid Technologies (Wolters Kluwer Health), Vol. 8, No. 15 ( 2019-08-06)
    Abstract: Ischemia/reperfusion (I/R) injury is a critical issue in the development of treatment strategies for ischemic heart disease. MURC (muscle‐restricted coiled‐coil protein)/Cavin‐4 (caveolae‐associated protein 4), which is a component of caveolae, is involved in the pathophysiology of dilated cardiomyopathy and cardiac hypertrophy. However, the role of MURC in cardiac I/R injury remains unknown. Methods and Results The systems network genomic analysis based on PC ‐corr network inference on microarray data between wild‐type and MURC knockout mouse hearts predicted a network of discriminating genes associated with reactive oxygen species. To demonstrate the prediction, we analyzed I/R‐injured mouse hearts. MURC deletion decreased infarct size and preserved heart contraction with reactive oxygen species–related molecule EGR 1 (early growth response protein 1) and DDIT 4 (DNA‐damage‐inducible transcript 4) suppression in I/R‐injured hearts. Because PC ‐corr network inference integrated with a protein–protein interaction network prediction also showed that MURC is involved in the apoptotic pathway, we confirmed the upregulation of STAT 3 (signal transducer and activator of transcription 3) and BCL 2 (B‐cell lymphoma 2) and the inactivation of caspase 3 in I/R‐injured hearts of MURC knockout mice compared with those of wild‐type mice. STAT 3 inhibitor canceled the cardioprotective effect of MURC deletion in I/R‐injured hearts. In cardiomyocytes exposed to hydrogen peroxide, MURC overexpression promoted apoptosis and MURC knockdown inhibited apoptosis. STAT 3 inhibitor canceled the antiapoptotic effect of MURC knockdown in cardiomyocytes. Conclusions Our findings, obtained by prediction from systems network genomic analysis followed by experimental validation, suggested that MURC modulates cardiac I/R injury through the regulation of reactive oxygen species–induced cell death and STAT 3‐meditated antiapoptosis. Functional inhibition of MURC may be effective in reducing cardiac I/R injury.
    Type of Medium: Online Resource
    ISSN: 2047-9980
    URL: Article
    DOI: 10.1161/JAHA.119.012047
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2019
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  • 4
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    Cardiac-Specific Bdh1 Overexpression Ameliorates Oxidative Stress and Cardiac Remodeling in Pressure Overload–Induced Heart Failure
    Ovid Technologies (Wolters Kluwer Health) ; 2017
    In:  Circulation: Heart Failure Vol. 10, No. 12 ( 2017-12)
    Details
    In: Circulation: Heart Failure, Ovid Technologies (Wolters Kluwer Health), Vol. 10, No. 12 ( 2017-12)
    Abstract: Energy starvation and the shift of energy substrate from fatty acids to glucose is the hallmark of metabolic remodeling during heart failure progression. However, ketone body metabolism in the failing heart has not been fully investigated. Methods and Results Microarray data analysis and mitochondrial isobaric tags for relative and absolute quantification proteomics revealed that the expression of D-β-hydroxybutyrate dehydrogenase I (Bdh1), an enzyme that catalyzes the NAD + /NADH coupled interconversion of acetoacetate and β-hydroxybutyrate, was increased 2.5- and 2.8-fold, respectively, in the heart after transverse aortic constriction. In addition, ketone body oxidation was upregulated 2.2-fold in transverse aortic constriction hearts, as determined by the amount of 14 CO 2 released from the metabolism of [1- 14 C] β-hydroxybutyrate in isolated perfused hearts. To investigate the significance of this augmented ketone body oxidation, we generated heart-specific Bdh1-overexpressing transgenic mice to recapitulate the observed increase in basal ketone body oxidation. Bdh1 transgenic mice showed a 1.7-fold increase in ketone body oxidation but did not exhibit any differences in other baseline characteristics. When subjected to transverse aortic constriction, Bdh1 transgenic mice were resistant to fibrosis, contractile dysfunction, and oxidative damage, as determined by the immunochemical detection of carbonylated proteins and histone acetylation. Upregulation of Bdh1 enhanced antioxidant enzyme expression. In our in vitro study, flow cytometry revealed that rotenone-induced reactive oxygen species production was decreased by adenovirus-mediated Bdh1 overexpression. Furthermore, hydrogen peroxide–induced apoptosis was attenuated by Bdh1 overexpression. Conclusions We demonstrated that ketone body oxidation increased in failing hearts, and increased ketone body utilization decreased oxidative stress and protected against heart failure.
    Type of Medium: Online Resource
    ISSN: 1941-3289 , 1941-3297
    URL: Article
    DOI: 10.1161/CIRCHEARTFAILURE.117.004417
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2017
    detail.hit.zdb_id: 2428100-1
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  • 5
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    Abstract 363: Systems Network Genomic Analysis Reveals the Role Of MURC/Cavin-4 in Cardiac Ischemia/reperfusion Injury
    Ovid Technologies (Wolters Kluwer Health) ; 2019
    In:  Circulation Research Vol. 125, No. Suppl_1 ( 2019-08-02)
    Details
    In: Circulation Research, Ovid Technologies (Wolters Kluwer Health), Vol. 125, No. Suppl_1 ( 2019-08-02)
    Abstract: Background: Ischemia/reperfusion (I/R) injury is a critical issue in the development of treatment strategies for ischemic heart disease. Muscle-restricted coiled-coil protein (MURC)/Cavin-4, which is a component of caveolae, is involved in the pathophysiology of dilated cardiomyopathy and cardiac hypertrophy. However, the role of MURC in cardiac I/R injury remains unknown. Objective: To elucidate the role of MURC in cardiac I/R injury. Methods and Results: The systems network genomic analysis based on PC-corr network inference on microarray data between wild-type and MURC knockout (KO) mouse hearts described a network of discriminating genes associated with reactive oxygen species (ROS). To demonstrate the prediction, we investigated the effect of MURC deletion in cardiac I/R injury. MURC deletion in IR-injured mouse hearts decreased infarct size and preserved heart contraction with the inhibition of ROS production and ROS-related gene expressions such as EGR1 and DDIT4 as well as EGR1 protein level. PC-corr network inference integrated with a protein-protein interaction network prediction showed that MURC is also involved in the apoptotic pathway. We confirmed the upregulated activity of STAT3, which is a transcription factor of anti-apoptotic signaling, with the increase of BCL2 mRNA expression and protein level and the decrease of cleaved Caspase 3 protein level in MURC KO compared with WT mouse hearts after I/R. TUNEL assay showed that MURC modulates the apoptosis in cardiomyocytes exposed to hydrogen peroxide. STAT3 inhibitor cancelled the cardioprotective effect of MURC deletion in I/R-injured heart and the anti-apoptotic effect of MURC knockdown in cardiomyocytes. Conclusions: Our findings suggest that MURC plays a pivotal role in the regulation of ROS-induced cell death and STAT3-meditated anti-apoptotic signaling in cardiac I/R injury. MURC may be a therapeutic target for cardiac I/R injury.
    Type of Medium: Online Resource
    ISSN: 0009-7330 , 1524-4571
    URL: Article
    DOI: 10.1161/res.125.suppl_1.363
    RVK:
    XA 10000
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2019
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  • 6
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    Abstract 520: Cavin-2/SDPR in Cardiac Fibroblasts Modulates TGF-β/Smad Signaling and Promotes Pressure Overload-induced Fibrosis
    Ovid Technologies (Wolters Kluwer Health) ; 2019
    In:  Circulation Research Vol. 125, No. Suppl_1 ( 2019-08-02)
    Details
    In: Circulation Research, Ovid Technologies (Wolters Kluwer Health), Vol. 125, No. Suppl_1 ( 2019-08-02)
    Abstract: Introduction: Heart failure (HF) is a debilitating disease associated with high morbidity and mortality. The high mortality rate reflects the inadequacy of modern therapy and calls for new treatments. A major cause of HF is the adverse tissue remodeling with fibrosis. Excessive extracellular matrix (ECM) turnover is involved in the poor outcome. Resident fibroblasts are responsible for cardiac fibrosis on pressure-overload heart failure. Caveolins and Cavins are known as caveolar-related proteins. Caveolin-1 inhibits TGF-β1-induced fibrosis in the previous reports. Although Cavin-2/Serum deprivation response protein (SDPR), which is one of the caveolar-relatedproteins, is also abundant in fibroblasts, the role of Cavin-2 in cardiac fibrosis and function remains unknown. Methods and Results: To clarify the role of Cavin-2 in the cardiac fibroblasts in the pressure-overloadedheart, we performed transverse aortic constriction (TAC) operation on SDPR flox/flox mice and fibroblast-specific Cavin-2 cKO mice (Postin Cre ; SDPR flox/flox ). Four weeks after TAC, left ventricular fractionalshortening (LVFS) was preservedwith a significant reduction of cardiac fibrosis in PostinCre; SDPRflox/flox mice. Fibrosis-associated mRNA expressions ( Col1a1 , Ctgf , Col3 ), α1 type I collagen deposition, and αSMA-positive cells were also reducedin the hearts of Cavin-2 cKO mice after TAC. Trans-differentiation of fibroblasts into activated myofibroblasts is a defining feature of fibrosis. Myofibroblasts express α-smooth muscle actin (αSMA) and secrete ECM proteins via Smad signaling. In mouse embryonic fibroblasts (MEFs),Cavin-2 deficiency reduced the levels of αSMA protein and fibrosis-associated mRNA expressions by TGF-β1 stimulation. Furthermore, TGF-β1-induced Smad2 phosphorylation was attenuatedin Cavin-2 KO MEFs compared to WT MEFs. On the other hand, adenovirus-mediated Cavin-2 overexpression significantly increased αSMA and the fibrosis-associated mRNA expressions. Conclusions: Our observations suggest that Cavin-2 contributes to the development of cardiac fibrosis through the differentiation from fibroblasts into myofibroblasts via TGF-β/Smad signaling. Cavin-2 may be a novel therapeutic target for cardiac fibrosis.
    Type of Medium: Online Resource
    ISSN: 0009-7330 , 1524-4571
    URL: Article
    DOI: 10.1161/res.125.suppl_1.520
    RVK:
    XA 10000
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2019
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  • 7
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    Abstract 301: Cavin-2 Deletion Attenuates Fibroblast Activation and Cardiac Fibrosis via TGF-β Signaling by Interacting With Hsp90
    Ovid Technologies (Wolters Kluwer Health) ; 2020
    In:  Circulation Research Vol. 127, No. Suppl_1 ( 2020-07-31)
    Details
    In: Circulation Research, Ovid Technologies (Wolters Kluwer Health), Vol. 127, No. Suppl_1 ( 2020-07-31)
    Abstract: Introduction: Heart failure (HF) is a progressive disease associated with high morbidity and mortality. A major cause of HF is the adverse tissue remodeling with interstitial fibrosis. Excessive extracellular matrix (ECM) accumulation is involved in the poor outcome. Transformation to myofibroblasts in resident fibroblasts has an important role for cardiac fibrosis on pressure-overload heart failure. TGF-β signaling is one of the critical pathways in fibroblast activation. Caveolae are major plasma membrane domain defined as 50-100 nm vesicular structures. Caveolins and cavins are known as caveolar-related proteins. TGF-β signaling is tightly connected with caveolae. A previous report shows that induction of Cav-1 expression leads to suppression of TGF-β signaling and an improvement of fibrosis. Although cavin-2/Serum deprivation response protein (SDPR) is also abundant in fibroblasts, the role of cavin-2 in cardiac fibrosis and function remains unknown. Methods and Results: To clarify the role of cavin-2 in cardiac fibroblasts in the pressure-overloaded heart, we performed TAC operation on cavin-2 flox/flox mice and fibroblast-specific cavin-2 knockout (Postin Cre ; SDPR flox/flox ) mice (cavin-2 cKO). Four weeks after TAC, left ventricular fractional shortening (LVFS) was preserved with a significant reduction of cardiac fibrosis in cavin-2 cKO mice. Fibrosis-associated mRNA expression ( Col1a1, Ctgf, Col3 ) and α1 type I collagen deposition were reduced in the hearts of cavin-2-cKO mice after TAC. Transdifferentiation of fibroblasts into activated myofibroblasts is a defining feature of fibrosis. Myofibroblasts express αSMA and secrete ECM proteins via Smad signaling. αSMA-positive cells without showing vascular structure were reduced in cavin-2 cKO after TAC. In mouse embryonic fibroblasts (MEFs), cavin-2 deficiency reduced TGF-β1-induced αSMA production and fibrosis-associated mRNA expression. On the other hand, adenovirus-mediated cavin-2 overexpression significantly increased αSMA production and the fibrosis-associated mRNA expressions. Furthermore, TGF-β1-induced Smad2/3 phosphorylation was attenuated in cavin-2 KO MEFs compared to wild-type (WT) MEFs. A protein-Protein interaction screening using a promiscuous biotin ligase, called BioID, revealed that cavin-2 interacted with Hsp90ab1 and Hsp90b1 which modulate collagen synthesis through regulation of SMA and SMAD pathway. The protein expression level of Hsp90 in cavin-2 KO MEFs significantly decreased compared with that in WT MEFs. Conclusions: Our observations suggest that cavin-2 contributes to the development of cardiac fibrosis through the differentiation from fibroblasts into myofibroblasts via TGF-β/Smad signaling. cavin-2 may be a novel therapeutic target for cardiac fibrosis.
    Type of Medium: Online Resource
    ISSN: 0009-7330 , 1524-4571
    URL: Article
    DOI: 10.1161/res.127.suppl_1.301
    RVK:
    XA 10000
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2020
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  • 8
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    ChGn‐2 Plays a Cardioprotective Role in Heart Failure Caused by Acute Pressure Overload
    Ovid Technologies (Wolters Kluwer Health) ; 2022
    In:  Journal of the American Heart Association Vol. 11, No. 7 ( 2022-04-05)
    Details
    In: Journal of the American Heart Association, Ovid Technologies (Wolters Kluwer Health), Vol. 11, No. 7 ( 2022-04-05)
    Abstract: Cardiac extracellular matrix is critically involved in cardiac homeostasis, and accumulation of chondroitin sulfate glycosaminoglycans (CS‐GAGs) was previously shown to exacerbate heart failure by augmenting inflammation and fibrosis at the chronic phase. However, the mechanism by which CS‐GAGs affect cardiac functions remains unclear, especially at the acute phase. Methods and Results We explored a role of CS‐GAG in heart failure using mice with target deletion of ChGn‐2 (chondroitin sulfate N‐acetylgalactosaminyltransferase‐2) that elongates CS chains of glycosaminoglycans. Heart failure was induced by transverse aortic constriction in mice. The role of CS‐GAG derived from cardiac fibroblasts in cardiomyocyte death was analyzed. Cardiac fibroblasts were subjected to cyclic mechanical stretch that mimics increased workload in the heart. Significant CS‐GAGs accumulation was detected in the heart of wild‐type mice after transverse aortic constriction, which was substantially reduced in ChGn‐2 ‐/‐ mice. Loss of ChGn‐2 deteriorated the cardiac dysfunction caused by pressure overload, accompanied by augmented cardiac hypertrophy and increased cardiomyocyte apoptosis. Cyclic mechanical stretch increased ChGn‐2 expression and enhanced glycosaminoglycan production in cardiac fibroblasts. Conditioned medium derived from the stretched cardiac fibroblasts showed cardioprotective effects, which was abolished by CS‐GAGs degradation. We found that CS‐GAGs elicits cardioprotective effects via dual pathway; direct pathway through interaction with CD44, and indirect pathway through binding to and activating insulin‐like growth factor‐1. Conclusions Our data revealed the cardioprotective effects of CS‐GAGs; therefore, CS‐GAGs may play biphasic role in the development of heart failure; cardioprotective role at acute phase despite its possible unfavorable role in the advanced phase.
    Type of Medium: Online Resource
    ISSN: 2047-9980
    URL: Article
    DOI: 10.1161/JAHA.121.023401
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2022
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