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  • Ovid Technologies (Wolters Kluwer Health)  (6)
  • Wang, Yajing  (6)
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  • Ovid Technologies (Wolters Kluwer Health)  (6)
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  • 1
    Online Resource
    Online Resource
    Abstract P2012: GRK2-Induced Cardiomyocyte AdipoR1 Phosphorylation Blocks Adipocytes-Derived Exosomes Cardioprotection Against Ischemic Heart Failure
    Ovid Technologies (Wolters Kluwer Health) ; 2022
    In:  Circulation Research Vol. 131, No. Suppl_1 ( 2022-08-05)
    Details
    In: Circulation Research, Ovid Technologies (Wolters Kluwer Health), Vol. 131, No. Suppl_1 ( 2022-08-05)
    Abstract: Background: Despite significant reduction in acute MI death, ischemic heart failure (IHF) and resultant death continually escalate with incompletely understood mechanism. We recently reported that adipocyte-derived exosomes (ADp-Exo) protect heart from acute MI/R injury. However, it remains unknown whether and how cardiomyocytes (CM) response to ADp-Exo is altered during the chronic phase of MI, negatively impacting IHF development. Methods and Results: Intramyocardial injection of ADp-Exo (isolated from epididymal fat pad) immediately after MI (90 min MI/4 weeks reperfusion) significantly attenuated post-MI remodeling. However, the protective effects were completely lost when ADp-Exo were administered 1 week after MI. To identify the molecular mechanisms responsible for ADp-Exo cardioprotection and its alteration during chronic MI, a series of in vitro experiments were performed. Adiponectin (APN), a potent cardioprotective adipokine, was detected on the surface of ADp-Exo (Exo-flow kit). Treatment of CM with ADp-Exo activated multiple cell salvage kinases (e.g., ACC, ERK and AMPK). These effects were lost in APN neutralization antibody pre-incubated ADp-Exo or ADp-Exo from APNKO mice, suggesting Exo surface APN may mediate ADp-Exo cardioprotection. Moreover, ADp-Exo cell salvage kinase activation effect was absent in CM from AdipoR1KO mice or GRK2 transfected CM, suggesting GRK2-induced AdipoR1 phosphorylation at Ser 205 (as we demonstrated in Circulation, 2015 and Circ Res, 2022) is likely responsible for incapability of ADp-Exo protection during post-MI remodeling. To obtain direct evidence supporting this novel hypothesis, AdipoR1 S205A or AdipoR1 S205E (pseudo-phosphorylation) mice were generated. ADp-Exo cardioprotection was restored in AdipoR1 S205A mice, even when they were administered 1 week after MI. In contrast, ADp-Exo cardioprotection was lost in AdipoR1 S205E mice, even when they were administered immediately after MI. Conclusions: We demonstrate for the first time that, APN located on the surface of ADp-Exo acts as the critical executor of ADp-CM communication, mediating ADp-Exo cardioprotection. GRK2-induced CM AdipoR1 phosphorylation blocks ADp-Exo protective action, contributing to IHF progression.
    Type of Medium: Online Resource
    ISSN: 0009-7330 , 1524-4571
    URL: Article
    DOI: 10.1161/res.131.suppl_1.P2012
    RVK:
    XA 10000
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2022
    detail.hit.zdb_id: 1467838-X
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  • 2
    Online Resource
    Online Resource
    Nitrative Modification of Caveolin-3: A Novel Mechanism of Cardiac Insulin Resistance and a Potential Therapeutic Target Against Ischemic Heart Failure in Prediabetic Animals
    Ovid Technologies (Wolters Kluwer Health) ; 2023
    In:  Circulation Vol. 147, No. 15 ( 2023-04-11), p. 1162-1179
    Details
    In: Circulation, Ovid Technologies (Wolters Kluwer Health), Vol. 147, No. 15 ( 2023-04-11), p. 1162-1179
    Abstract: Myocardial insulin resistance is a hallmark of diabetic cardiac injury. However, the underlying molecular mechanisms remain unclear. Recent studies demonstrate that the diabetic heart is resistant to other cardioprotective interventions, including adiponectin and preconditioning. The “universal” resistance to multiple therapeutic interventions suggests impairment of the requisite molecule(s) involved in broad prosurvival signaling cascades. Cav (Caveolin) is a scaffolding protein coordinating transmembrane signaling transduction. However, the role of Cav3 in diabetic impairment of cardiac protective signaling and diabetic ischemic heart failure is unknown. Methods: Wild-type and gene-manipulated mice were fed a normal diet or high-fat diet for 2 to 12 weeks and subjected to myocardial ischemia and reperfusion. Insulin cardioprotection was determined. Results: Compared with the normal diet group, the cardioprotective effect of insulin was significantly blunted as early as 4 weeks of high-fat diet feeding (prediabetes), a time point where expression levels of insulin-signaling molecules remained unchanged. However, Cav3/insulin receptor-β complex formation was significantly reduced. Among multiple posttranslational modifications altering protein/protein interaction, Cav3 (not insulin receptor-β) tyrosine nitration is prominent in the prediabetic heart. Treatment of cardiomyocytes with 5-amino-3-(4-morpholinyl)-1,2,3-oxadiazolium chloride reduced the signalsome complex and blocked insulin transmembrane signaling. Mass spectrometry identified Tyr 73 as the Cav3 nitration site. Phenylalanine substitution of Tyr 73 (Cav3 Y73F ) abolished 5-amino-3-(4-morpholinyl)-1,2,3-oxadiazolium chloride–induced Cav3 nitration, restored Cav3/insulin receptor-β complex, and rescued insulin transmembrane signaling. It is most important that adeno-associated virus 9–mediated cardiomyocyte-specific Cav3 Y73F reexpression blocked high-fat diet–induced Cav3 nitration, preserved Cav3 signalsome integrity, restored transmembrane signaling, and rescued insulin-protective action against ischemic heart failure. Last, diabetic nitrative modification of Cav3 at Tyr 73 also reduced Cav3/AdipoR1 complex formation and blocked adiponectin cardioprotective signaling. Conclusions: Nitration of Cav3 at Tyr 73 and resultant signal complex dissociation results in cardiac insulin/adiponectin resistance in the prediabetic heart, contributing to ischemic heart failure progression. Early interventions preserving Cav3-centered signalsome integrity is an effective novel strategy against diabetic exacerbation of ischemic heart failure.
    Type of Medium: Online Resource
    ISSN: 0009-7322 , 1524-4539
    URL: Article
    DOI: 10.1161/CIRCULATIONAHA.122.063073
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2023
    detail.hit.zdb_id: 1466401-X
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  • 3
    Online Resource
    Online Resource
    Abstract 15194: Nitrative Modification of Caveolin-3, a Novel Mechanism Revealing Cardiac Insulin Resistance in Ischemic Heart Failure
    Ovid Technologies (Wolters Kluwer Health) ; 2022
    In:  Circulation Vol. 146, No. Suppl_1 ( 2022-11-08)
    Details
    In: Circulation, Ovid Technologies (Wolters Kluwer Health), Vol. 146, No. Suppl_1 ( 2022-11-08)
    Abstract: Introduction: Myocardial insulin resistant is a hallmark of diabetic cardiac injury. However, underlying molecular mechanisms remain unclear. Recent studies show that diabetic heart is resistant to other cardioprotective interventions, including adiponectin and pre-conditioning. The “universal” resistance to multiple therapeutic interventions suggests impairment of the requisite molecule(s) involved in broad pro-survival signaling cascades. Caveolin (Cav) is a scaffolding protein coordinating transmembrane signaling transduction. However, role of Cav3 in diabetic impairment of cardiac protective signaling and diabetic ischemic heart failure (HF) is unknown. Methods and Results: Mice were fed normal diet (ND) or high-fat-diet (HFD) and subjected to myocardial ischemia and reperfusion. The cardioprotective effect of insulin was significantly blunted as early as 4 weeks of HFD feeding (pre-diabetes), when insulin signals remain unchanged. However, Cav3/IRβ complex formation, requisite for insulin transmembrane signaling, was significantly reduced. Among multiple post-translational modifications altering proteins interaction, Cav3 (not IRβ or AdipoR1) tyrosine nitration is prominent in the pre-diabetic heart. SIN-1 treatment reduced the signalsome formation and blocked insulin transmembrane signaling. Mass spectrometry identified Tyr 73 is the Cav3 nitration site. Phenylalanine substitution of Tyr 73 (Cav3 Y73F ) abolished SIN-1 induced Cav3 nitration, restored Cav3/IRβ complex, and rescued insulin transmembrane signaling. AAV9-mediated cardiac Cav3 Y73F re-expression blocked HFD-induced Cav3 nitration, preserved Cav3 signalsome integrity, and rescued insulin protective action against ischemic HF. Finally, diabetic nitrative modification of Cav3 at Tyr 73 also reduced Cav3/AdipoR1 complex formation and blocked adiponectin cardioprotective signaling. Conclusion: Nitration of Cav3 at Tyr 73 and resultant signal complex dissociation is responsible for cardiac insulin/adiponectin resistance in the pre-diabetic heart, contributing to ischemic HF progression. Early interventions preserving Cav3-centered signalsome integrity is an effective novel strategy against diabetic exacerbation of ischemic HF.
    Type of Medium: Online Resource
    ISSN: 0009-7322 , 1524-4539
    URL: Article
    DOI: 10.1161/circ.146.suppl_1.15194
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2022
    detail.hit.zdb_id: 1466401-X
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  • 4
    Online Resource
    Online Resource
    Abstract 10526: Surface Located Adiponectin On Adipocytes-derived Exosomes Mediates Adipocytes/cardiomyocytes Communication And Contributes To Cardioprotection
    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 and Hypothesis: Increasing evidence emphasizes the roles of adipocyte-cardiomyocyte (ADp-CM) communication plays in health and diabetes. We recently reported that diabetes switched ADp-derived Exosomes (ADp-Exo) from carrying cardioprotective molecules to delivering cardiotoxic molecules to CM. However, the molecular mechanisms mediating ADp-Exo cardioprotection and its alteration by diabetes remain unknown. Methods and Results: ADp-Exo was isolated from epididymal white adipocytes of WT mice. Western Blot demonstrated high level of adiponectin (APN), a potent cardioprotective adipokine, present in ADp-Exo. More interestingly, APN was detected on the surface of ADp-Exo by flow cytometry using Exo-flow kit (System Biosciences). To determine whether surface-located APN on ADp-Exo protect heart, WT ADp-Exo were intramyocardially injected. Mice were subjected to 90 minutes coronary occlusion, followed by 4 weeks of reperfusion. Cardiac function was evaluated by echocardiograph weekly. WT ADp-Exo significantly reduced MI/R injury in vivo , as evidenced by improved LVEF, radial and longitudinal myocardial Strain and SR (vs vehicle group, p 〈 0.05). Importantly, pre-incubation of ADp-Exo with an APN neutralization antibody blocked ADp-Exo cardioprotection. To determine the role of CM AdipoR1, ex vivo and in vitro experiments were performed. WT ADp-Exo activated AdipoR1 pathway (increased phosphorylation of ACC, ERK and AMPK) in CM and protected against cell injury and death (MTT and LDH assay). However, surface APN blocked WT ADp-Exo or APN -/- ADp-Exo failed to active this signaling and protection. WT ADp-Exo failed to activate cell salvage kinases in AdipoR1 -/- CM. Finally, overexpression of GRK2, a pathogenic molecule that we reported to cause AdipoR1 S205 phosphorylation, blocked WT ADp-Exo cardioprotection. AAV9-mediated overexpression of a phosphorylation resistant AdipoR1 (AdipoR1 S205A ) restored ADp-Exo protective action. Conclusions: We demonstrate for the first time that ADp-Exo surface located APN mediates ADp-CM communication via CM AdipoR1 pathway, promoting cardioprotection. This protective system is blocked by GRK2-induced AdipoR1 phosphorylation in diabetic heart, promoting MI/R injury.
    Type of Medium: Online Resource
    ISSN: 0009-7322 , 1524-4539
    URL: Article
    DOI: 10.1161/circ.144.suppl_1.10526
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2021
    detail.hit.zdb_id: 1466401-X
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  • 5
    Online Resource
    Online Resource
    Targeting Adiponectin Receptor 1 Phosphorylation Against Ischemic Heart Failure
    Ovid Technologies (Wolters Kluwer Health) ; 2022
    In:  Circulation Research Vol. 131, No. 2 ( 2022-07-08)
    Details
    In: Circulation Research, Ovid Technologies (Wolters Kluwer Health), Vol. 131, No. 2 ( 2022-07-08)
    Abstract: Despite significantly reduced acute myocardial infarction (MI) mortality in recent years, ischemic heart failure continues to escalate. Therapeutic interventions effectively reversing pathological remodeling are an urgent unmet medical need. We recently demonstrated that AdipoR1 (APN [adiponectin] receptor 1) phosphorylation by GRK2 (G-protein–coupled receptor kinase 2) contributes to maladaptive remodeling in the ischemic heart. The current study clarified the underlying mechanisms leading to AdipoR1 phosphorylative desensitization and investigated whether blocking AdipoR1 phosphorylation may restore its protective signaling, reversing post-MI remodeling. Methods: Specific sites and underlying molecular mechanisms responsible for AdipoR1 phosphorylative desensitization were investigated in vitro (neonatal and adult cardiomyocytes). The effects of AdipoR1 phosphorylation inhibition upon APN post-MI remodeling and heart failure progression were investigated in vivo. Results: Among 4 previously identified sites sensitive to GRK2 phosphorylation, alanine substitution of Ser 205 (AdipoR1 S205A ), but not other 3 sites, rescued GRK2-suppressed AdipoR1 functions, restoring APN-induced cell salvage kinase activation and reducing oxidative cell death. The molecular investigation followed by functional determination demonstrated that AdipoR1 phosphorylation promoted clathrin-dependent (not caveolae) endocytosis and lysosomal-mediated (not proteasome) degradation, reducing AdipoR1 protein level and suppressing AdipoR1-mediated cytoprotective action. GRK2-induced AdipoR1 endocytosis and degradation were blocked by AdipoR1 S205A overexpression. Moreover, AdipoR1 S205E (pseudophosphorylation) phenocopied GRK2 effects, promoted AdipoR1 endocytosis and degradation, and inhibited AdipoR1 biological function. Most importantly, AdipoR1 function was preserved during heart failure development in AdipoR1-KO (AdipoR1 knockout) mice reexpressing hAdipoR1 S205A . APN administration in the failing heart reversed post-MI remodeling and improved cardiac function. However, reexpressing hAdipoR1 WT in AdipoR1-KO mice failed to restore APN cardioprotection. Conclusions: Ser 205 is responsible for AdipoR1 phosphorylative desensitization in the failing heart. Blockade of AdipoR1 phosphorylation followed by pharmacological APN administration is a novel therapy effective in reversing post-MI remodeling and mitigating heart failure progression.
    Type of Medium: Online Resource
    ISSN: 0009-7330 , 1524-4571
    URL: Article
    DOI: 10.1161/CIRCRESAHA.121.319976
    RVK:
    XA 10000
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2022
    detail.hit.zdb_id: 1467838-X
    Location Call Number Limitation Availability
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    Online Resource
  • 6
    Online Resource
    Online Resource
    Abstract 9633: Caveolin-3 Nitrative Modification Exacerbates Ischemic Heart Failure in Pre-Diabetic Mice by Disassembling Cardioprotective Signalosomes
    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: Rationale: Diabatic heart is “universally” resistant to protective interventions, including insulin, adiponectin exacerbating ischemic heart failure (HF). Caveolin (Cav) serves as scaffolding regulator, coordinating signal transduction in cell survival. However, whether and how diabetes alter Cav3-centered signalosome integrity, contributing to diabetic ischemic HF remains unclear.We hypothesized that preserving Cav3 signalosome integrity restore cardioprotective signaling, protecting against diabetic exacerbation of ischemia HF. Methods and Results: Mice with normal diet (ND) or high-fat-diet (HFD) were subjected to myocardial ischemia and reperfusion (MI/R). Administration of insulin or adiponectin markedly attenuated MI injury (60 minutes MI/24 hours reperfusion) in ND mice, an effect lost in diabetic animals (12 weeks HFD, n=18-20/group). Interestingly, cardioprotective effect of insulin and adiponectin was blunted as early as 4 weeks of HFD (pre-diabetes). In ND heart, Cav3 interacts with AdipoR1 and insulin receptor-β (IRβ), forming signalosomes. Those complexes were significantly reduced in pre-diabetic heart. However, the level of Cav3, AdipoR1, AdipoR2, and IRβ remain unchanged. Among multiple post-translational modifications, Cav3 nitration was the dominant in pre-diabetic heart. SIN-1 (a nitration donor) reduced Cav3/AdipoR1 and Cav3/IRβ complex, and blocked their transmembrane signaling. Mass spectrometry identified Tyr 73 is the site modified in pre-diabetic cardiomyocytes. Phenylalanine substitution of Tyr 73 (Cav3 Y73F ) blocked SIN-1 induced Cav3 nitration, restored signalosome assembling, and rescued insulin and adiponectin transmembrane signaling in diabetic cardiomyocytes. Finally, AAV9-mediated cardiomyocyte specific Cav3 Y73F re-expression blocked HFD-induced Cav3 nitration, restored transmembrane signaling, rescued the protective action against ischemic HF. Conclusion: Nitration of Cav3 at Tyr 73 and complex dissociation is responsible for cardiac insulin/adiponectin resistance in pre-diabetic heart, contributing to ischemic HF progression. Early intervention preserving Cav3-centered signalosome integrity is an effective novel strategy against diabetic ischemic HF.
    Type of Medium: Online Resource
    ISSN: 0009-7322 , 1524-4539
    URL: Article
    DOI: 10.1161/circ.144.suppl_1.9633
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2021
    detail.hit.zdb_id: 1466401-X
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