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Ischemic Heart-Derived Small Extracellular Vesicles Impair Adipocyte Function.
Gan, Lu; Liu, Demin; Xie, Dina; Bond Lau, Wayne; Liu, Jing; Christopher, Theodore A; Lopez, Bernard; Liu, Lian; Hu, Hang; Yao, Peng; He, Yarong; Gao, Erhe; Koch, Walter J; Zhao, Jianli; Ma, Xin-Liang; Cao, Yu; Wang, Yajing.
Afiliação
  • Gan L; Laboratory of Emergency Medicine, Department of Emergency Medicine and National Clinical Research Center for Geriatrics, West China Hospital (L.G., L.L., H.H., P.Y., Y.H., Y.C.), Sichuan University, Chengdu, China.
  • Liu D; Department of Emergency Medicine, Thomas Jefferson University, Philadelphia, PA (L.G., D.L., D.X., W.B.L., J.L., T.A.C., B.L., P.Y., J.Z., X.-L.M., Y.W.).
  • Xie D; Department of Emergency Medicine, Thomas Jefferson University, Philadelphia, PA (L.G., D.L., D.X., W.B.L., J.L., T.A.C., B.L., P.Y., J.Z., X.-L.M., Y.W.).
  • Bond Lau W; Department of Cardiology, The Second Hospital of Hebei Medical University, Shijiazhuang, China (D.L.).
  • Liu J; Department of Emergency Medicine, Thomas Jefferson University, Philadelphia, PA (L.G., D.L., D.X., W.B.L., J.L., T.A.C., B.L., P.Y., J.Z., X.-L.M., Y.W.).
  • Christopher TA; Department of Emergency Medicine, Thomas Jefferson University, Philadelphia, PA (L.G., D.L., D.X., W.B.L., J.L., T.A.C., B.L., P.Y., J.Z., X.-L.M., Y.W.).
  • Lopez B; Department of Emergency Medicine, Thomas Jefferson University, Philadelphia, PA (L.G., D.L., D.X., W.B.L., J.L., T.A.C., B.L., P.Y., J.Z., X.-L.M., Y.W.).
  • Liu L; Department of Emergency Medicine, Thomas Jefferson University, Philadelphia, PA (L.G., D.L., D.X., W.B.L., J.L., T.A.C., B.L., P.Y., J.Z., X.-L.M., Y.W.).
  • Hu H; Department of Emergency Medicine, Thomas Jefferson University, Philadelphia, PA (L.G., D.L., D.X., W.B.L., J.L., T.A.C., B.L., P.Y., J.Z., X.-L.M., Y.W.).
  • Yao P; Laboratory of Emergency Medicine, Department of Emergency Medicine and National Clinical Research Center for Geriatrics, West China Hospital (L.G., L.L., H.H., P.Y., Y.H., Y.C.), Sichuan University, Chengdu, China.
  • He Y; Laboratory of Emergency Medicine, Department of Emergency Medicine and National Clinical Research Center for Geriatrics, West China Hospital (L.G., L.L., H.H., P.Y., Y.H., Y.C.), Sichuan University, Chengdu, China.
  • Gao E; Department of Emergency Medicine, Thomas Jefferson University, Philadelphia, PA (L.G., D.L., D.X., W.B.L., J.L., T.A.C., B.L., P.Y., J.Z., X.-L.M., Y.W.).
  • Koch WJ; Laboratory of Emergency Medicine, Department of Emergency Medicine and National Clinical Research Center for Geriatrics, West China Hospital (L.G., L.L., H.H., P.Y., Y.H., Y.C.), Sichuan University, Chengdu, China.
  • Zhao J; Laboratory of Emergency Medicine, Department of Emergency Medicine and National Clinical Research Center for Geriatrics, West China Hospital (L.G., L.L., H.H., P.Y., Y.H., Y.C.), Sichuan University, Chengdu, China.
  • Ma XL; Center for Translational Medicine, Temple University, Philadelphia, PA (E.G., W.J.K.).
  • Cao Y; Center for Translational Medicine, Temple University, Philadelphia, PA (E.G., W.J.K.).
  • Wang Y; Department of Emergency Medicine, Thomas Jefferson University, Philadelphia, PA (L.G., D.L., D.X., W.B.L., J.L., T.A.C., B.L., P.Y., J.Z., X.-L.M., Y.W.).
Circ Res ; 130(1): 48-66, 2022 01 07.
Article em En | MEDLINE | ID: mdl-34763521
ABSTRACT

BACKGROUND:

Patients with acute myocardial infarction suffer systemic metabolic dysfunction via incompletely understood mechanisms. Adipocytes play critical role in metabolic homeostasis. The impact of acute myocardial infarction upon adipocyte function is unclear. Small extracellular vesicles (sEVs) critically contribute to organ-organ communication. Whether and how small extracellular vesicle mediate post-MI cardiomyocyte/adipocyte communication remain unknown.

METHODS:

Plasma sEVs were isolated from sham control (Pla-sEVSham) or 3 hours after myocardial ischemia/reperfusion (Pla-sEVMI/R) and incubated with adipocytes for 24 hours. Compared with Pla-sEVSham, Pla-sEVMI/R significantly altered expression of genes known to be important in adipocyte function, including a well-known metabolic regulatory/cardioprotective adipokine, APN (adiponectin). Pla-sEVMI/R activated 2 (PERK-CHOP and ATF6 [transcription factor 6]-EDEM [ER degradation enhancing alpha-mannosidase like protein 1] pathways) of the 3 endoplasmic reticulum (ER) stress pathways in adipocytes. These pathological alterations were also observed in adipocytes treated with sEVs isolated from adult cardiomyocytes subjected to in vivo myocardial ischemia/reperfusion (MI/R) (Myo-sEVMI/R). Bioinformatic/RT-qPCR analysis demonstrates that the members of miR-23-27-24 cluster are significantly increased in Pla-sEVMI/R, Myo-sEVMI/R, and adipose tissue of MI/R animals. Administration of cardiomyocyte-specific miR-23-27-24 sponges abolished adipocyte miR-23-27-24 elevation in MI/R animals, supporting the cardiomyocyte origin of adipocyte miR-23-27-24 cluster. In similar fashion to Myo-sEVMI/R, a miR-27a mimic activated PERK-CHOP and ATF6-EDEM-mediated ER stress. Conversely, a miR-27a inhibitor significantly attenuated Myo-sEVMI/R-induced ER stress and restored APN production.

RESULTS:

An unbiased approach identified EDEM3 (ER degradation enhancing alpha-mannosidase like protein 3) as a novel downstream target of miR-27a. Adipocyte EDEM3 deficiency phenocopied multiple pathological alterations caused by Myo-sEVMI/R, whereas EDEM3 overexpression attenuated Myo-sEVMI/R-resulted ER stress. Finally, administration of GW4869 or cardiomyocyte-specific miR-23-27-24 cluster sponges attenuated adipocyte ER stress, improved adipocyte endocrine function, and restored plasma APN levels in MI/R animals.

CONCLUSIONS:

We demonstrate for the first time that MI/R causes significant adipocyte ER stress and endocrine dysfunction by releasing miR-23-27-24 cluster-enriched small extracellular vesicle. Targeting small extracellular vesicle-mediated cardiomyocyte-adipocyte pathological communication may be of therapeutic potential to prevent metabolic dysfunction after MI/R.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Comunicação Celular / Adipócitos / Miócitos Cardíacos / Estresse do Retículo Endoplasmático / Vesículas Extracelulares / Infarto do Miocárdio Tipo de estudo: Prognostic_studies Limite: Animals Idioma: En Ano de publicação: 2022 Tipo de documento: Article
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Comunicação Celular / Adipócitos / Miócitos Cardíacos / Estresse do Retículo Endoplasmático / Vesículas Extracelulares / Infarto do Miocárdio Tipo de estudo: Prognostic_studies Limite: Animals Idioma: En Ano de publicação: 2022 Tipo de documento: Article