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Exosome Mediated Globular Adiponectin's Cardioprotective Role via the Adiponectin receptor‐dependent Uptake mechanism
Author(s) -
Wang Yajing,
Gan Lu,
Xie Dina,
Lau Wayne Bond,
Liu Jing,
Zhang Ling,
Gao Erhe,
Koch Walter,
Ma Xinliang
Publication year - 2019
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2019.33.1_supplement.833.21
Subject(s) - cardioprotection , exosome , microbiology and biotechnology , adiponectin , receptor , microvesicles , pharmacology , chemistry , medicine , biology , ischemia , biochemistry , insulin , gene , microrna , insulin resistance
Objectives Globular domain isotype adiponectin (gAPN) exerts cardioprotective effect against cardiac ischemia injury. T‐Cadherin (TCad) and adiponectin receptors are key molecules mediated adiponectin's cardioprotection. However, whether these receptors mediate the cardioprotective effects of gAPN, the isotype with more potent biological activity, most commonly utilized in metabolic/cardiovascular investigations, remains unclear. Methods and Results Adult male WT, AdipoR1KO, and TCadKO mice were subjected to MI, treated with vehicle or gAPN, and observed for 4 weeks. The cardioprotective effects of gAPN were abolished in AdipoR1 Knockout mice, but not Tcad, indicating that AdipoR1, but not Tcad, mediates gAPN cardioprotection. Unexpectedly, we observed that gAPN cardioprotection was significantly attenuated in animals pre‐treated with GW4869 (an exosome generation inhibitor). To further determine whether gAPN regulates exosome biological process, we investigated exosome's biogenesis and/or uptake and the precise involvement of AdipoRs., The effects of gAPN and HMW (high molecular weight APN isoform) upon exosome generation and uptake were determined on cardiomyocytes were isolated from adult AdipoR1KO and TCadKO mice. Surprisingly, cardiomyocyte exosome production increased markedly (8‐fold) when cells were treated with gAPN, but not with HMW. Moreover, gAPN increases cardiomyocyte exosome production in a receptor‐independent fashion, via regulation of the ESCRT‐multivesicular body (MVB) pathway. Furthermore, gAPN‐stimulated exosome uptake and cellular protection in WT cardiomyocytes were abolished in cardiomyocytes derived from AdipoR1KO, but not TCadKO, mice. Conclusions These data demonstrate that gAPN and HMW cardioprotection exhibits differential receptor dependence, and is mediated by distinct mechanisms. Whereas HMW protects the heart via TCad‐dependent mechanisms, gAPN promotes exosome biogenesis in a receptor‐independent fashion, and stimulating exosome uptake and cardioprotection in an AdipoR1‐dependent manner. Our results suggest gAPN is superior to HMW with respect to cardioprotection against ischemia heart injury, and represents a promising therapeutic strategy in patients with coronary artery disease. Support or Funding Information NIH RO1, ADA This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .