{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T21:20:25Z","timestamp":1790716825092,"version":"4.1.0"},"reference-count":33,"publisher":"American Diabetes Association","issue":"10","license":[{"start":{"date-parts":[[2016,9,22]],"date-time":"2016-09-22T00:00:00Z","timestamp":1474502400000},"content-version":"vor","delay-in-days":105,"URL":"http:\/\/www.diabetesjournals.org\/content\/license"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["2R01-HL-087861"],"award-info":[{"award-number":["2R01-HL-087861"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["R01-GM-112930"],"award-info":[{"award-number":["R01-GM-112930"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["diabetesjournals.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2016,10,1]]},"abstract":"<jats:p>Decreased heat shock protein (Hsp) expression in type 1 and type 2 diabetes has been implicated as a primary factor contributing to diabetes-induced organ damage. We recently showed that diabetic cardiomyocytes could release detrimental exosomes, which contain lower levels of Hsp20 than normal ones. To investigate whether such detrimental exosomes could be modified in cardiomyocytes by raising Hsp20 levels to become protective, we used a transgenic (TG) mouse model with cardiac-specific overexpression of Hsp20. TG and control wild-type (WT) mice were injected with streptozotocin (STZ) to induce diabetes. We observed that overexpression of Hsp20 significantly attenuated STZ-caused cardiac dysfunction, hypertrophy, apoptosis, fibrosis, and microvascular rarefaction. Moreover, Hsp20-TG cardiomyocytes exhibited an increased generation\/secretion of exosomes by direct interaction of Hsp20 with Tsg101. Of importance, exosomes derived from TG cardiomyocytes encased higher levels of Hsp20, p-Akt, survivin, and SOD1 than WT exosomes and protected against in vitro hyperglycemia-triggered cell death, as well as in vivo STZ-induced cardiac adverse remodeling. Last, blockade of exosome generation by GW4869 remarkably offset Hsp20-mediated cardioprotection in diabetic mice. Our results indicate that elevation of Hsp20 in cardiomyocytes can offer protection in diabetic hearts through the release of instrumental exosomes. Thus, Hsp20-engineered exosomes might be a novel therapeutic agent for diabetic cardiomyopathy.<\/jats:p>","DOI":"10.2337\/db15-1563","type":"journal-article","created":{"date-parts":[[2016,6,10]],"date-time":"2016-06-10T02:30:15Z","timestamp":1465525815000},"page":"3111-3128","update-policy":"https:\/\/doi.org\/10.2337\/ada-journal-policies","source":"Crossref","is-referenced-by-count":221,"title":["Hsp20-Mediated Activation of Exosome Biogenesis in Cardiomyocytes Improves Cardiac Function and Angiogenesis in Diabetic Mice"],"prefix":"10.2337","volume":"65","author":[{"given":"Xiaohong","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Cell Biophysics, University of Cincinnati College of Medicine, Cincinnati, OH"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haitao","family":"Gu","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Cell Biophysics, University of Cincinnati College of Medicine, Cincinnati, OH"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, University of Cincinnati College of Medicine, Cincinnati, OH"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiangtong","family":"Peng","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Cell Biophysics, University of Cincinnati College of Medicine, Cincinnati, OH"},{"name":"Department of Cardiovascular Diseases, Tongji Medical College Union Hospital, Huazhong University of Science and Technology, Wuhan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yutian","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Cell Biophysics, University of Cincinnati College of Medicine, Cincinnati, OH"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liwang","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Cell Biophysics, University of Cincinnati College of Medicine, Cincinnati, OH"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dongze","family":"Qin","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Cell Biophysics, University of Cincinnati College of Medicine, Cincinnati, OH"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kobina","family":"Essandoh","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Cell Biophysics, University of Cincinnati College of Medicine, Cincinnati, OH"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yigang","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, University of Cincinnati College of Medicine, Cincinnati, OH"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tianqing","family":"Peng","sequence":"additional","affiliation":[{"name":"Critical Illness Research, Lawson Health Research Institute, Ontario, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0439-8277","authenticated-orcid":false,"given":"Guo-Chang","family":"Fan","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Cell Biophysics, University of Cincinnati College of Medicine, Cincinnati, OH"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1167","published-online":{"date-parts":[[2016,6,9]]},"reference":[{"key":"2022031300445742600_B1","doi-asserted-by":"crossref","first-page":"2107","DOI":"10.1016\/S0140-6736(14)61402-1","article-title":"Heart failure in diabetes: effects of anti-hyperglycaemic drug therapy","volume":"385","author":"Gilbert","year":"2015","journal-title":"Lancet"},{"key":"2022031300445742600_B2","doi-asserted-by":"crossref","first-page":"660","DOI":"10.1007\/s00125-014-3171-6","article-title":"Molecular mechanisms of diabetic cardiomyopathy","volume":"57","author":"Bugger","year":"2014","journal-title":"Diabetologia"},{"key":"2022031300445742600_B3","doi-asserted-by":"crossref","first-page":"264","DOI":"10.2174\/157339911796397811","article-title":"Heat shock response regulates insulin sensitivity and glucose homeostasis: pathophysiological impact and therapeutic potential","volume":"7","author":"Kondo","year":"2011","journal-title":"Curr Diabetes Rev"},{"key":"2022031300445742600_B4","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1016\/j.molcel.2010.10.006","article-title":"The heat shock response: life on the verge of death","volume":"40","author":"Richter","year":"2010","journal-title":"Mol Cell"},{"key":"2022031300445742600_B5","doi-asserted-by":"crossref","first-page":"515","DOI":"10.1016\/j.molcel.2015.08.004","article-title":"Shockingly early: chromatin-mediated loss of the heat shock response","volume":"59","author":"Booth","year":"2015","journal-title":"Mol Cell"},{"key":"2022031300445742600_B6","doi-asserted-by":"crossref","first-page":"574","DOI":"10.1016\/j.yjmcc.2010.09.013","article-title":"Small heat shock protein 20 (HspB6) in cardiac hypertrophy and failure","volume":"51","author":"Fan","year":"2011","journal-title":"J Mol Cell Cardiol"},{"key":"2022031300445742600_B7","doi-asserted-by":"crossref","first-page":"1881","DOI":"10.2337\/db13-0967","article-title":"Activating HSP72 in rodent skeletal muscle increases mitochondrial number and oxidative capacity and decreases insulin resistance","volume":"63","author":"Henstridge","year":"2014","journal-title":"Diabetes"},{"key":"2022031300445742600_B8","doi-asserted-by":"crossref","first-page":"9364","DOI":"10.1074\/jbc.M608985200","article-title":"Protein kinase A-dependent translocation of Hsp90 alpha impairs endothelial nitric-oxide synthase activity in high glucose and diabetes","volume":"282","author":"Lei","year":"2007","journal-title":"J Biol Chem"},{"key":"2022031300445742600_B9"},{"key":"2022031300445742600_B10","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.abb.2014.06.008","article-title":"Expression and induction of small heat shock proteins in rat heart under chronic hyperglycemic conditions","volume":"558","author":"Reddy","year":"2014","journal-title":"Arch Biochem Biophys"},{"key":"2022031300445742600_B11","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1016\/j.yjmcc.2014.05.001","article-title":"Cardiomyocytes mediate anti-angiogenesis in type 2 diabetic rats through the exosomal transfer of miR-320 into endothelial cells","volume":"74","author":"Wang","year":"2014","journal-title":"J Mol Cell Cardiol"},{"key":"2022031300445742600_B12"},{"key":"2022031300445742600_B13","doi-asserted-by":"crossref","first-page":"13721","DOI":"10.1038\/srep13721","article-title":"Exosomal miR-223 contributes to mesenchymal stem cell-elicited cardioprotection in polymicrobial sepsis","volume":"5","author":"Wang","year":"2015","journal-title":"Sci Rep"},{"key":"2022031300445742600_B14","doi-asserted-by":"crossref","first-page":"818","DOI":"10.1097\/01.CCM.0000114829.17746.19","article-title":"Platelet-derived exosomes of septic individuals possess proapoptotic NAD(P)H oxidase activity: a novel vascular redox pathway","volume":"32","author":"Janiszewski","year":"2004","journal-title":"Crit Care Med"},{"key":"2022031300445742600_B15","doi-asserted-by":"crossref","first-page":"e32765","DOI":"10.1371\/journal.pone.0032765","article-title":"Hsp20 functions as a novel cardiokine in promoting angiogenesis via activation of VEGFR2","volume":"7","author":"Zhang","year":"2012","journal-title":"PLoS One"},{"key":"2022031300445742600_B16","doi-asserted-by":"crossref","first-page":"1792","DOI":"10.1161\/01.CIR.0000160851.41872.C6","article-title":"Novel cardioprotective role of a small heat-shock protein, Hsp20, against ischemia\/reperfusion injury","volume":"111","author":"Fan","year":"2005","journal-title":"Circulation"},{"key":"2022031300445742600_B17","doi-asserted-by":"crossref","first-page":"1429","DOI":"10.1161\/CIRCRESAHA.110.237644","article-title":"Small heat shock protein 20 interacts with protein phosphatase-1 and enhances sarcoplasmic reticulum calcium cycling","volume":"108","author":"Qian","year":"2011","journal-title":"Circ Res"},{"key":"2022031300445742600_B18","doi-asserted-by":"crossref","first-page":"H829","DOI":"10.1152\/ajpheart.00222.2009","article-title":"Decreased cardiac expression of vascular endothelial growth factor and redox imbalance in murine diabetic cardiomyopathy","volume":"297","author":"Han","year":"2009","journal-title":"Am J Physiol Heart Circ Physiol"},{"key":"2022031300445742600_B19","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1002\/dmrr.613","article-title":"Constant and intermittent high glucose enhances endothelial cell apoptosis through mitochondrial superoxide overproduction","volume":"22","author":"Piconi","year":"2006","journal-title":"Diabetes Metab Res Rev"},{"key":"2022031300445742600_B20","doi-asserted-by":"crossref","first-page":"793","DOI":"10.1038\/ni.2647","article-title":"Exosomes mediate the cell-to-cell transmission of IFN-\u03b1-induced antiviral activity","volume":"14","author":"Li","year":"2013","journal-title":"Nat Immunol"},{"key":"2022031300445742600_B21","doi-asserted-by":"crossref","first-page":"1194","DOI":"10.1016\/j.jaci.2012.12.1565","article-title":"Proinflammatory role of epithelial cell-derived exosomes in allergic airway inflammation","volume":"131","author":"Kulshreshtha","year":"2013","journal-title":"J Allergy Clin Immunol"},{"key":"2022031300445742600_B22"},{"key":"2022031300445742600_B23","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1016\/j.jconrel.2014.12.013","article-title":"Biodistribution and delivery efficiency of unmodified tumor-derived exosomes","volume":"199","author":"Smyth","year":"2015","journal-title":"J Control Release"},{"key":"2022031300445742600_B24","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1038\/mt.2012.180","article-title":"Systemically injected exosomes targeted to EGFR deliver antitumor microRNA to breast cancer cells","volume":"21","author":"Ohno","year":"2013","journal-title":"Mol Ther"},{"key":"2022031300445742600_B25","doi-asserted-by":"crossref","first-page":"382","DOI":"10.1016\/j.yjmcc.2009.05.016","article-title":"Overexpression of Hsp20 prevents endotoxin-induced myocardial dysfunction and apoptosis via inhibition of NF-kappaB activation","volume":"47","author":"Wang","year":"2009","journal-title":"J Mol Cell Cardiol"},{"key":"2022031300445742600_B26","doi-asserted-by":"crossref","first-page":"3021","DOI":"10.1002\/stem.230","article-title":"Hsp20-engineered mesenchymal stem cells are resistant to oxidative stress via enhanced activation of Akt and increased secretion of growth factors","volume":"27","author":"Wang","year":"2009","journal-title":"Stem Cells"},{"key":"2022031300445742600_B27"},{"key":"2022031300445742600_B28","doi-asserted-by":"crossref","first-page":"981","DOI":"10.1038\/cr.2015.82","article-title":"Circular RNA is enriched and stable in exosomes: a promising biomarker for cancer diagnosis","volume":"25","author":"Li","year":"2015","journal-title":"Cell Res"},{"key":"2022031300445742600_B29","doi-asserted-by":"crossref","first-page":"606","DOI":"10.1016\/j.stemcr.2014.04.006","article-title":"Exosomes as critical agents of cardiac regeneration triggered by cell therapy","volume":"2","author":"Ibrahim","year":"2014","journal-title":"Stem Cell Rep"},{"key":"2022031300445742600_B30","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1016\/j.vph.2015.02.008","article-title":"Exosomes and exosomal miRNAs in cardiovascular protection and repair","volume":"71","author":"Emanueli","year":"2015","journal-title":"Vascul Pharmacol"},{"key":"2022031300445742600_B31","doi-asserted-by":"crossref","first-page":"226","DOI":"10.1182\/blood-2012-01-407106","article-title":"AngiomiR-126 expression and secretion from circulating CD34(+) and CD14(+) PBMCs: role for proangiogenic effects and alterations in type 2 diabetics","volume":"121","author":"Mocharla","year":"2013","journal-title":"Blood"},{"key":"2022031300445742600_B32","doi-asserted-by":"crossref","first-page":"1008","DOI":"10.2337\/db13-0859","article-title":"Exosomes released by islet-derived mesenchymal stem cells trigger autoimmune responses in NOD mice","volume":"63","author":"Rahman","year":"2014","journal-title":"Diabetes"},{"key":"2022031300445742600_B33","doi-asserted-by":"crossref","first-page":"10977","DOI":"10.1074\/jbc.M111.324616","article-title":"Sphingolipid-modulated exosome secretion promotes clearance of amyloid-\u03b2 by microglia","volume":"287","author":"Yuyama","year":"2012","journal-title":"J Biol Chem"}],"container-title":["Diabetes"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/diabetes.diabetesjournals.org\/syndication\/doi\/10.2337\/db15-1563","content-type":"unspecified","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/journals.org\/diabetes\/diabetes\/article-pdf\/65\/10\/3111\/582183\/db151563.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/diabetesjournals.org\/diabetes\/article-pdf\/65\/10\/3111\/582183\/db151563.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,11,2]],"date-time":"2022-11-02T16:49:05Z","timestamp":1667407745000},"score":1,"resource":{"primary":{"URL":"https:\/\/diabetesjournals.org\/diabetes\/article\/65\/10\/3111\/34975\/Hsp20-Mediated-Activation-of-Exosome-Biogenesis-in"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,6,9]]},"references-count":33,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2016,6,9]]},"published-print":{"date-parts":[[2016,10,1]]}},"URL":"https:\/\/doi.org\/10.2337\/db15-1563","relation":{},"ISSN":["0012-1797","1939-327X"],"issn-type":[{"value":"0012-1797","type":"print"},{"value":"1939-327X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2016,6,9]]}}}