Hsp20-Mediated Activation of Exosome Biogenesis in Cardiomyocytes Improves Cardiac Function and Angiogenesis in Diabetic Mice.
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.
Department of Pharmacology and Cell Biophysics, University of Cincinnati College of Medicine, Cincinnati, OH.
Xiaohong
X
Wang
Department of Pharmacology and Cell Biophysics, University of Cincinnati College of Medicine, Cincinnati, OH.
Haitao
H
Gu
Department of Pathology and Laboratory Medicine, University of Cincinnati College of Medicine, Cincinnati, OH.
Wei
W
Huang
Department of Pharmacology and Cell Biophysics, University of Cincinnati College of Medicine, Cincinnati, OH Department of Cardiovascular Diseases, Tongji Medical College Union Hospital, Huazhong University of Science and Technology, Wuhan, China.
Jiangtong
J
Peng
Department of Pharmacology and Cell Biophysics, University of Cincinnati College of Medicine, Cincinnati, OH.
Yutian
Y
Li
Department of Pharmacology and Cell Biophysics, University of Cincinnati College of Medicine, Cincinnati, OH.
Liwang
L
Yang
Department of Pharmacology and Cell Biophysics, University of Cincinnati College of Medicine, Cincinnati, OH.
Dongze
D
Qin
Department of Pharmacology and Cell Biophysics, University of Cincinnati College of Medicine, Cincinnati, OH.
Kobina
K
Essandoh
Department of Pathology and Laboratory Medicine, University of Cincinnati College of Medicine, Cincinnati, OH.
Yigang
Y
Wang
Critical Illness Research, Lawson Health Research Institute, Ontario, Canada.
Tianqing
T
Peng
Department of Pharmacology and Cell Biophysics, University of Cincinnati College of Medicine, Cincinnati, OH fangg@ucmail.uc.edu.
Guo-Chang
0000-0002-0439-8277
GC
Fan
D000814:Aniline Compounds / Q000494:pharmacology; D000818:Animals; D001597:Benzylidene Compounds / Q000494:pharmacology; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology; D049109:Cell Proliferation / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D024042:Collagen Type I / Q000378:metabolism; D024061:Collagen Type III / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism* / Q000503:physiopathology*; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D055354:Exosomes / Q000187:drug effects / Q000378:metabolism*; D050886:HSP20 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006321:Heart / Q000187:drug effects; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009206:Myocardium / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology*; D018919:Neovascularization, Physiologic / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D011485:Protein Binding; D017382:Reactive Oxygen Species / Q000378:metabolism; D000072105:Superoxide Dismutase-1 / Q000378:metabolism
D000814:Aniline Compounds; D001597:Benzylidene Compounds; D024042:Collagen Type I; D024061:Collagen Type III; C468773:GW 4869; D050886:HSP20 Heat-Shock Proteins; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D017382:Reactive Oxygen Species; C000606291:Sod1 protein, mouse; D000072105:Superoxide Dismutase-1