title: Diminished autophagy limits cardiac injury in mouse models of type 1 diabetes.
abstract: Cardiac autophagy is inhibited in type 1 diabetes. However, it remains unknown if the reduced autophagy contributes to the pathogenesis of diabetic cardiomyopathy. We addressed this question using mouse models with gain- and loss-of-autophagy. Autophagic flux was inhibited in diabetic hearts when measured at multiple time points after diabetes induction by streptozotocin as assessed by protein levels of microtubule-associated protein light chain 3 form 2 (LC3-II) or GFP-LC3 puncta in the absence and presence of the lysosome inhibitor bafilomycin A1. Autophagy in diabetic hearts was further reduced in beclin 1- or Atg16-deficient mice but was restored partially or completely by overexpression of beclin 1 to different levels. Surprisingly, diabetes-induced cardiac damage was substantially attenuated in beclin 1- and Atg16-deficient mice as shown by improved cardiac function as well as reduced levels of oxidative stress, interstitial fibrosis, and myocyte apoptosis. In contrast, diabetic cardiac damage was dose-dependently exacerbated by beclin 1 overexpression. The cardioprotective effects of autophagy deficiency were reproduced in OVE26 diabetic mice. These effects were associated with partially restored mitophagy and increased expression and mitochondrial localization of Rab9, an essential regulator of a non-canonical alternative autophagic pathway. Together, these findings demonstrate that the diminished autophagy is an adaptive response that limits cardiac dysfunction in type 1 diabetes, presumably through up-regulation of alternative autophagy and mitophagy.
authors: Cardiovascular Health Research Center, Sanford Research/University of South Dakota, Department of Internal Medicine, University of South Dakota Sanford School of Medicine, Sioux Falls, South Dakota 57104, USA.
authors: Xianmin
authors: X
authors: Xu
authors: Satoru
authors: S
authors: Kobayashi
authors: Kai
authors: K
authors: Chen
authors: Derek
authors: D
authors: Timm
authors: Paul
authors: P
authors: Volden
authors: Yuan
authors: Y
authors: Huang
authors: James
authors: J
authors: Gulick
authors: Zhenyu
authors: Z
authors: Yue
authors: Jeffrey
authors: J
authors: Robbins
authors: Paul N
authors: PN
authors: Epstein
authors: Qiangrong
authors: Q
authors: Liang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D001343:Autophagy; D000071183:Autophagy-Related Proteins; D000071186:Beclin-1; D015153:Blotting, Western; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D058065:Diabetic Cardiomyopathies / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D017382:Reactive Oxygen Species / Q000378:metabolism; D020691:rab GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; C532820:Atg16l1 protein, mouse; D000071183:Autophagy-Related Proteins; D000071186:Beclin-1; C115010:Becn1 protein, mouse; D002352:Carrier Proteins; C480860:Map1lc3b protein, mouse; D008869:Microtubule-Associated Proteins; D017382:Reactive Oxygen Species; C544263:rab9 protein, mouse; D020691:rab GTP-Binding Proteins
keywords: Alternative Autophagy; Apoptosis; Autophagy; Beclin 1; Cardiomyopathy; Diabetes; Mitochondria; Mitophagy; Oxidative Stress; Rab9
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