Resveratrol-enhanced autophagic flux ameliorates myocardial oxidative stress injury in diabetic mice

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Abstract

Autophagic dysfunction is observed in diabetes mellitus. Resveratrol has a beneficial effect on diabetic cardiomyopathy. Whether the resveratrol-induced improvement in cardiac function in diabetes is via regulating autophagy remains unclear. We investigated the mechanisms underlying resveratrol-mediated protection against heart failure in diabetic mice, with a focus on the role of sirtuin 1 (SIRT1) in regulating autophagic flux. Diabetic cardiomyopathy in mice was induced by streptozotocin (STZ). Long-term resveratrol treatment improved cardiac function, ameliorated oxidative injury and reduced apoptosis in the diabetic mouse heart. Western blot analysis revealed that resveratrol decreased p62 protein expression and promoted SIRT1 activity and Rab7 expression. Inhibiting autophagic flux with bafilomycin A1 increased diabetic mouse mortality and attenuated resveratrol-induced down-regulation of p62, but not SIRT1 activity or Rab7 expression in diabetic mouse hearts. In cultured H9C2 cells, redundant or overactive H ₂O ₂ increased p62 and cleaved caspase 3 expression as well as acetylated forkhead box protein O1 (FOXO1) and inhibited SIRT1 expression. Sirtinol, SIRT1 and Rab7 siRNA impaired the resveratrol amelioration of dysfunctional autophagic flux and reduced apoptosis under oxidative conditions. Furthermore, resveratrol enhanced FOXO1 DNA binding at the Rab7 promoter region through a SIRT1-dependent pathway. These results highlight the role of the SIRT1/FOXO1/Rab7 axis in the effect of resveratrol on autophagic flux in vivo and in vitro, which suggests a therapeutic strategy for diabetic cardiomyopathy.

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Burden of systolic and diastolic ventricular dysfunction in the community: appreciating the scope of the heart failure epidemic.

Margaret M. Redfield, Steven J Jacobsen, John C Burnett … (2003)

Approximately half of patients with overt congestive heart failure (CHF) have diastolic dysfunction without reduced ejection fraction (EF). Yet, the prevalence of diastolic dysfunction and its relation to systolic dysfunction and CHF in the community remain undefined. To determine the prevalence of CHF and preclinical diastolic dysfunction and systolic dysfunction in the community and determine if diastolic dysfunction is predictive of all-cause mortality. Cross-sectional survey of 2042 randomly selected residents of Olmsted County, Minnesota, aged 45 years or older from June 1997 through September 2000. Doppler echocardiographic assessment of systolic and diastolic function. Presence of CHF diagnosis by review of medical records with designation as validated CHF if Framingham criteria are satisfied. Subjects without a CHF diagnosis but with diastolic or systolic dysfunction were considered as having either preclinical diastolic or preclinical systolic dysfunction. The prevalence of validated CHF was 2.2% (95% confidence interval [CI], 1.6%-2.8%) with 44% having an EF higher than 50%. Overall, 20.8% (95% CI, 19.0%-22.7%) of the population had mild diastolic dysfunction, 6.6% (95% CI, 5.5%-7.8%) had moderate diastolic dysfunction, and 0.7% (95% CI, 0.3%-1.1%) had severe diastolic dysfunction with 5.6% (95% CI, 4.5%-6.7%) of the population having moderate or severe diastolic dysfunction with normal EF. The prevalence of any systolic dysfunction (EF < or =50%) was 6.0% (95% CI, 5.0%-7.1%) with moderate or severe systolic dysfunction (EF < or =40%) being present in 2.0% (95% CI, 1.4%-2.5%). CHF was much more common among those with systolic or diastolic dysfunction than in those with normal ventricular function. However, even among those with moderate or severe diastolic or systolic dysfunction, less than half had recognized CHF. In multivariate analysis, controlling for age, sex, and EF, mild diastolic dysfunction (hazard ratio, 8.31 [95% CI, 3.00-23.1], P<.001) and moderate or severe diastolic dysfunction (hazard ratio, 10.17 [95% CI, 3.28-31.0], P<.001) were predictive of all-cause mortality. In the community, systolic dysfunction is frequently present in individuals without recognized CHF. Furthermore, diastolic dysfunction as rigorously defined by comprehensive Doppler techniques is common, often not accompanied by recognized CHF, and associated with marked increases in all-cause mortality.

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Differential regulation of distinct Vps34 complexes by AMPK in nutrient stress and autophagy.

Joungmok Kim, Young Chul Kim, Chong Fang … (2013)

Autophagy is a stress response protecting cells from unfavorable conditions, such as nutrient starvation. The class III phosphatidylinositol-3 kinase, Vps34, forms multiple complexes and regulates both intracellular vesicle trafficking and autophagy induction. Here, we show that AMPK plays a key role in regulating different Vps34 complexes. AMPK inhibits the nonautophagy Vps34 complex by phosphorylating T163/S165 in Vps34 and therefore suppresses overall PI(3)P production and protects cells from starvation. In parallel, AMPK activates the proautophagy Vps34 complex by phosphorylating S91/S94 in Beclin1 to induce autophagy. Atg14L, an autophagy-essential gene present only in the proautophagy Vps34 complex, inhibits Vps34 phosphorylation but increases Beclin1 phosphorylation by AMPK. As such, Atg14L dictates the differential regulation (either inhibition or activation) of different Vps34 complexes in response to glucose starvation. Our study reveals an intricate molecular regulation of Vps34 complexes by AMPK in nutrient stress response and autophagy. Copyright © 2013 Elsevier Inc. All rights reserved.

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Role for Rab7 in maturation of late autophagic vacuoles.

Stefanie Jäger, Cecilia Bucci, Isei Tanida … (2004)

The small GTP binding protein Rab7 has a role in the late endocytic pathway and lysosome biogenesis. The role of mammalian Rab7 in autophagy is, however, unknown. We have addressed this by inhibiting Rab7 function with RNA interference and overexpression of dominant negative Rab7. We show here that Rab7 was needed for the formation of preferably perinuclear, large aggregates, where the autophagosome marker LC3 colocalised with Rab7 and late endosomal and lysosomal markers. By electron microscopy we showed that these large aggregates corresponded to autophagic vacuoles surrounding late endosomal or lysosomal vesicles. Our experiments with quantitative electron microscopy showed that Rab7 was not needed for the initial maturation of early autophagosomes to late autophagic vacuoles, but that it participated in the final maturation of late autophagic vacuoles. Finally, we showed that the recruitment of Rab7 to autophagic vacuoles was retarded in cells deficient in the lysosomal membrane proteins Lamp1 and Lamp2, which we have recently shown to accumulate late autophagic vacuoles during starvation. In conclusion, our results showed a role for Rab7 in the final maturation of late autophagic vacuoles.

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Author and article information

Journal

Journal ID (nlm-ta): J Cell Mol Med

Journal ID (iso-abbrev): J. Cell. Mol. Med

Journal ID (publisher-id): jcmm

Title: Journal of Cellular and Molecular Medicine

Publisher: Blackwell Publishing Ltd (Oxford, UK )

ISSN (Print): 1582-1838

ISSN (Electronic): 1582-4934

Publication date (Print): August 2014

Publication date (Electronic): 01 June 2014

Volume: 18

Issue: 8

Pages: 1599-1611

Affiliations

[a ]Department of Traditional Chinese Medicine, Qilu Hospital of Shandong University Jinan, China

[b ]Institute of Pathogen Biology, Shandong University Jinan, China

[c ]Key Laboratory of Cardiovascular Remodeling and Function Research, Qilu Hospital of Shandong University Jinan, China

Author notes

*Correspondence to: Yu-xia ZHAO, Department of Traditional Chinese Medicine, Qilu Hospital of Shandong University, 107 West Wenhuaxi Rd, Jinan 250012, China. Tel.: +86 531 82169420 Fax: +86 531 86927544 E-mail: yu_xia_zhao@ 123456163.com

Article

DOI: 10.1111/jcmm.12312

PMC ID: 4190906

PubMed ID: 24889822

SO-VID: 47dfe23f-a322-449d-b732-02260fb09f58

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This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Resveratrol-enhanced autophagic flux ameliorates myocardial oxidative stress injury in diabetic mice

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Most cited references 26

Burden of systolic and diastolic ventricular dysfunction in the community: appreciating the scope of the heart failure epidemic.

Differential regulation of distinct Vps34 complexes by AMPK in nutrient stress and autophagy.

Role for Rab7 in maturation of late autophagic vacuoles.

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