Upregulated autophagy protects cardiomyocytes from oxidative stress-induced toxicity

Dutta, Debapriya; Xu, Jinze; Kim, Jae-Sung; Dunn, William A.; Leeuwenburgh, Christiaan

doi:10.4161/auto.22971

Cited by 130 publications

(112 citation statements)

References 77 publications

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“…However, other studies reported that diabetes did not increase the extent of autophagy in the heart following persistent ischemia (32,33). By blocking the inhibitory effect of mTOR, rapamycin induces autophagy and protects cardiomyocytes from oxidative stress-induced toxicity (31). In the present study, the expression of Beclin was increased in diabetic heart, which was further enhanced following rapamycin treatment (Fig.…”

Section: Discussionmentioning

confidence: 49%

Mammalian Target of Rapamycin (mTOR) Inhibition with Rapamycin Improves Cardiac Function in Type 2 Diabetic Mice

Das

Durrant

Koka

et al. 2014

Journal of Biological Chemistry

134

122

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Background: Elevated mammalian target of rapamycin (mTOR) signaling contributes to diabetic complications. Results: mTOR inhibitor, rapamycin, improves metabolic status and cardiac function, attenuates oxidative stress, and alters antioxidant and contractile protein expression in type 2 diabetic mice. Conclusion: Rapamycin may provide metabolic and cardiac benefits in diabetic mice. Significance: mTOR inhibition may be an attractive novel therapeutic strategy for diabetes-related complications.

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Section: Discussionmentioning

confidence: 49%

Mammalian Target of Rapamycin (mTOR) Inhibition with Rapamycin Improves Cardiac Function in Type 2 Diabetic Mice

Das

Durrant

Koka

et al. 2014

Journal of Biological Chemistry

134

122

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“…Cellular components, including soluble and aggregated proteins, as well as organelles, are sequestered in autophagosomes and degraded in lysosomes to adapt to nutrient restriction or to eliminate modified macromolecules and damaged organelles (9,25,41,42,77). While autophagy is essential for cell survival, differentiation and development, dysfunctional autophagy is associated with a number of pathological conditions, including cardiovascular and neurodegenerative diseases, muscular dystrophies, and cancer (32,48,50).…”

Section: Introductionmentioning

confidence: 99%

Disturbed Flow Induces Autophagy, but Impairs Autophagic Flux to Perturb Mitochondrial Homeostasis

Jen

et al. 2015

Antioxidants & Redox Signaling

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Aim: Temporal and spatial variations in shear stress are intimately linked with vascular metabolic effects. Autophagy is tightly regulated in intracellular bulk degradation/recycling system for maintaining cellular homeostasis. We postulated that disturbed flow modulates autophagy with an implication in mitochondrial superoxide (mtO 2 -) production. Results: In the disturbed flow or oscillatory shear stress (OSS)-exposed aortic arch, we observed prominent staining of p62, a reverse marker of autophagic flux, whereas in the pulsatile shear stress (PSS)-exposed descending aorta, p62 was attenuated. OSS significantly increased (i) microtubuleassociated protein light chain 3 (LC3) II to I ratios in human aortic endothelial cells, (ii) autophagosome formation as quantified by green fluorescent protein (GFP)-LC3 dots per cell, and (iii) p62 protein levels, whereas manganese superoxide dismutase (MnSOD) overexpression by recombinant adenovirus, N-acetyl cysteine treatment, or c-Jun N-terminal kinase ( JNK) inhibition reduced OSS-mediated LC3-II/LC3-I ratios and mitochondrial DNA damage. Introducing bafilomycin to Earle's balanced salt solution or to OSS condition incrementally increased both LC3-II/LC3-I ratios and p62 levels, implicating impaired autophagic flux. In the OSS-exposed aortic arch, both anti-phospho-JNK and anti-8-hydroxy-2¢-deoxyguanosine (8-OHdG) staining for DNA damage were prominent, whereas in the PSS-exposed descending aorta, the staining was nearly absent. Knockdown of ATG5 with siRNA increased OSS-mediated mtO 2 -, whereas starvation or rapamycin-induced autophagy reduced OSS-mediated mtO 2 -, mitochondrial respiration, and complex II activity. Innovation: Disturbed flow-mediated oxidative stress and JNK activation induce autophagy. Conclusion: OSS impairs autophagic flux to interfere with mitochondrial homeostasis.

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“…This quality control process is indispensable in the heart, as impaired autophagy can trigger cell death during ischemia (55,56), cause a cardiomyopathy (57,58), and exacerbate overload-induced heart failure (59). Conversely, autophagy protects cardiomyocytes from mitochondrial stress induced by antimycin A treatment (60). The high rate of autophagy that occurred after treating Acsl1 T2/2 mice with rapamycin suggests that chronically activated mTORC1 had inhibited autophagy.…”

Section: Discussionmentioning

confidence: 99%

Loss of long‐chain acyl‐CoA synthetase isoform 1 impairs cardiac autophagy and mitochondrial structure through mechanistic target of rapamycin complex 1 activation

et al. 2015

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Because hearts with a temporally induced knockout of acyl-CoA synthetase 1 (Acsl1 T2/2 ) are virtually unable to oxidize fatty acids, glucose use increases 8-fold to compensate. This metabolic switch activates mechanistic target of rapamycin complex 1 (mTORC1), which initiates growth by increasing protein and RNA synthesis and fatty acid metabolism, while decreasing autophagy. Compared with controls, Acsl1 T2/2 hearts contained 3 times more mitochondria with abnormal structure and displayed a 35-43% lower respiratory function. To study the effects of mTORC1 activation on mitochondrial structure and function, mTORC1 was inhibited by treating Acsl1 T2/2 and littermate control mice with rapamycin or vehicle alone for 2 wk. Rapamycin treatment normalized mitochondrial structure, number, and the maximal respiration rate in Acsl1 T2/2 hearts, but did not improve ADP-stimulated oxygen consumption, which was likely caused by the 33-51% lower ATP synthase activity present in both vehicle-and rapamycintreated Acsl1 T2/2 hearts. The turnover of microtubule associated protein light chain 3b in Acsl1 T2/2 hearts was 88% lower than controls, indicating a diminished rate of autophagy. Rapamycin treatment increased autophagy to a rate that was 3.1-fold higher than in controls, allowing the formation of autophagolysosomes and the clearance of damaged mitochondria. Thus, long-chain acyl-CoA synthetase isoform 1 (ACSL1) deficiency in the heart activated mTORC1, thereby inhibiting autophagy and increasing the number of damaged mitochondria.-Grevengoed, T. J., Cooper, D. E., Young, P. A., Ellis, J. M., Coleman, R. A. Loss of long-chain acyl-CoA synthetase isoform 1 impairs cardiac autophagy and mitochondrial structure through mechanistic target of rapamycin complex 1 activation. FASEB J. 29, 4641-4653 (2015). www.fasebj.orgThe heart alters its substrate use to meet the constant high demand for energy. For example, whereas the heart normally obtains 60-90% of its energy from very LDL-derived fatty acids (1), feeding or hypoxia can increase the use of glucose, whereas fasting can increase the use of amino acids and ketone bodies (2). In diabetes, the impaired uptake of glucose increases the use of fatty acids (3, 4), and conversely, glucose use increases with both heart failure and the pathologic hypertrophy caused by pressure overload (5-8). Because it is unclear whether the switch in substrate use in each of these states is compensatory or pathologic, we asked whether predominant glucose use, in the absence of other cardiac dysfunction, would be detrimental.Acyl-CoA synthetases (ACSLs) convert fatty acids to acylCoAs, which can then be oxidized in the mitochondria to produce energy, incorporated into triacylglycerol (TAG) for storage, or incorporated into phospholipids for membrane biogenesis. Of the 5 long-chain mammalian ACSL isoforms, long-chain acyl-CoA synthetase isoform 1 (ACSL1) is the major isoform in the heart, accounting for 90% of total ACSL activity. In the temporally induced mouse model deficient in ACSL isof...

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Upregulated autophagy protects cardiomyocytes from oxidative stress-induced toxicity

Cited by 130 publications

References 77 publications

Mammalian Target of Rapamycin (mTOR) Inhibition with Rapamycin Improves Cardiac Function in Type 2 Diabetic Mice

Mammalian Target of Rapamycin (mTOR) Inhibition with Rapamycin Improves Cardiac Function in Type 2 Diabetic Mice

Disturbed Flow Induces Autophagy, but Impairs Autophagic Flux to Perturb Mitochondrial Homeostasis

Loss of long‐chain acyl‐CoA synthetase isoform 1 impairs cardiac autophagy and mitochondrial structure through mechanistic target of rapamycin complex 1 activation

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