Type-2 diabetes increases autophagy in the human heart through promotion of Beclin-1 mediated pathway

Munasinghe, Pujika Emani; Riu, Federica; Dixit, Priyadarshini; Edamatsu, Midori; Saxena, Pankaj; Hamer, Nathan S J; Galvin, Ivor F.; Bunton, Richard; Lequeux, Sharon; Jones, Gregory T.; Lamberts, Regis R.; Emanueli, Costanza; Madeddu, Paolo; Katare, Rajesh

doi:10.1016/j.ijcard.2015.08.111

Cited by 98 publications

(77 citation statements)

References 38 publications

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“…However, chloroquine treatment reduced rather than further increased the LC3-II levels[129], suggesting that cardiac autophagic flux was actually inhibited. Cardiac autophagy is also reduced in several forms of metabolic syndrome and type 2 diabetic animal models[127–129], but it is not as consistent since other studies reported either increased[130] or unchanged autophagy in the type 2 diabetic hearts[127, 128]. These different conclusions could be attributed partly to the fact that not all studies have followed the suggested guidelines to determine autophagic flux [84, 85].…”

Section: Autophagy and Mitophagy In The Diabetic Heartmentioning

confidence: 99%

Mitochondrial quality control in the diabetic heart

Liang

Kobayashi

2016

Journal of Molecular and Cellular Cardiology

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Diabetes is a well known risk factor for heart failure. Diabetic heart damage is closely related to mitochondrial dysfunction and increased ROS generation. However, clinical trials have shown no effects of antioxidant therapies on heart failure in diabetic patients, suggesting that simply antagonizing existing ROS by antioxidants is not sufficient to reduce diabetic cardiac injury. A potentially more effective treatment strategy may be to enhance the overall capacity of mitochondrial quality control to maintain a pool of healthy mitochondria that are needed for supporting cardiac contractile function in diabetic patients. Mitochondrial quality is controlled by a number of coordinated mechanisms including mitochondrial fission and fusion, mitophagy and biogenesis. The mitochondrial damage consistently observed in the diabetic hearts indicates a failure of the mitochondrial quality control mechanisms. Recent studies have demonstrated a crucial role for each of these mechanisms in cardiac homeostasis and have begun to interrogate the relative contribution of insufficient mitochondrial quality control to diabetic cardiac injury. In this review, we will present currently available literature that links diabetic heart disease to the dysregulation of major mitochondrial quality control mechanisms. We will discuss the functional roles of these mechanisms in the pathogenesis of diabetic heart disease and their potentials for targeted therapeutical manipulation.

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Section: Autophagy and Mitophagy In The Diabetic Heartmentioning

confidence: 99%

Mitochondrial quality control in the diabetic heart

Liang

Kobayashi

2016

Journal of Molecular and Cellular Cardiology

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“…13 characterized by hyperglycemia resulting from pancreatic β-cell failure and insulin resistance, and high glucose has been reported to induce autophagy in human renal tubular epithelial cells [122], chick cranial neural crest cells [123], rat cardiomyocytes [124], rat INS-1 cells [125], and human mesenchymal stem cells [126]. Using NP and AF cells isolated from 24-week-old adult rats, Kong et al found that high glucose significantly enhances the expression of Beclin-1, LC3-II, Atg 3, Atg5, Atg7, and…”

Section: Accepted Manuscriptmentioning

confidence: 99%

Autophagy: A double-edged sword in intervertebral disk degeneration

Zhang

Yang

Wang

et al. 2016

Clinica Chimica Acta

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“…A modest number of publications report measurements of autophagosome clearance in experimental models of diabetes, determined by the extent of autophagy marker accumulation observed with an acute lysosomal block (via bafilomycin or chloroquine). These studies show an increase, 124 or decrease 125–130 in autophagosome clearance rate in diabetic hearts relative to control. In human type 2 diabetic patients with ischemic heart disease, right atrial appendage tissue expression of LC3 (lipidated form) and Beclin1 protein is increased, p62 expression decreased, and immuno-visualization of cardiomyocyte LC3 and Beclin1 augmented with accumulation of autophagosomes.…”

Section: Cardiopathology Involvementmentioning

confidence: 64%

“…In human type 2 diabetic patients with ischemic heart disease, right atrial appendage tissue expression of LC3 (lipidated form) and Beclin1 protein is increased, p62 expression decreased, and immuno-visualization of cardiomyocyte LC3 and Beclin1 augmented with accumulation of autophagosomes. 124 In contrast, a similar type 2 diabetic patient cohort exhibits decreased cardiac Atg5 protein expression, and no change in LC3. 131 The autophagic response to fasting-and ischemia-induced metabolic stress is blunted in obese insulin resistant mice, 59, 128 which may underlie exacerbated ischemic injury evident in diabetes.…”

Section: Cardiopathology Involvementmentioning

confidence: 99%

Myocardial stress and autophagy: mechanisms and potential therapies

et al. 2017

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Autophagy is a ubiquitous cellular catabolic process responsive to energy stress status. Research over the last decade has revealed that cardiomyocyte autophagy is a prominent homeostatic pathway, important in adaptation to altered myocardial metabolic demand. The cellular machinery of autophagy involves targeted direction of macromolecules and organelles for lysosomal degradation. Autophagy activation has been identified as cardio-protective in some settings (i.e. ischemia and ischemic preconditioning). In other situations chronically elevated levels of autophagy have been linked with cardiopathology (i.e. sustained pressure overload and failure). Autophagy perturbation in diabetic cardiomyopathy is also observed – and has been associated with both adaptive and maladaptive stress responses. Recent findings indicate that various forms of selective autophagy operate in parallel to manage different catabolic ‘cargo’ types including mitochondria, large proteins, glycogen and lipid stores. In this Review, specific circumstances of autophagy induction associated with cardiac benefit or detriment are considered. The various static and dynamic approaches used for measurement of autophagy are critiqued and current inconsistencies in the understanding of autophagy regulation in the heart are highlighted. The future prospects for pharmacological intervention to achieve therapeutic manipulation of autophagic processes are canvassed.

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Type-2 diabetes increases autophagy in the human heart through promotion of Beclin-1 mediated pathway

Cited by 98 publications

References 38 publications

Mitochondrial quality control in the diabetic heart

Mitochondrial quality control in the diabetic heart

Autophagy: A double-edged sword in intervertebral disk degeneration

Myocardial stress and autophagy: mechanisms and potential therapies

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