Resveratrol Reverses Remodeling in Hearts with Large, Old Myocardial Infarctions through Enhanced Autophagy-Activating AMP Kinase Pathway

Kanamori, Hiromitsu; Takemura, Genzou; Goto, Kazuko; Tsujimoto, Akiko; Oginö, Kazuhíde; Takahashi, Toshiaki; Kawaguchi, Tomonori; Watanabe, Takatomo; Morishita, Kentaro; Kawasaki, Masanori; Mikami, Atsushi; Fujiwara, Takako; Fujiwara, Hisayoshi; Seishima, Mitsuru; Minatoguchi, Shinya

doi:10.1016/j.ajpath.2012.11.009

Cited by 135 publications

(125 citation statements)

References 46 publications

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“…Both strategies probably rely on a delicate degree of modulation. For example, mitigation of protein synthesis by partial inhib ition of mechanistic target of rapamycin (mTOR), by rapamycin or resveratrol, reversed cardiac hyper trophy and impaired cardiac function in aortic banded mice 176 and protected against myocardial infarction induced HF 177 . Likewise, rapamycin improved cardiac function in DCM in Lmna −/− mice 178 .…”

Section: Pharmacological Modulation Of Pqcmentioning

confidence: 99%

Proteostasis in cardiac health and disease

Henning

Brundel²

2017

Nat Rev Cardiol

140

126

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The worldwide increase in life expectancy gives rise to an increasing prevalence of cardiac diseases, which remain the leading cause of disability and death in the developed world [1][2][3] . Currently, the mechanisms under lying how ageing contributes to the initiation or acceler ation of cardiac diseases are essentially unresolved. Prevailing theories of ageing centre on gradual derail ment of cellular protein homeostasis -proteostasis -either by design (genetically) or by 'wear and tear' (environmentally) 3 . Central to the role of proteostasis derailment as a major factor in ageing is the observation that protein function declines over time.Proteins are the most versatile and complex macro molecules and are involved in the proper functioning of every biological process 4 . After synthesis as a poly peptide chain from the genetic code, proper function of a protein relies heavily on its correct folding into a 3D native state and on various post translational modifi cations, mostly involving the addition of chem ical groups (including phosphate, acetate, and carbo hydrate). Protein maturation, transport, and ultimately breakdown is monitored and supported by various classes of proteins, collectively called 'protein quality control' (PQC) [3][4][5] . Balanced proteostasis, therefore, depends on proper PQC and is crucial for cellular and organismal health 6 . The intricate network making up the PQC involves numerous proteins, of which the main players are the chaperones and their regula tors 4,7-9 (assisting in folding and refolding of proteins) and the pathways that clear irreversibly misfolded and aggregation prone proteins (the ubiquitin-proteasome system [UPS] and autophagy systems) 9-11 . With ageing, the gradual accumulation of misfolded or damaged pro teins, together with concomitant failure of PQC, results in proteotoxic stress and compromised defence against reactive oxygen species (ROS) 10 , a process that is likely to be accelerated in various age related diseases includ ing neurodegenerative diseases 12,13 , type 2 diabetes mel litus 14 , cancer 15 , and cardiac diseases [16][17][18][19][20] . In addition to the accumulation of misfolded proteins, ageing is accompanied by an imbalance in the proteome, as indi cated by lowered expression of chaperone, proteaso mal, ribosomal, and mitochondrial proteins, whereas proteins related to oxidative stress are upregulated 21,22 . Although mild impairment of proteostasis extends lifespan in Caenorhabditis elegans, referred to as hormesis, sustained impairment is accompanied by loss of PQC to neutralize this effect 3,5 . Importantly, evidence indicates that the amount of soluble, aggregate prone protein oligomers, rather than the abundance of pro tein aggregates, correlates with disease severity 23,24 . Therefore, protein aggregates, which contain both misfolded proteins and elevated levels of chaper ones, constitute an adequate PQC response, aimed at sequestering potentially harmful protein oligomers, rather than embodying the ultimate cellular threat 25 . This ...

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Section: Pharmacological Modulation Of Pqcmentioning

confidence: 99%

Proteostasis in cardiac health and disease

Henning

Brundel²

2017

Nat Rev Cardiol

140

126

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“…132,[136][137][138] During chronic ICM (4 weeks post MI), mice treated with resveratrol, which possess proautophagic functions, exhibited partially reversed LV dilation and improved LV function in the chronic state, whereas the inhibition of autophagy worsened LV function. 139 Mitochondria are responsible for supplying the beating myocardium with ATP and are intimately involved in regulating apoptosis in stressed or damaged cells. During cardiac stress, such as ischemic injury or hypertrophy, mitochondria activate prosurvival and prodeath pathways regulating the balance between life and death of the cardiomyocyte.…”

Section: Autophagy Chronic Hf and Inflammationmentioning

confidence: 99%

Chronic Heart Failure and Inflammation

Dick

Epelman

2016

Circulation Research

523

380

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As a greater proportion of patients survive their initial cardiac insult, medical systems worldwide are being faced with an ever-growing need to understand the mechanisms behind the pathogenesis of chronic heart failure (HF). There is a wealth of information about the role of inflammatory cells and pathways during acute injury and the reparative processes that are subsequently activated. We discuss the different causes that lead to chronic HF development and how the sum of initial inflammatory and reparative responses only sets the trajectory for disease progression. Unfortunately, comparatively little is known about the contribution of the immune system once the trajectory has been set, and chronic HF has been established—which clinically represents the majority of patients. It is known that chronic HF is associated with circulating inflammatory cytokines that can predict clinical outcomes, yet the causative role inflammation plays in disease progression is not well defined, and the majority of clinical trials that target aspects of inflammation in patients with chronic HF have largely been negative. This review will present what is currently known about inflammation in chronic HF in both humans and animal models as a means to highlight the gap in our knowledge base that requires further examination.

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“…Macroautophagy (hereafter referred to as autophagy) is a physiological self-degradation and recycling process that proceeds within double-membrane organelles via the lysosomal digestive pathway and functions to maintain the intracellular environment. 6 Autophagy occurs not only in healthy hearts under basal conditions, but is also activated under pathological conditions, including heart failure, 7,8 cardiac hypertrophy, 9 ischemic cardiomyopathy, 10 acute myocardial infarction, 11 postinfarction remodeling, 12,13 and cardiac senescence. 14 This suggests that autophagy plays a key role in maintaining cardiac function but may also contribute to the pathogenesis of heart disease.…”

Section: Introductionmentioning

confidence: 99%

Autophagic adaptations in diabetic cardiomyopathy differ between type 1 and type 2 diabetes

Kanamori¹,

Takemura

Goto³

et al. 2015

Autophagy

Self Cite

204

168

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Abbreviations: AMPK, AMP-activated protein kinase; CTSD, cathepsin D; DM, diabetes mellitus; GFP, green fluorescent protein; HBA1c, glycated hemoglobin a 1; MAP1LC3/LC3, microtubule-associated protein 1 light chain 3; LV, left ventricular; MTOR, mechanistic target of rapamycin; SIRT1, sirtuin 1; Mn-SOD, superoxide dismutase 2, mitochondrial; STZ, streptozotocin; SQSTM1/p62, sequestosome 1.Little is known about the association between autophagy and diabetic cardiomyopathy. Also unknown are possible distinguishing features of cardiac autophagy in type 1 and type 2 diabetes. In hearts from streptozotocin-induced type 1 diabetic mice, diastolic function was impaired, though autophagic activity was significantly increased, as evidenced by increases in microtubule-associated protein 1 light chain 3/LC3 and LC3-II/-I ratios, SQSTM1/p62 (sequestosome 1) and CTSD (cathepsin D), and by the abundance of autophagic vacuoles and lysosomes detected electronmicroscopically. AMP-activated protein kinase (AMPK) was activated and ATP content was reduced in type 1 diabetic hearts. Treatment with chloroquine, an autophagy inhibitor, worsened cardiac performance in type 1 diabetes. In addition, hearts from db/db type 2 diabetic model mice exhibited poorer diastolic function than control hearts from db/C mice. However, levels of LC3-II, SQSTM1 and phosphorylated MTOR (mechanistic target of rapamycin) were increased, but CTSD was decreased and very few lysosomes were detected ultrastructurally, despite the abundance of autophagic vacuoles. AMPK activity was suppressed and ATP content was reduced in type 2 diabetic hearts. These findings suggest the autophagic process is suppressed at the final digestion step in type 2 diabetic hearts. Resveratrol, an autophagy enhancer, mitigated diastolic dysfunction, while chloroquine had the opposite effects in type 2 diabetic hearts. Autophagy in the heart is enhanced in type 1 diabetes, but is suppressed in type 2 diabetes. This difference provides important insight into the pathophysiology of diabetic cardiomyopathy, which is essential for the development of new treatment strategies.

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Resveratrol Reverses Remodeling in Hearts with Large, Old Myocardial Infarctions through Enhanced Autophagy-Activating AMP Kinase Pathway

Cited by 135 publications

References 46 publications

Proteostasis in cardiac health and disease

Proteostasis in cardiac health and disease

Chronic Heart Failure and Inflammation

Autophagic adaptations in diabetic cardiomyopathy differ between type 1 and type 2 diabetes

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