FoxO Transcription Factors Promote Autophagy in Cardiomyocytes

Sengupta, Arunima; Molkentin, Jeffery D.; Yutzey, Katherine E.

doi:10.1074/jbc.m109.024406

Cited by 388 publications

(316 citation statements)

References 64 publications

(124 reference statements)

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“…Indeed, one might imagine that activation of autophagy in isolation would lead to myocyte shrinkage, and such a finding has been reported previously (43). However, we and others have reported unequivocal growth-associated increases in autophagic flux.…”

Section: Discussionmentioning

confidence: 42%

Histone deacetylase (HDAC) inhibitors attenuate cardiac hypertrophy by suppressing autophagy

Cao¹,

Wang²,

Battiprolu³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

361

302

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Histone deacetylases (HDACs) regulate cardiac plasticity; however, their molecular targets are unknown. As autophagy contributes to pathological cardiac remodeling, we hypothesized that HDAC inhibitors target autophagy. The prototypical HDAC inhibitor (HDACi), trichostatin A (TSA), attenuated both load-and agonistinduced hypertrophic growth and abolished the associated activation of autophagy. Phenylephrine (PE)-triggered hypertrophy and autophagy in cultured cardiomyocytes were each blocked by a panel of structurally distinct HDAC inhibitors. RNAi-mediated knockdown of either Atg5 or Beclin 1, two essential autophagy effectors, was similarly capable of suppressing ligand-induced autophagy and myocyte growth. RNAi experiments uncovered the class I isoforms HDAC1 and HDAC2 as required for the autophagic response. To test the functional requirement of autophagic activation, we studied mice that overexpress Beclin 1 in cardiomyocytes. In these animals with a fourfold amplified autophagic response to TAC, TSA abolished TAC-induced increases in autophagy and blunted load-induced hypertrophy. Finally, we subjected animals with preexisting hypertrophy to HDACi, finding that ventricular mass reverted to nearnormal levels and ventricular function normalized completely. Together, these data implicate autophagy as an obligatory element in pathological cardiac remodeling and point to HDAC1/2 as required effectors. Also, these data reveal autophagy as a previously unknown target of HDAC inhibitor therapy.

show abstract

Section: Discussionmentioning

confidence: 42%

Histone deacetylase (HDAC) inhibitors attenuate cardiac hypertrophy by suppressing autophagy

Cao¹,

Wang²,

Battiprolu³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

361

302

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“…Defects in autophagy, the process of degradation and recycling of cytoplasmic proteins and organelles in response to starvation have been associated with premature aging and age‐related disorders (Hara et al ., 2006; Komatsu et al ., 2006; Jung et al ., 2008; Pickford et al ., 2008; Masiero et al ., 2009; Lee et al ., 2010a, 2010b). FOXOs affect the expression of genes involved in autophagy and mitophagy (muscle‐specific autophagy) in muscle cells from flies (dFOXO) to mammals (FOXO3), allowing adaptation of the tissues to starvation (Zhao et al ., 2007; Sengupta et al ., 2009; Demontis & Perrimon, 2010). Additionally, FOXO1 and FOXO3 activate autophagy mechanisms in diverse cell types: neurons, cardiomyocytes, renal tubular cells, and HSCs (Webb & Brunet, 2014).…”

Section: Foxo and Autophagymentioning

confidence: 99%

“…These results suggest a determinant role for FOXO3 in Parkinson's disease, via neuronal survival in the substantia nigra (Kume et al ., 2010). Furthermore, FoxO1 and FoxO3 factors have also shown to promote autophagy in rat neonatal cardiomyocytes and primary renal proximal tubular cells (Sengupta et al ., 2009; Kume et al ., 2010). …”

Section: Animal Modelsmentioning

confidence: 99%

Long live FOXO: unraveling the role of FOXO proteins in aging and longevity

2015

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SummaryAging constitutes the key risk factor for age‐related diseases such as cancer and cardiovascular and neurodegenerative disorders. Human longevity and healthy aging are complex phenotypes influenced by both environmental and genetic factors. The fact that genetic contribution to lifespan strongly increases with greater age provides basis for research on which “protective genes” are carried by long‐lived individuals. Studies have consistently revealed FOXO (Forkhead box O) transcription factors as important determinants in aging and longevity. FOXO proteins represent a subfamily of transcription factors conserved from Caenorhabditis elegans to mammals that act as key regulators of longevity downstream of insulin and insulin‐like growth factor signaling. Invertebrate genomes have one FOXO gene, while mammals have four FOXO genes: FOXO1, FOXO3, FOXO4, and FOXO6. In mammals, this subfamily is involved in a wide range of crucial cellular processes regulating stress resistance, metabolism, cell cycle arrest, and apoptosis. Their role in longevity determination is complex and remains to be fully elucidated. Throughout this review, the mechanisms by which FOXO factors contribute to longevity will be discussed in diverse animal models, from Hydra to mammals. Moreover, compelling evidence of FOXOs as contributors for extreme longevity and health span in humans will be addressed.

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“…During the neonatal period, FoxOs promote neonatal cell cycle withdrawal through activation of cell cycle inhibitor genes p21 CIP1 and p27 KIP1 (5). FoxOs also function in cardiomyocyte cell size regulation through induction of autophagy and inhibition of hypertrophy (6,9). In multiple cell types, FoxOs have a protective role in resistance to oxidative stress through regulation of antioxidant genes SOD2 and catalase (Cat) as well as additional cell survival pathways (10).…”

mentioning

confidence: 99%

“…Understanding the intracellular processes that protect the heart from oxidative damage following I/R injury is important for the development of therapies to prevent the progression of heart disease. FoxO transcription factors (FoxO1, FoxO3, FoxO4, and FoxO6) belong to the forkhead family of transcriptional regulators, of which FoxO1 and FoxO3 are expressed in developing and adult cardiomyocytes (5,6). Mice lacking FoxO1 are embryonic lethal by E10.5 due to impaired vasculogenesis, and mice lacking FoxO3 are viable but develop a mild hemolytic anemia and premature ovarian failure as well as cardiac hypertrophy as adults (7)(8)(9).…”

mentioning

confidence: 99%

FoxO Transcription Factors Promote Cardiomyocyte Survival upon Induction of Oxidative Stress

Sengupta

Molkentin

Paik

et al. 2011

Journal of Biological Chemistry

Self Cite

294

235

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Transcriptional regulatory mechanisms of cardiac oxidative stress resistance are not well defined. FoxO transcription factors are critical mediators of oxidative stress resistance in multiple cell types, but cardioprotective functions have not been reported previously. FoxO function in oxidative stress resistance was investigated in cultured cardiomyocytes and in mice with cardiomyocyte-specific combined deficiency of FoxO1 and FoxO3 subjected to myocardial infarction (MI) or acute ischemia/reperfusion (I/R) injury. Induction of oxidative stress in cardiomyocytes promotes FoxO1 and FoxO3 nuclear localization and target gene activation. Infection of cardiomyocytes with a dominant-negative FoxO1(⌬256) adenovirus results in a significant increase in reactive oxygen species and cell death, whereas increased FoxO1 or FoxO3 expression reduces reactive oxygen species and cell death. Mice generated with combined conditional deletion of FoxO1 and FoxO3 specifically in cardiomyocytes were subjected to I/R or MI. Loss of FoxO1 and FoxO3 in cardiomyocytes results in a significant increase in infarct area with decreased expression of the antiapoptotic molecules, PTEN-induced kinase1 (PINK1) and CBP/P300-interacting transactivator (CITED2). Expressions of the antioxidants catalase and manganese superoxide dismutase-2 (SOD2) and the autophagy-related proteins LC3II and Gabarapl1 also are decreased following I/R compared with controls. Mice with cardiomyocyte-specific FoxO deficiency subjected to MI have reduced cardiac function, increased scar formation, induction of stress-responsive signaling, and increased apoptotic cell death relative to controls. These data support a critical role for FoxOs in promoting cardiomyocyte survival during conditions of oxidative stress through induction of antioxidants and cell survival pathways.Ischemic heart disease or myocardial ischemia/reperfusion (I/R) 2 injury is a leading cause of mortality worldwide (1).Cardiac oxidative injury can lead to cardiomyocyte cell death followed by fibrosis, hypertrophy, ventricular chamber dilation, decreased cardiac function, and ultimately heart failure.Oxidative stress is associated with increased formation of reactive oxygen species (ROS) that contribute to the pathophysiology of I/R injury (1). Increased ROS leads to DNA, protein and lipid modifications, as well as activates stress-signaling pathways leading to heart failure in I/R injury (2). Protective factors in ROS-mediated cardiac injury include AMP-activated protein kinase (AMPK) and sirtuins (Sirts) (3, 4). Understanding the intracellular processes that protect the heart from oxidative damage following I/R injury is important for the development of therapies to prevent the progression of heart disease. FoxO transcription factors (FoxO1, FoxO3, FoxO4, and FoxO6) belong to the forkhead family of transcriptional regulators, of which FoxO1 and FoxO3 are expressed in developing and adult cardiomyocytes (5, 6). Mice lacking FoxO1 are embryonic lethal by E10.5 due to impaired vasculogenesis, and mice l...

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FoxO Transcription Factors Promote Autophagy in Cardiomyocytes

Abstract: In the heart, autophagy is required for normal cardiac function and also has been implicated in cardiovascular disease.

Cited by 388 publications

References 64 publications

Histone deacetylase (HDAC) inhibitors attenuate cardiac hypertrophy by suppressing autophagy

Histone deacetylase (HDAC) inhibitors attenuate cardiac hypertrophy by suppressing autophagy

Long live FOXO: unraveling the role of FOXO proteins in aging and longevity

FoxO Transcription Factors Promote Cardiomyocyte Survival upon Induction of Oxidative Stress

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