Contribution of Impaired Mitochondrial Autophagy to Cardiac Aging

Dutta, Debapriya; Calvani, Riccardo; Bernabei, Roberto; Leeuwenburgh, Christiaan; Marzetti, Emanuele

doi:10.1161/circresaha.111.246108

Cited by 213 publications

(165 citation statements)

References 138 publications

(201 reference statements)

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“…Mitochondrial dysfunction and mitochondria oxidative stress have linked to age-related heart diseases. [36][37][38][39] To examine the effects of age on heart function of Gab1-cKO mice, we continued to monitor cardiac function of Gab1-WT and Gab1-cKO mice via echocardiography as they aged from 4 weeks to 6 months. We found that at 3 months of age, Gab1-cKO mice exhibited a decreased EF and increased LVIDd, without obvious morphological changes and no apparent differences in LVPW compared with Gab1-WT mice.…”

Section: Resultsmentioning

confidence: 99%

Cardiac Gab1 deletion leads to dilated cardiomyopathy associated with mitochondrial damage and cardiomyocyte apoptosis

et al. 2015

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A vital step in the development of heart failure is the transition from compensatory cardiac hypertrophy to decompensated dilated cardiomyopathy (DCM) during cardiac remodeling under mechanical or pathological stress. However, the molecular mechanisms underlying the development of DCM and heart failure remain incompletely understood. In the present study, we investigate whether Gab1, a scaffolding adaptor protein, protects against hemodynamic stress-induced DCM and heat failure. We first observed that the protein levels of Gab1 were markedly reduced in hearts from human patients with DCM and from mice with experimental viral myocarditis in which DCM developed. Next, we generated cardiac-specific Gab1 knockout mice (Gab1-cKO) and found that GabcKO mice developed DCM in hemodynamic stress-dependent and age-dependent manners. Under transverse aorta constriction (TAC), Gab1-cKO mice rapidly developed decompensated DCM and heart failure, whereas Gab1 wild-type littermates exhibited adaptive left ventricular hypertrophy without changes in cardiac function. Mechanistically, we showed that Gab1-cKO mouse hearts displayed severe mitochondrial damages and increased cardiomyocyte apoptosis. Loss of cardiac Gab1 in mice impaired Gab1 downstream MAPK signaling pathways in the heart under TAC. Gene profiles further revealed that ablation of Gab1 in heart disrupts the balance of anti-and pro-apoptotic genes in cardiomyocytes. These results demonstrate that cardiomyocyte Gab1 is a critical regulator of the compensatory cardiac response to aging and hemodynamic stress. These findings may provide new mechanistic insights and potential therapeutic target for DCM and heart failure. The progression of heart failure is associated with cardiac remodeling, the changes of cardiac structure and function in response to various stress conditions such as pressure overload-generated hemodynamic stress and agingassociated oxidative stress. 1 Under hemodynamic stress, the heart undergoes a stage of compensated hypertrophy and then progresses into decompensated dilated cardiomyopathy (DCM) and heart failure. 2 Cardiac hypertrophy is an adaptive, regulatory process, in which activation of cardiomyocyte survival pathways maintains cardiac homeostasis against external stress. During the transition from compensatory hypertrophy to DCM, cardiomyocyte death plays a critical role in development of heart failure. [3][4][5][6] However, the molecular mechanisms for controlling the balance of cell survival and cell death during cardiac remodeling remain poorly understood.The Grb2-associated binder 1 (Gab1) is a member of the insulin receptor substrate-like multi-substrate docking protein family and expressed in various types of cells, including cardiomyocytes. [7][8][9] It is a central mediator of growth factor receptor signaling. 10,11 Gab1 is phosphorylated by tyrosine kinases, and then phosphorylated Gab1 recruits and activates phosphatidylinositol 3-kinase (PI3K)/Akt and protein tyrosine phosphatase SHP2 (PTPN11)/mitogen-activated protein kinase (MAPK...

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Section: Resultsmentioning

confidence: 99%

Cardiac Gab1 deletion leads to dilated cardiomyopathy associated with mitochondrial damage and cardiomyocyte apoptosis

et al. 2015

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“…2013; Palmer et al ., 2015). Interestingly, HF is associated with similar cellular perturbations, which suggests that HF could be considered as an accelerated form of aging (Dutta et al ., 2012; Wohlgemuth et al ., 2014). Thus, it is possible that the processes that underlie both frailty and HF could each perturb homeostasis to lead to low‐level chronic inflammation.…”

Section: How Aging Frailty and Hf Interact To Induce Inflammationmentioning

confidence: 99%

Pathophysiology of heart failure and frailty: a common inflammatory origin?

et al. 2017

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SummaryFrailty, a clinical syndrome that typically occurs in older adults, implies a reduced ability to tolerate biological stressors. Frailty accompanies many age‐related diseases but can also occur without overt evidence of end‐organ disease. The condition is associated with circulating inflammatory cytokines and sarcopenia, features that are shared with heart failure (HF). However, the biological underpinnings of frailty remain unclear and the interaction with HF is complex. Here, we describe the inflammatory pathophysiology that is associated with frailty and speculate that the inflammation that occurs with frailty shares common origins with HF. We discuss the limitations in investigating the pathophysiology of frailty due to few relevant experimental models. Leveraging current therapies for advanced HF and current known therapies to address frailty in humans may enable translational studies to better understand the inflammatory interactions between frailty and HF.

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“…The clamps were then removed, and the incisions were closed. Rats were euthanized at 0, 3,6,12,24,48, and 72 h after surgery (n ϭ 5 rats/group). The left kidney was rapidly removed and processed for histological evaluation, protein extraction, and RNA extraction, as previously described (38,40).…”

Section: Induction Of Akimentioning

confidence: 99%

Sestrin-2 and BNIP3 regulate autophagy and mitophagy in renal tubular cells in acute kidney injury

Imamura

Urushido

Hamada

et al. 2013

American Journal of Physiology-Renal Physiology

178

125

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Autophagy is a cellular recycling process induced in response to many types of stress. However, little is known of the signaling pathways that regulate autophagy during acute kidney injury (AKI). Bcl-2/adenovirus E1B 19 kDa-interacting protein (BNIP)3 and sestrin-2 are the target proteins of hypoxia-inducible factor (HIF)-1␣ and p53, respectively. The aim of this study was to investigate the roles of BNIP3 and sestrin-2 in oxidative stressinduced autophagy during AKI. We used rat ischemia-reperfusion injury and cultured renal tubular (NRK-52E) cells as in vivo and in vitro models of AKI, respectively. Renal ischemia-reperfusion injury upregulated the expression of BNIP3 and sestrin-2 in the proximal tubules, as measured by immunohistochemical staining and Western blot analysis. In vitro, NRK-52E cells exposed to hypoxia showed increased expression of BNIP3 mRNA and protein in a HIF-1␣-dependent manner. In contrast, sestrin-2 mRNA and protein expression were upregulated in a p53-dependent manner after exposure to oxidative stress (exogenous H2O2). NRK-52E cells stably transfected with a fusion protein between green fluorescent protein and light chain 3 were used to investigate autophagy. Overexpression of BNIP3 or sestrin-2 in these cells induced light chain 3 expression and formation of autophagosomes. Interestingly, BNIP3-induced autophagosomes were mainly localized to the mitochondria, suggesting that this protein selectively induces mitophagy. These observations demonstrate that autophagy is induced in renal tubules by at least two independent pathways involving p53-sestrin-2 and HIF-1␣-BNIP3, which may be activated by different types of stress to protect the renal tubules during AKI.Bcl-2/adenovirus E1B 19 kDa-interacting protein-3; acute kidney injury; autophagy; mitophagy; sestrin-2 ISCHEMIA is the leading cause of acute kidney injury (AKI) in the adult population. Prominent morphological features of ischemic AKI include effacement and loss of the proximal tubule brush border, patchy loss of tubular cells, focal areas of proximal tubular dilation, and increased apoptosis (9). The mechanisms that dictate the survival or death of renal cells under oxidative stress must be more completely understood before novel therapeutic strategies for the treatment of ischemic AKI can be explored. Proximal renal tubular cells have high rates of ATP consumption and are very sensitive to hypoxia; thus, mitochondrial damage is one of the most important factors in determining the survival of these cells (1,43).Autophagy is one of the cellular processes that protect cells from genotoxic stress, oxidative stress, accumulation of misfolded proteins, and nutrient deprivation. We (20) have previously reported results from a study of autophagy in a mouse model of AKI. Autophagy plays roles in the pathogenesis of many diseases, and, in kidney disease, both beneficial and detrimental effects of autophagy have been reported (19 -22). Our understanding of autophagy has expanded greatly in recent years, largely due to the identification...

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Contribution of Impaired Mitochondrial Autophagy to Cardiac Aging

Cited by 213 publications

References 138 publications

Cardiac Gab1 deletion leads to dilated cardiomyopathy associated with mitochondrial damage and cardiomyocyte apoptosis

Cardiac Gab1 deletion leads to dilated cardiomyopathy associated with mitochondrial damage and cardiomyocyte apoptosis

Pathophysiology of heart failure and frailty: a common inflammatory origin?

Sestrin-2 and BNIP3 regulate autophagy and mitophagy in renal tubular cells in acute kidney injury

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