Nix-Mediated Apoptosis Links Myocardial Fibrosis, Cardiac Remodeling, and Hypertrophy Decompensation

Diwan, Abhinav; Wansapura, Janaka; Syed, Faisal M.; Matkovich, Scot J.; Lorenz, John N.; Dorn, Gerald W.

doi:10.1161/circulationaha.107.727073

Cited by 151 publications

(148 citation statements)

References 65 publications

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“…Among several hundreds of genes that were altered in the heart of Gab1-cKO under TAC conditions, we found that many pro-apoptotic genes, such as Bax (Bcl-2-associated X protein) and Bnip3 (Bcl-2 and adenovirus E1B-19 kDa-interacting protein 3, an apoptotic inducer), 31,32 were upregulated (Supplementary Table S5), whereas several anti-apoptotic genes, including Bcl-2 (B-cell CLL/lymphoma 2) and Egr1 (early growth response 1), were down-regulated (Supplementary Table S6). A major checkpoint in cell death pathway is the ratio of pro-apoptotic (Bax) to anti-apoptotic (Bcl-2) members.…”

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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“…A similar phenotype that included hemolytic anemia was subsequently described by two other groups who independently produced NIX/BNIP3L knockout mice (Schweers et al, 2007;Sandoval et al, 2008). Because hematopoietic abnormalities such as these had the potential to confound cardiac studies, a Cre-lox strategy was used to create mice in which the NIX/BNIP3L gene was selectively ablated in cardiac myocytes, which were subjected to surgical transverse aortic constriction (TAC) (Diwan et al, 2008b). This surgical model produces chronic pressure overload that can be modified to the needs of the particular experiment (mild, moderate or severe), and is therefore somewhat analogous to clinical hypertension or valvular aortic stenosis.…”

Section: Transgenic Cardiac Overexpression Studies Of Bnip3 and Nix/bmentioning

confidence: 88%

“…Both proteins are also subject to rapid degradation by the ubiquitin-proteosome pathway (Chen et al, 1999;Cizeau et al, 2000), accounting for barely detectable levels observed in the unstressed myocardium. Importantly, there appears to be no essential physiological or developmental function for either NIX/BNIP3L or BNIP3 in the heart, as cardiac structure and function are normal in the respective cardiac-specific and germ-line gene knockout mouse models (Diwan et al, 2007b(Diwan et al, , 2008b.…”

Section: Cardiomyocyte Apoptosis and Bcl2 Proteins In Myocardial Diseasementioning

confidence: 99%

Cardiac reanimation: targeting cardiomyocyte death by BNIP3 and NIX/BNIP3L

Dorn

Kirshenbaum

2008

Oncogene

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Programmed cardiac myocyte death contributes to pathological ventricular remodeling and the progression of myocardial infarction or pressure overload hypertrophy to dilated cardiomyopathy. Recent work has identified importance of stress-mediated transcriptional induction of BNIP3 (BCL2 and 19-kDa interacting protein-3) and NIX/BNIP3L in cardiac remodeling. Here, the regulatory mechanisms for these two factors in the heart and their effects on programmed cardiomyocyte death are reviewed, with a focus on information derived from studies using mouse models of cardiac BNIP3 and NIX/BNIP3L overexpression and gene ablation.

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“…Other Bcl-2 family members such as Bcl-2, Bcl-XL, Bcl-w, Bid, Bim and Puma are also involved in this process (Adams and Cory, 2001). Mitochondrial protein Nix triggers apoptotic cardiomyopathy (Yussman et al, 2002), and Nix overexpression induces cardiomyocyte apoptosis (Diwan et al, 2008).…”

Section: Mitochondria Mediate Apoptosis In Heartmentioning

confidence: 99%

Mitochondrial network in the heart

Zhou

Gao

et al. 2012

Protein Cell

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Mitochondria are subcellular organelles that provide energy for the cell. They form a dynamic tubular network and play an important role in maintaining the cell function and integrity. Heart is a powerful organ that supplies the motivation for circulation, thereby requiring large amounts of energy. Thus, the healthiness of cardiomyocytes and mitochondria is necessary for the normal cardiac function. Mitochondria not only lie in the center of the cell apoptotic pathway, but also are the major source of reactive oxygen species (ROS) generation. Mitochondrial morphological change includes fission and fusion that are regulated by a large number of proteins. In this review we discuss the regulators of mitochondrial fission/fusion and their association with cell apoptosis, autophagy and ROS production in the heart.

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Nix-Mediated Apoptosis Links Myocardial Fibrosis, Cardiac Remodeling, and Hypertrophy Decompensation

Cited by 151 publications

References 65 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

Cardiac reanimation: targeting cardiomyocyte death by BNIP3 and NIX/BNIP3L

Mitochondrial network in the heart

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