Moderate and high amounts of tamoxifen in <i>α-MHC-MerCreMer</i> mice induce a DNA damage response, leading to heart failure and death

Bersell, Kevin; Choudhury, Sangita; Mollova, Mariya; Polizzotti, Brian D.; Ganapathy, Balakrishnan; Walsh, Stuart; Wadugu, Brian A.; Arab, Shima; Kühn, Bernhard

doi:10.1242/dmm.010447

Cited by 132 publications

(143 citation statements)

References 42 publications

(82 reference statements)

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“…We used moderate amounts of tamoxifen (35 mg/kg/day) as many other laboratories described previously. [44][45][46] In this dose of tamoxifen, its cardiac toxicity was minimal as reported by Bersell et al 42 Indeed, we observed a small but significant adverse effect of tamoxifen injection on cardiac ejection fraction of WT mice (Figure 8e). However, compared with Gab1-WT mice treated with tamoxifen, we found that Gab1-icKO mice treated with tamoxifen had much greater reduction of cardiac function (Figure 8e), and this could be because of intrinsic defects of cardiac function in Gab1-icKO mice or the intolerance of Gab1-icKO mice to mild tamoxifen cardiac toxicity.…”

Section: Resultssupporting

confidence: 82%

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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: Resultssupporting

confidence: 82%

“…These results suggest that Gab1 deficiency in adult mice impairs cardiac function and potentially increased sensitivity to mild tamoxifen toxicity. 41,42 Discussion…”

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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“…7H). These results indicate that the hypertrophic effect was caused by tamoxifen and Creinduced expression of the SA mutation in cardiomyocytes rather than by cardiac toxicity of tamoxifen-induced Cre activity in cardiomyocytes, as has been observed previously with higher doses of tamoxifen (35). Evidently, the SA mutation is sufficient to impair cardiovascular homeostasis and cause cardiac hypertrophy within 4 wk when expressed only in cardiomyocytes.…”

Section: Cardiomyocyte-specific Expression Of the Sa Mutation Leads Tosupporting

confidence: 79%

“…To induce αMHC-MerCreMer activation, mice were injected i.p. with tamoxifen (T5648; Sigma) once a day at 30 mg·kg −1 ·d −1 for three consecutive days (35). All mice used in this study were pathogen free and were housed in the University of Washington Animal Facility at constant temperature (22°C), on 12-h light/12-h dark cycles, with ad libitum access to food and water.…”

Section: Methodsmentioning

confidence: 99%

Loss of β-adrenergic–stimulated phosphorylation of Ca _V 1.2 channels on Ser1700 leads to heart failure

Yang

Dai

Yuan

et al. 2016

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

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L-type Ca 2+ currents conducted by voltage-gated calcium channel 1.2 (Ca V 1.2) initiate excitation-contraction coupling in the heart, and altered expression of Ca V 1.2 causes heart failure in mice. Here we show unexpectedly that reducing β-adrenergic regulation of Ca V 1.2 channels by mutation of a single PKA site, Ser1700, in the proximal C-terminal domain causes reduced contractile function, cardiac hypertrophy, and heart failure without changes in expression, localization, or function of the Ca V 1.2 protein in the mutant mice (SA mice). These deficits were aggravated with aging. Dual mutation of Ser1700 and a nearby casein-kinase II site (Thr1704) caused accelerated hypertrophy, heart failure, and death in mice with these mutations (STAA mice). Cardiac hypertrophy was increased by voluntary exercise and by persistent β-adrenergic stimulation. PKA expression was increased, and PKA sites Ser2808 in ryanodine receptor type-2, Ser16 in phospholamban, and Ser23/24 in troponin-I were hyperphosphorylated in SA mice, whereas phosphorylation of substrates for calcium/calmodulin-dependent protein kinase II was unchanged. The Ca 2+ pool in the sarcoplasmic reticulum was increased, the activity of calcineurin was elevated, and calcineurin inhibitors improved contractility and ameliorated cardiac hypertrophy. Cardio-specific expression of the SA mutation also caused reduced contractility and hypertrophy. These results suggest engagement of compensatory mechanisms, which initially may enhance the contractility of individual myocytes but eventually contribute to an increased sensitivity to cardiovascular stress and to heart failure in vivo. Our results demonstrate that normal regulation of Ca V 1.2 channels by phosphorylation of Ser1700 in cardiomyocytes is required for cardiovascular homeostasis and normal physiological regulation in vivo.calcium channel | heart failure | excitation-contraction coupling | PKA | casein kinase II E xcitation-contraction (EC) coupling in the heart is initiated by L-type calcium (Ca 2+ ) currents conducted by voltagegated calcium 1.2 (Ca V 1.2) channels that are activated by membrane depolarization (1). Ca 2+ influx via Ca V 1.2 channels activates Ca 2+ release from the sarcoplasmic reticulum (SR), leading to rapid and forceful contraction of myofilaments. Ryanodine receptor type-2 (RyR2) is the major channel for this release of Ca 2+ from cardiac SR (2, 3). Mobilized Ca 2+ is transported back into the SR by the SR Ca 2+ ATPase (SERCA) during muscle relaxation (4). SERCA activity is controlled by the inhibitor protein phospholamban (PLB), which is phosphorylated by PKA to release its inhibition of SERCA activity (4). The force and rate of cardiac contractions are critically dependent on the amplitude and kinetics of the Ca 2+ signal generated by Ca V 1.2 channels and RyR2 (1). In the fight-or-flight response, a marked increase in the beating rate and force of contraction of the heart is triggered by activation of the sympathetic nervous system and stimulation of the β-adrenergic signaling p...

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“…It should be noted that high doses of tamoxifen in combination with merCremer (mCrem, a modified tamoxifen inducible Cre construct) may cause focal cardiac fibrosis in a strain dependent manner [35]. Additionally, there are several reports that indicate that Cre expression itself can be cytotoxic, and appropriate controls for monitoring this issue should be established [36-39]. …”

Section: Fibroblast Definitionmentioning

confidence: 99%

Genetic tools for identifying and manipulating fibroblasts in the mouse

et al. 2016

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The use of mouse genetic tools to track and manipulate fibroblasts has provided invaluable in vivo information regarding the activities of these cells. Recently, many new mouse strains have been described for the specific purpose of studying fibroblast behavior. Colorimetric reporter mice and lines expressing Cre are available for the study of fibroblasts in the organs prone to fibrosis, including heart, kidney, liver, lung, and skeletal muscle. In this review we summarize the current state of the models that have been used to define tissue resident fibroblast populations. While these complex genetic reagents provide unique insights into the process of fibrosis, they also require a thorough understanding of the caveats and limitations. Here, we discuss the specificity and efficiency of the available genetic models and briefly describe how they have been used to document the mechanisms of fibrosis.

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Moderate and high amounts of tamoxifen in α-MHC-MerCreMer mice induce a DNA damage response, leading to heart failure and death

Cited by 132 publications

References 42 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

Loss of β-adrenergic–stimulated phosphorylation of Ca _V 1.2 channels on Ser1700 leads to heart failure

Genetic tools for identifying and manipulating fibroblasts in the mouse

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Moderate and high amounts of tamoxifen in α-MHC-MerCreMer mice induce a DNA damage response, leading to heart failure and death

Cited by 132 publications

References 42 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

Loss of β-adrenergic–stimulated phosphorylation of Ca V 1.2 channels on Ser1700 leads to heart failure

Genetic tools for identifying and manipulating fibroblasts in the mouse

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Loss of β-adrenergic–stimulated phosphorylation of Ca _V 1.2 channels on Ser1700 leads to heart failure