Systolic dysfunction in cardiac-specific ligand-inducible MerCreMer transgenic mice

Hall, Michael E.; Smith, Grant; Hall, John E.; Stec, David E.

doi:10.1152/ajpheart.00786.2010

Cited by 62 publications

(78 citation statements)

References 30 publications

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“…Cre-recombination was activated once the mice reached 12 wk of age by intraperitoneal injections of tamoxifen (2 mg/day) for 5 consecutive days. The concentration and duration of the tamoxifen injections used have been shown to cause effective cardiomyocytespecific recombination without any obvious long-term (Ͼ6 wk) tamoxifen toxicity as assessed by changes in the structure, function, and ECG (data not shown) (8,20,24). Parallel control mice (iCS⌬Bmal1 ϩ/ϩ ) were generated by injecting Cre ϩ/Ϫ ;Bmal1 flox/flox mice with vehicle (15% ethanol in sunflower seed oil) instead of tamoxifen.…”

Section: Methodsmentioning

confidence: 99%

The cardiomyocyte molecular clock, regulation of Scn5a, and arrhythmia susceptibility

Schroder

Lefta

Zhang

et al. 2013

American Journal of Physiology-Cell Physiology

116

154

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The molecular clock mechanism underlies circadian rhythms and is defined by a transcription-translation feedback loop. Bmal1 encodes a core molecular clock transcription factor. Germline Bmal1 knockout mice show a loss of circadian variation in heart rate and blood pressure, and they develop dilated cardiomyopathy. We tested the role of the molecular clock in adult cardiomyocytes by generating mice that allow for the inducible cardiomyocyte-specific deletion of Bmal1 (iCS⌬Bmal1). ECG telemetry showed that cardiomyocyte-specific deletion of Bmal1 (iCS⌬Bmal1 Ϫ/Ϫ ) in adult mice slowed heart rate, prolonged RR and QRS intervals, and increased episodes of arrhythmia. Moreover, isolated iCS⌬Bmal1 Ϫ/Ϫ hearts were more susceptible to arrhythmia during electromechanical stimulation. Examination of candidate cardiac ion channel genes showed that Scn5a, which encodes the principle cardiac voltage-gated Na ϩ channel (NaV1.5), was circadianly expressed in control mouse and rat hearts but not in iCS⌬Bmal1 Ϫ/Ϫ hearts. In vitro studies confirmed circadian expression of a human Scn5a promoter-luciferase reporter construct and determined that overexpression of clock factors transactivated the Scn5a promoter. Loss of Scn5a circadian expression in iCS⌬Bmal1 Ϫ/Ϫ hearts was associated with decreased levels of NaV1.5 and Na ϩ current in ventricular myocytes. We conclude that disruption of the molecular clock in the adult heart slows heart rate, increases arrhythmias, and decreases the functional expression of Scn5a. These findings suggest a potential link between environmental factors that alter the cardiomyocyte molecular clock and factors that influence arrhythmia susceptibility in humans. cardiac excitability; circadian; heart; ion channels; Scn5a; Na ϩ current CIRCADIAN RHYTHMS are approximate 24-h cycles in biology. These rhythms are present at the systems level, the tissue level, the single cell and molecular levels (16,33,34,38). There are several examples of circadian rhythms in the cardiovascular system, with heart rate, blood pressure, and substrate metabolism exhibiting distinct oscillations over time of day (12,13,40,41). The mechanism that underlies circadian function is the molecular clock. The molecular clock is defined, in a simple way, by a transcription-translation feedback mechanism that is composed of the core clock genes Clock, Bmal1, Per1, Per2, Cry1, and Cry2. CLOCK and BMAL1 are transcription factors that heterodimerize and activate transcription of Per1, Per2, Cry1, and Cry2. PER1, PER2, CRY1, and CRY2 form multimers in the cytoplasm of the cell, translocate to the nucleus, and act to inhibit CLOCK:BMAL1 function. This cycle takes ϳ24 h and is the fundamental mechanism underlying circadian rhythms. Components of the core clock have also been shown to regulate the expression of genes outside the clock mechanism, and these genes are designated as clock-controlled genes (CCGs). CCGs often encode transcription factors or proteins that control rate-limiting steps in cell physiology (42).In the last 8 years, resear...

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Section: Methodsmentioning

confidence: 99%

The cardiomyocyte molecular clock, regulation of Scn5a, and arrhythmia susceptibility

Schroder

Lefta

Zhang

et al. 2013

American Journal of Physiology-Cell Physiology

116

154

View full text Add to dashboard Cite

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“…Echocardiographic assessment of cardiac function was conducted using a Vevo 770 High Resolution In Vivo Imaging System (Visualsonics, Toronto, ON, Canada), as described previously (16,17). Measurements were made with a 710B RMV scanhead with a center frequency of 25 MHz.…”

Section: Methodsmentioning

confidence: 99%

Rescue of cardiac leptin receptors indb/dbmice prevents myocardial triglyceride accumulation

Hall

Maready

Hall

et al. 2014

American Journal of Physiology-Endocrinology and Metabolism

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Hall ME, Maready MW, Hall JE, Stec DE. Rescue of cardiac leptin receptors in db/db mice prevents myocardial triglyceride accumulation. Am J Physiol Endocrinol Metab 307: E316 -E325, 2014. First published June 17, 2014 doi:10.1152/ajpendo.00005.2014.-Increased leptin levels have been suggested to contribute to cardiac hypertrophy and attenuate cardiac lipid accumulation in obesity, although it has been difficult to separate leptin's direct effects from those caused by changes in body weight and adiposity. To determine whether leptin attenuates cardiac lipid accumulation in obesity or directly causes left ventricular hypertrophy (LVH), we generated a novel mouse model in which the long form of the leptin receptor (LepR) was "rescued" only in cardiomyocytes of obese db/db mice. Reexpression of cardiomyocyte leptin receptors in db/db mice did not cause LVH but reduced cardiac triglycerides and improved cardiac function. Compared with lean wild-type (WT) or db/db-cardiac LepR rescue mice, db/db mice exhibited significantly lower E/A ratio, a measurement of early to late diastolic filling, which averaged 1.5 Ϯ 0.07 in db/db vs. 1.9 Ϯ 0.08 and 1.8 Ϯ 0.11 in WT and db/db-cardiac LepR rescue mice, respectively. No differences in systolic function were observed. Although db/db and db/db-cardiac LepR rescue mice exhibited similar increases in plasma triglycerides, insulin, glucose, and body weight, cardiac triglycerides were significantly higher in db/db compared with WT and db/db cardiac LepR rescue mice, averaging 13.4 Ϯ 4.2 vs. 3.8 Ϯ 1.6 vs. 3.8 Ϯ 0.7 mg/g, respectively. These results demonstrate that despite significant obesity and increases in plasma glucose and triglycerides, db/db cardiac LepR rescue mice are protected against myocardial lipid accumulation. However, we found no evidence that leptin directly causes LVH.

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“…However, the severe cardiac phenotype that we observe after TAM-induced deletion of Mdm2 in adult mice could be due to multiple damaging effects separate from Mdm2's role in βAR signaling. These effects may involve transient cardiomyopathy observed in the MCM mice with TAM treatment (47,(57)(58)(59), an increase in p53-dependent caspase activation (60,61), and cardiomyocyte apoptosis upon deletion of Mdm2 (27), in addition to other mechanisms that remain to be identified.…”

Section: Discussionmentioning

confidence: 99%

Mdm2 regulates cardiac contractility by inhibiting GRK2-mediated desensitization of β-adrenergic receptor signaling

Jean-Charles¹,

Yu²,

Abraham³

et al. 2017

JCI Insight

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Systolic dysfunction in cardiac-specific ligand-inducible MerCreMer transgenic mice

Cited by 62 publications

References 30 publications

The cardiomyocyte molecular clock, regulation of Scn5a, and arrhythmia susceptibility

The cardiomyocyte molecular clock, regulation of Scn5a, and arrhythmia susceptibility

Rescue of cardiac leptin receptors indb/dbmice prevents myocardial triglyceride accumulation

Mdm2 regulates cardiac contractility by inhibiting GRK2-mediated desensitization of β-adrenergic receptor signaling

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