Differential effects of REV-ERBα/β agonism on cardiac gene expression, metabolism, and contractile function in a mouse model of circadian disruption

Circadian clocks are composed of more than 10 interconnected transcriptional modulators, all of which have the potential to influence the cardiac transcriptome (and ultimately cardiac processes). Previous studies indicate that cardiomyocyte-specific BMAL1 knockout (CBK) mice exhibit a dysfunctional circadian clock (including decreased REV-ERBα/β expression) in the heart, associated with abnormalities in cardiac mitochondrial function, metabolism, signaling, and contractile function. Here we highlight decreased REV-ERBα/β as a mediator of glycogen synthesis, cardiomyocyte size, interstitial fibrosis, and contractile function abnormalities observed in CBK hearts.

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Calcium handling precedes cardiac differentiation to initiate the first heartbeat

eLife ◽

10.7554/elife.17113 ◽

2016 ◽

Vol 5 ◽

Cited By ~ 30

Author(s):

Richard CV Tyser ◽

Antonio MA Miranda ◽

Chiann-mun Chen ◽

Sean M Davidson ◽

Shankar Srinivas ◽

...

Keyword(s):

Gene Expression ◽

Contractile Function ◽

Rapid Development ◽

Mouse Embryos ◽

Cardiac Differentiation ◽

Calcium Handling ◽

Heart Tube ◽

Cardiac Gene Expression ◽

Stage Of Development ◽

Cardiac Gene

The mammalian heartbeat is thought to begin just prior to the linear heart tube stage of development. How the initial contractions are established and the downstream consequences of the earliest contractile function on cardiac differentiation and morphogenesis have not been described. Using high-resolution live imaging of mouse embryos, we observed randomly distributed spontaneous asynchronous Ca2+-oscillations (SACOs) in the forming cardiac crescent (stage E7.75) prior to overt beating. Nascent contraction initiated at around E8.0 and was associated with sarcomeric assembly and rapid Ca2+ transients, underpinned by sequential expression of the Na+-Ca2+ exchanger (NCX1) and L-type Ca2+ channel (LTCC). Pharmacological inhibition of NCX1 and LTCC revealed rapid development of Ca2+ handling in the early heart and an essential early role for NCX1 in establishing SACOs through to the initiation of beating. NCX1 blockade impacted on CaMKII signalling to down-regulate cardiac gene expression, leading to impaired differentiation and failed crescent maturation.

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Doppler Echocardiographic Assessment and Cardiac Gene Expression Analysis of the Left Ventricle in Myocardial lnfarcted Rats

Japanese Circulation Journal ◽

10.1253/jcj.62.436 ◽

1998 ◽

Vol 62 (6) ◽

pp. 436-442 ◽

Cited By ~ 14

Author(s):

Naruhito Shimizu ◽

Minoru Yoshiyama ◽

Kazuhide Takeuchi ◽

Akihisa Hanatani ◽

Shokei Kim ◽

...

Keyword(s):

Gene Expression ◽

Left Ventricle ◽

Expression Analysis ◽

Gene Expression Analysis ◽

Cardiac Gene Expression ◽

Cardiac Gene ◽

Echocardiographic Assessment

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Myocardin Marks the Earliest Cardiac Gene Expression and Plays an Important Role in Heart Development

The Anatomical Record ◽

10.1002/ar.20756 ◽

2008 ◽

Vol 291 (10) ◽

pp. 1200-1211 ◽

Cited By ~ 8

Author(s):

Jian-Fu Chen ◽

Shusheng Wang ◽

Qiulian Wu ◽

Dongsun Cao ◽

Thiha Nguyen ◽

...

Keyword(s):

Gene Expression ◽

Heart Development ◽

Cardiac Gene Expression ◽

Cardiac Gene

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Abstract 247: Scaffold-stiffness Dependent Notch1 Activation Regulates Cardiogenic Gene Expression In Cardiac Progenitor Cells

Circulation Research ◽

10.1161/res.113.suppl_1.a247 ◽

2013 ◽

Vol 113 (suppl_1) ◽

Author(s):

Archana V Boopathy ◽

Pao L Che ◽

Yoshie Narui ◽

Khalid Salaita ◽

Michael E Davis

Keyword(s):

Gene Expression ◽

Smooth Muscle ◽

Cardiac Function ◽

Progenitor Cells ◽

Adult Stem Cells ◽

Cardiac Progenitor Cells ◽

Critical Pathway ◽

Cardiac Gene Expression ◽

Self Assembling ◽

Cardiac Gene

Rationale: Cardiac progenitor cells (CPCs) are multipotent, self-renewing cells that can regenerate the myocardium and improve cardiac function in animal models of myocardial infarction (MI). However, limited survival of stem/progenitor cells inhibits cardiac regeneration. Force dependent Notch activation promotes cardiac development and cardiac gene expression in many adult stem cells. As dysregulation of Notch signaling leads to embryonic lethal cardiovascular defects, activating this critical pathway during cell transplantation could improve efficacy of stem cell therapy. Objective: Investigate i) whether self-assembling peptide scaffolds can be used to activate Notch1 signaling in CPCs to promote cardiogenic differentiation and ii) the effect of scaffold stiffness on Notch1 activation and differentiation. Methods: Rat CPCs (c-kit + ) were cultured for 48h in 3D self-assembling scaffolds of varying stiffness (1% low, 2% high): empty scaffolds (RADA), scaffolds modified with peptide mimicking Notch1 ligand, Jagged1 (RJAG), or scaffolds modified with a scrambled peptide (RSCR) and cardiogenic gene expression measured by qRT-PCR. CHO cells expressing Notch1 responsive YFP were also cultured in the above scaffolds for 48h and YFP expression was determined. Results are mean ± SEM with p<0.05 considered significant by one or two-way ANOVA with appropriate post test. Results: In the Notch1 reporter cells, Notch1 activation increased significantly in presence of RJAG (p<0.01) and on increasing scaffold stiffness (p<0.01,n=6) indicating scaffold stiffness-dependent Notch1 activation. Culture of CPCs in RJAG containing 1% scaffolds (low stiffness) significantly increased early endothelial and smooth muscle but not cardiac gene expression while in 2% scaffolds (high stiffness) significantly increased only cardiac and not endothelial or smooth muscle gene expression (p<0.05, n≥4). Conclusions: Taken together, these data show that i) Notch1 activation in 3D is dependent on ligand density and scaffold stiffness and ii) stiffness dependent Notch1 activation differentially regulates cardiogenic gene expression in CPCs. Therefore, delivery of CPCs in JAG containing scaffolds could be used to improve cardiac function following MI.

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