Apoptosis in Heart Failure - The Role of the .BETA.-Adrenergic Receptor-Mediated Signaling Pathway and p53-Mediated Signaling Pathway in the Apoptosis of Cardiomyocytes -

Fujita, Takayuki; Ishikawa, Yoshihiro

doi:10.1253/circj.cj-11-0025

Cited by 71 publications

(35 citation statements)

References 78 publications

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“…Major mechanism of c-jun mediated suppression of apoptosis is by attenuating expression of pro-apoptotic protein p53 and its target gene noxa [37]. Interestingly, recent studies point towards p53 as a central molecule in mediating cardiomyocyte apoptosis and heart failure (for review see [65]). Although in our study deletion of Jun in heart was restricted to cardiomyocytes, based on our results we cannot define whether deletion of Jun promotes apoptosis of cardiomyocytes directly or rather cardiomyocytes deficient for this protein secrete factor/-s which promotes apoptosis of the neighboring cells in heart.…”

Section: Discussionmentioning

confidence: 99%

The AP-1 Transcription Factor c-Jun Prevents Stress-Imposed Maladaptive Remodeling of the Heart

Windak

Müller²,

Felley³

et al. 2013

PLoS ONE

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Systemic hypertension increases cardiac workload and subsequently induces signaling networks in heart that underlie myocyte growth (hypertrophic response) through expansion of sarcomeres with the aim to increase contractility. However, conditions of increased workload can induce both adaptive and maladaptive growth of heart muscle. Previous studies implicate two members of the AP-1 transcription factor family, junD and fra-1, in regulation of heart growth during hypertrophic response. In this study, we investigate the function of the AP-1 transcription factors, c-jun and c-fos, in heart growth. Using pressure overload-induced cardiac hypertrophy in mice and targeted deletion of Jun or Fos in cardiomyocytes, we show that c-jun is required for adaptive cardiac hypertrophy, while c-fos is dispensable in this context. c-jun promotes expression of sarcomere proteins and suppresses expression of extracellular matrix proteins. Capacity of cardiac muscle to contract depends on organization of principal thick and thin filaments, myosin and actin, within the sarcomere. In line with decreased expression of sarcomere-associated proteins, Jun-deficient cardiomyocytes present disarrangement of filaments in sarcomeres and actin cytoskeleton disorganization. Moreover, Jun-deficient hearts subjected to pressure overload display pronounced fibrosis and increased myocyte apoptosis finally resulting in dilated cardiomyopathy. In conclusion, c-jun but not c-fos is required to induce a transcriptional program aimed at adapting heart growth upon increased workload.

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Section: Discussionmentioning

confidence: 99%

The AP-1 Transcription Factor c-Jun Prevents Stress-Imposed Maladaptive Remodeling of the Heart

Windak

Müller²,

Felley³

et al. 2013

PLoS ONE

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“…With respect to the apoptosis, it is surprising that a p53/Caspase-3 independent pathway is being employed. However, there are many ways to trigger apoptosis as both cell culture and zebrafish studies have uncovered p53-independent apoptotic pathways (Fujita and Ishikawa, 2011; Pyati et al, 2007; Sidi et al, 2008). Moreover, a recent study in zebrafish elucidated a conserved Chk1/Caspase-2 dependent and p53/Caspase-3 independent apoptotic pathway (Sidi et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

Distinct phases of Wnt/β-catenin signaling direct cardiomyocyte formation in zebrafish

Dohn

Waxman

2012

Developmental Biology

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Normal heart formation requires reiterative phases of canonical Wnt/β-catenin (Wnt) signaling. Understanding the mechanisms by which Wnt signaling directs cardiomyocyte (CM) formation in vivo is critical to being able to precisely direct differentiated CMs from stem cells in vitro. Here, we investigate the roles of Wnt signaling in zebrafish CM formation using heat-shock inducible transgenes that increase and decrease Wnt signaling. We find that there are three phases during which CM formation is sensitive to modulation of Wnt signaling through the first 24 hours of development. In addition to the previously recognized roles for Wnt signaling during mesoderm specification and in the pre-cardiac mesoderm, we find a previously unrecognized role during CM differentiation where Wnt signaling is necessary and sufficient to promote the differentiation of additional atrial cells. We also extend the previous studies of the roles of Wnt signaling during mesoderm specification and in pre-cardiac mesoderm. Importantly, in pre-cardiac mesoderm we define a new mechanism where Wnt signaling is sufficient to prevent CM differentiation, in contrast to a proposed role in inhibiting cardiac progenitor (CP) specification. The inability of the CPs to differentiate appears to lead to cell death through a p53/Caspase-3 independent mechanism. Together with a report for an even later role for Wnt signaling in restricting proliferation of differentiated ventricular CMs, our results indicate that during the first 3 days of development in zebrafish there are four distinct phases during which CMs are sensitive to Wnt signaling.

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“…One study found that, in patients with end-stage heart failure, the incidence of myocardial apoptosis was 0.08–0.25%, while the normal myocardium apoptosis rate was 0.001-0.002% [8]. Moderate and sustained levels of myocardial apoptosis may lead to heart failure [9]. Therefore, drugs that inhibit cardiomyocyte apoptosis in patients with residual cardiac function may be protective and may delay and inhibit the progression of heart failure.…”

Section: Introductionmentioning

confidence: 99%

Time‐Course of the Effects of QSYQ in Promoting Heart Function in Ameroid Constrictor‐Induced Myocardial Ischemia Pigs

Qiu

Yang

Xiao

et al. 2014

Evidence-Based Complementary and Alternative Medicine

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We aim to investigate the therapeutic effects of QSYQ on a pig myocardial ischemia (MI) model and to determine its mechanism of action. The MI model was induced by Ameroid constriction of the left anterior descending coronary (LAD) in Ba-Ma miniature pigs. Four groups were created: model group, digoxin group, QSYQ group, and sham-operated group. Heart function, Ang II, CGMP, TXB2, BNP, and cTnT were evaluated before (3 weeks after operation: 0 weeks) and at 2, 4, and 8 weeks after drug administration. After 8 weeks of administration, the pigs were sacrificed for cardiac injury measurements. Pigs with MI showed obvious histological changes, including BNP, cTnT, Ang II, CGRP, TXB2, and ET, deregulated heart function, and increased levels of apoptotic cells in myocardial tissue. Treatment with QSYQ improved cardiac remodeling by counteracting those events. The administration of QSYQ was accompanied by a restoration of heart function and of the levels of Ang II, CGRP, TXB2, ET BNP, and cTnT. In addition, QSYQ attenuated administration, reduced the apoptosis, and decreased the level of TNF-α and active caspase-3. In conclusion, administration of QSYQ could attenuate Ameroid constrictor induced myocardial ischemia, and TNF-α and active caspase-3 seemed to be the critical potential target of QSYQ.

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Apoptosis in Heart Failure - The Role of the .BETA.-Adrenergic Receptor-Mediated Signaling Pathway and p53-Mediated Signaling Pathway in the Apoptosis of Cardiomyocytes -

Cited by 71 publications

References 78 publications

The AP-1 Transcription Factor c-Jun Prevents Stress-Imposed Maladaptive Remodeling of the Heart

The AP-1 Transcription Factor c-Jun Prevents Stress-Imposed Maladaptive Remodeling of the Heart

Distinct phases of Wnt/β-catenin signaling direct cardiomyocyte formation in zebrafish

Time‐Course of the Effects of QSYQ in Promoting Heart Function in Ameroid Constrictor‐Induced Myocardial Ischemia Pigs

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