Inhibition of cell proliferation in the embryonic myocardium by A1 adenosine receptor activation

Zhao, Zhiyong; Rivkees, Scott A.

doi:10.1002/dvdy.1130

Cited by 25 publications

(15 citation statements)

References 17 publications

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“…Mouse embryos dissected at 8-8.5 dpc were cultured using the roller system, as described (11,12). Embryos were cultured, six per 60-ml bottle, at 38°C for 48 h in 5 ml of rat serum to reach the 9.5-to 10-dpc developmental stage.…”

Section: Methodsmentioning

confidence: 99%

“…To determine whether NRG-1 was capable of inducing ectopic lacZ expression within the context of intact, developing embryos, we isolated 8-to 8.5-dpc CCS-lacZ embryos and cultured them for 48 h by using techniques described (11,12), in the presence or absence of NRG-1. NRG-1-treated embryos seemed similar to control embryos on gross examination, and both had reached the 9.5-10.0 dpc developmental stage (Fig.…”

Section: Nrg-1 Induces Ectopic Ccs Formation In Treatment Of Whole Emmentioning

confidence: 99%

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Neuregulin-1 promotes formation of the murine cardiac conduction system

Rentschler

Zander²,

Meyers³

et al. 2002

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

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222

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The cardiac conduction system is a network of cells responsible for the rhythmic and coordinated excitation of the heart. Components of the murine conduction system, including the peripheral Purkinje fibers, are morphologically indistinguishable from surrounding cardiomyocytes, and a paucity of molecular markers exists to identify these cells. The murine conduction system develops in close association with the endocardium. Using the recently identified CCS-lacZ line of reporter mice, in which lacZ expression delineates the embryonic and fully mature conduction system, we tested the ability of several endocardial-derived paracrine factors to convert contractile cardiomyocytes into conduction-system cells as measured by ectopic reporter gene expression in the heart. In this report we show that neuregulin-1, a growth and differentiation factor essential for ventricular trabeculation, is sufficient to induce ectopic expression of the lacZ conduction marker. This inductive effect of neuregulin-1 was restricted to a window of sensitivity between 8.5 and 10.5 days postcoitum. Using the whole mouse embryo culture system, neuregulin-1 was shown to regulate lacZ expression within the embryonic heart, whereas its expression in other tissues remained unaffected. We describe the electrical activation pattern of the 9.5-days postcoitum embryonic mouse heart and show that treatment with neuregulin-1 results in electrophysiological changes in the activation pattern consistent with a recruitment of cells to the conduction system. This study supports the hypothesis that endocardial-derived neuregulins may be the major endogenous ligands responsible for inducing murine embryonic cardiomyocytes to differentiate into cells of the conduction system.

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Section: Methodsmentioning

confidence: 99%

Section: Nrg-1 Induces Ectopic Ccs Formation In Treatment Of Whole Emmentioning

confidence: 99%

Neuregulin-1 promotes formation of the murine cardiac conduction system

Rentschler

Zander²,

Meyers³

et al. 2002

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

Self Cite

222

202

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“…The mechanisms for causing these cardiac defects remain to be well deciphered. Several studies on G protein coupled receptors (Yanagisawa et al, 1998;Nebigil et al, 2000;Zhao and Rivkees, 2001), growth factor receptors (Gaussin et al, 2002), and intracellular signal mediators (Jaber et al, 1996;Koera et al, 1997;Kuwahara et al, 1999;Wei et al, 2002) have shown hypoplastic myocardium and trabeculae in the heart. In these cases, either cell proliferation or apoptosis is found to be associated with the phenotypes, suggesting that myocardium development is regulated by various signaling systems and different mechanisms.…”

Section: Figmentioning

confidence: 99%

“…The parietal yolk sac was removed by using a pair of fine forceps and the visceral yolk sac was left intact. Embryos (2-5/bottle) were cultured in 5 ml of rat serum at 38°C in 30 rev/min rotation in the roller bottle system (Sturm and Tam, 1993;Wei et al, 2001;Zhao and Rivkees, 2001). Embryos were treated with vehicle or Y27632 (Calbiochem), a selective ROCK kinase inhibitor Iwamoto et al, 2000;Narumiya et al, 2000).…”

Section: Experimental Procedures Embryo and Heart Culturementioning

confidence: 99%

Rho‐associated kinases play an essential role in cardiac morphogenesis and cardiomyocyte proliferation

Zhao

Rivkees

2002

Developmental Dynamics

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Rho-associated coiled-coil kinases (ROCKs), initially identified as effectors for Rho GTPases, play a role in cardiac cell physiology and are also expressed in the developing heart. However, their role in cardiac development is not known. To investigate the role of these kinases in cardiac development, we examined cardiac development in cultured murine embryos treated with the ROCK inhibitor Y27632. After inhibition of ROCK activity, we found disturbed cardiac chamber formation and trabeculation. To further examine the mechanisms by which ROCK blockade causes cardiac hypoplasia, we assessed programmed cell death and cell proliferation in the hearts. We found decreased cell proliferation in the Y27632-treated hearts, but no changes in programmed cell death. We further observed that ROCK inhibition decreased cardiac myocyte proliferation, suggesting that ROCK kinases regulate cardiomyocyte division. To identify factors involved in ROCK action in regulation of cardiac cell division, we examined expression of cell cycle proteins by using Western blot analysis. We found that ROCK blockade decreased expression of cell cycle proteins, cyclin D3, CDK6, and p27 KIP1 in the hearts and cardiomyocytes, which are required for initiation of cell cycle and G1/S phase transition. These observations show that ROCK kinases play a role in cardiac development and that ROCK kinases regulate cardiac cell proliferation and cell cycle protein expression. Developmental Dynamics 226:24 -32, 2003.

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“…Increased activation of A 1 AR leads to reduced heart rates in embryonic hearts (13). Activation of A 1 ARs in embryos has also been observed to reduce myocyte proliferation (14). As the fetus matures, A 1 AR expression becomes greater in the atria than the ventricles, and A 1 AR expression persists in the heart throughout adulthood (11).…”

mentioning

confidence: 99%

A1 adenosine receptors play an essential role in protecting the embryo against hypoxia

Wendler

Amatya

McClaskey

et al. 2007

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

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Embryos can be exposed to environmental factors that induce hypoxia. Currently, our understanding of the effects of hypoxia on early mammalian development is modest. Potential mediators of hypoxia action include the nucleoside adenosine, which acts through A 1 adenosine receptors (A1ARs) and mediates adverse effects of hypoxia on the neonatal brain. We hypothesized that A 1ARs may also play a role in mediating effects of hypoxia on the embryo. When pregnant dams were exposed to hypoxia (10% O2) beginning at embryonic day (E) 7.5 or 8.5 and continued for 24 -96 h, A 1AR؉/؉ embryos manifested growth inhibition and a disproportionate reduction in heart size, including thinner ventricular walls. Yet, when dams were exposed to hypoxia, embryos lacking A 1ARs (A1AR؊/؊) had much more severe growth retardation than A 1AR؉/؉ or ؉/؊ embryos. When levels of hypoxia-inducible factor 1␣ (HIF1␣) were examined, A1AR؊/؊ embryos had less stabilized HIF1␣ protein than A1AR؉/؊ littermates. Normal patterns of cardiac gene expression were also disturbed in A1AR؊/؊ embryos exposed to hypoxia. These results show that short periods of hypoxia during early embryogenesis can result in intrauterine growth retardation. We identify adenosine and A1ARs as playing an essential role in protecting the embryo from hypoxia.cardiac ͉ heart development ͉ hypoxia-inducible factor ͉ intrauterine growth retardation

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Inhibition of cell proliferation in the embryonic myocardium by A1 adenosine receptor activation

Cited by 25 publications

References 17 publications

Neuregulin-1 promotes formation of the murine cardiac conduction system

Neuregulin-1 promotes formation of the murine cardiac conduction system

Rho‐associated kinases play an essential role in cardiac morphogenesis and cardiomyocyte proliferation

A1 adenosine receptors play an essential role in protecting the embryo against hypoxia

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