Reactivation of cardiomyocyte cell cycle: A potential approach for myocardial regeneration

McMullen, Nichole; Gaspard, Gerard J.; Pasumarthi, Kishore B.S.

doi:10.1002/sita.200400050

Signal Transduction

2005

DOI: 10.1002/sita.200400050

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Reactivation of cardiomyocyte cell cycle: A potential approach for myocardial regeneration

Nichole McMullen

Gerard J. Gaspard

Kishore B.S. Pasumarthi

Abstract: Regulation of cardiomyocyte cell cycle appears to be more complex in mammals compared to the lower vertebrates. Cardiomyocytes from the adult newt and zebrafish can proliferate in response to myocardial injury and regenerate the damaged area. In contrast, cardiomyocytes in the mammalian heart cease to proliferate soon after birth. This limits the ability of the mammalian heart to regenerate the damaged myocardium following heart disease. It is believed that increasing the number of myocytes in a diseased heart… Show more

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Cited by 3 publications

(2 citation statements)

References 176 publications

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“…While there is growing body of knowledge on the subject of phenocoversion of fibroblasts to myofibroblasts (12,49), additional studies are required to characterize the mechanisms involved in the regulation of fibroblast proliferation during disease states. Identification of key cell cycle regulators in diseased hearts may serve as effective drug targets to control cardiac fibrosis (1,34,35). A previous study showed that treatment with ISO induced expression of cell cycle proteins and subsequently acinar cell proliferation in rodent salivary glands (61).…”

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confidence: 98%

A novel β-adrenergic response element regulates both basal and agonist-induced expression of cyclin-dependent kinase 1 gene in cardiac fibroblasts

Gaspard

MacLean

Rioux

et al. 2014

American Journal of Physiology-Cell Physiology

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Cardiac fibrosis, a known risk factor for heart disease, is typically caused by uncontrolled proliferation of fibroblasts and excessive deposition of extracellular matrix proteins in the myocardium. Cyclin-dependent kinase 1 (CDK1) is involved in the control of G2/M transit phase of the cell cycle. Here, we showed that isoproterenol (ISO)-induced cardiac fibrosis is associated with increased levels of CDK1 exclusively in fibroblasts in the adult mouse heart. Treatment of primary embryonic ventricular cell cultures with ISO (a nonselective β-adrenergic receptor agonist) increased CDK1 protein expression in fibroblasts and promoted their cell cycle activity. Quantitative PCR analysis confirmed that ISO increases CDK1 transcription in a transient manner. Further, the ISO-responsive element was mapped to the proximal -100-bp sequence of the CDK1 promoter region using various 5'-flanking sequence deletion constructs. Sequence analysis of the -100-bp CDK1 minimal promoter region revealed two putative nuclear factor-Y (NF-Y) binding elements. Overexpression of the NF-YA subunit in primary ventricular cultures significantly increased the basal activation of the -100-bp CDK1 promoter construct but not the ISO-induced transcription of the minimal promoter construct. In contrast, dominant negative NF-YA expression decreased the basal activity of the minimal promoter construct and ISO treatment fully rescued the dominant negative effects. Furthermore, site-directed mutagenesis of the distal NF-Y binding site in the -100-bp CDK1 promoter region completely abolished both basal and ISO-induced promoter activation of the CDK1 gene. Collectively, our results raise an exciting possibility that targeting CDK1 or NF-Y in the diseased heart may inhibit fibrosis and subsequently confer cardioprotection.

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mentioning

confidence: 98%

A novel β-adrenergic response element regulates both basal and agonist-induced expression of cyclin-dependent kinase 1 gene in cardiac fibroblasts

Gaspard

MacLean

Rioux

et al. 2014

American Journal of Physiology-Cell Physiology

Self Cite

View full text Add to dashboard Cite

show abstract

“…[1,2] As a result, myocytes that die in response to several patients. [1,2] As a result, myocytes that die in response to several patients.…”

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confidence: 99%

Embryonic Stem Cell Transplantation

Zhang

Pasumarthi

2008

BioDrugs

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Cardiovascular diseases remain the leading cause of death worldwide, and the burden is equally shared between men and women around the globe. Cardiomyocytes that die in response to disease processes or aging are replaced by scar tissue instead of new muscle cells. Although recent reports suggest an intrinsic capacity for the mammalian myocardium to regenerate via endogenous stem/progenitor cells, the magnitude of such a response appears to be minimal and has yet to be realized fully in cardiovascular patients. Despite the advances in pharmacotherapy and new biomedical technologies, the prognosis for patients diagnosed with end-stage heart failure appears to be grave. While heart transplantation is a viable option, this life-saving intervention suffers from an acute shortage of cardiac organ donors. In view of these existing issues, donor cell transplantation is emerging as a promising strategy to regenerate diseased myocardium. Studies from multiple laboratories have shown that transplantation of donor cells (e.g. fetal cardiomyocytes, skeletal myoblasts, smooth muscle cells, and adult stem cells) can improve the function of diseased hearts over a short period of time (1-4 weeks). While long-term follow-up studies are warranted, it is generally perceived that the beneficial effects of transplanted cells are mainly due to increased angiogenesis or favorable scar remodeling in the engrafted myocardium. Although skeletal myoblasts and bone marrow stem cells hold the highest potential for implementation of autologous therapies, initial results from phase I trials are not promising. In contrast, transplantation of fetal cardiomyocytes has been shown to confer protection against the induction of ventricular tachycardia in experimental myocardial injury models. Furthermore, results from multiple laboratories suggest that fetal cardiomyocytes can couple functionally with host myocytes, stimulate formation of new blood vessels, and improve myocardial function. While it is neither practical nor ethical to test the potential of fetal cardiomyocytes in clinical trials, embryonic stem (ES) cells serve as a novel source for generation of unlimited quantities of cardiomyocytes for myocardial repair. The initial success in the application of ES cells to partially repair and improve myocardial function in experimental models of heart disease has been quite promising. However, multiple hurdles need to be crossed before the potential benefits of ES cells can be translated to the clinic. In this review, we summarize the current knowledge of cardiomyocyte derivation and enrichment from ES-cell cultures and provide a brief survey of factors increasing cardiomyogenic induction in both mouse and human ES cultures. Subsequently, we summarize the current state of research using mouse and human ES cells for the treatment of heart disease in various experimental models. Furthermore, we discuss the challenges that need to be overcome prior to the successful clinical utilization of ES-derived cardiomyocytes for the treatment of end-stage hear...

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Yin and Yang in BMP signaling: Impact on the pathology of diseases and potential for tissue regeneration

Hartung

Sieber

Knaus³

2006

Signal Transduction

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Bone morphogenetic proteins (BMPs) are multi‐functional growth factors belonging to the transforming growth factor β (TGFβ) superfamily. BMPs are expressed in a large variety of tissues and organs, where they exhibit pleiotropic functions during development as well as in the adult organism. Thus maintenance of the BMP signaling pathways requires strict control and regulation by antagonists, co‐receptors and inhibitors. BMPs exert their signals by binding to hetero‐oligomeric signaling complexes composed of type I and type II receptors with serine/threonine kinase activity. They play a decisive role in the development of several diseases but are also involved in self‐renewal of stem cells and tissue regeneration. These insights may lead to the design of future therapeutic treatments. This review focuses on the differential BMP signaling pathways initiated at distinct oligomerized signaling complexes as well as on the pathological aspects of BMP signaling in diseases and their potential for tissue regeneration.

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Reactivation of cardiomyocyte cell cycle: A potential approach for myocardial regeneration

Cited by 3 publications

References 176 publications

A novel β-adrenergic response element regulates both basal and agonist-induced expression of cyclin-dependent kinase 1 gene in cardiac fibroblasts

A novel β-adrenergic response element regulates both basal and agonist-induced expression of cyclin-dependent kinase 1 gene in cardiac fibroblasts

Embryonic Stem Cell Transplantation

Yin and Yang in BMP signaling: Impact on the pathology of diseases and potential for tissue regeneration

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