Altered Expression of Cell Cycle Proteins and Prolonged Duration of Cardiac Myocyte Hyperplasia in p27
            <sup>KIP1</sup>
            Knockout Mice

Poolman, Robert A.; Li, Jianmei; Durand, Béatrice; Brooks, Gavin

doi:10.1161/01.res.85.2.117

Cited by 92 publications

(68 citation statements)

References 48 publications

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“…Transgenic mice over-expressing c-myc in the heart displayed mild developmental hyperplasia but cardiac myocytes eventually ceased cell division (Jackson et al 1991). Similarly, p27 null mice also demonstrated an increased number of cardiac myocytes in the adult mouse heart suggesting that this molecule acts as part of the timing mechanism that controls myocyte cell cycle exit (Poolman et al 1999). Other recent studies from our laboratory have shown that over-expression of cyclin B1 in neonatal cardiac myocytes extends the proliferative potential of these cells (Bicknell & Brooks 2002b).…”

Section: Targeting the Cell Cycle Machinery In Cardiovascular Cellsmentioning

confidence: 99%

Targeting the cell cycle machinery for the treatment of cardiovascular disease

Bicknell

Surry

Brooks

2003

Journal of Pharmacy and Pharmacology

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Cardiovascular disease represents a major clinical problem affecting a significant proportion of the world's population and remains the main cause of death in the UK. The majority of therapies currently available for the treatment of cardiovascular disease do not cure the problem but merely treat the symptoms. Furthermore, many cardioactive drugs have serious side effects and have narrow therapeutic windows that can limit their usefulness in the clinic. Thus, the development of more selective and highly effective therapeutic strategies that could cure specific cardiovascular diseases would be of enormous benefit both to the patient and to those countries where healthcare systems are responsible for an increasing number of patients. In this review, we discuss the evidence that suggests that targeting the cell cycle machinery in cardiovascular cells provides a novel strategy for the treatment of certain cardiovascular diseases. Those cell cycle molecules that are important for regulating terminal differentiation of cardiac myocytes and whether they can be targeted to reinitiate cell division and myocardial repair will be discussed as will the molecules that control vascular smooth muscle cell (VSMC) and endothelial cell proliferation in disorders such as atherosclerosis and restenosis. The main approaches currently used to target the cell cycle machinery in cardiovascular disease have employed gene therapy techniques. We will overview the different methods and routes of gene delivery to the cardiovascular system and describe possible future drug therapies for these disorders. Although the majority of the published data comes from animal studies, there are several instances where potential therapies have moved into the clinical setting with promising results.

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Section: Targeting the Cell Cycle Machinery In Cardiovascular Cellsmentioning

confidence: 99%

Targeting the cell cycle machinery for the treatment of cardiovascular disease

Bicknell

Surry

Brooks

2003

Journal of Pharmacy and Pharmacology

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“…This is caused by the lack of G1 cyclin/cyclin-dependent kinases (Cdk), crucial positive cell-cycle modulators, and high levels of cell-cycle inhibitors (8), such as the retinoblastoma proteins pRb/p130 (9) and the Cdk inhibitors (Cdki) p21/p27 (10). The limited mitotic capacity of mature CM (11) renders the adult mammalian heart functionally unable to repair itself after ischemic injury (12).…”

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confidence: 99%

p53 regulates the cardiac transcriptome

Mak

Hauck

Grothe

et al. 2017

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

112

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The tumor suppressor Trp53 (p53) inhibits cell growth after acute stress by regulating gene transcription. The mammalian genome contains hundreds of p53-binding sites. However, whether p53 participates in the regulation of cardiac tissue homeostasis under normal conditions is not known. To examine the physiologic role of p53 in adult cardiomyocytes in vivo, Cre-loxP–mediated conditional gene targeting in adult mice was used. Genome-wide transcriptome analyses of conditional heart-specific p53 knockout mice were performed. Genome-wide annotation and pathway analyses of >5,000 differentially expressed transcripts identified many p53-regulated gene clusters. Correlative analyses identified >20 gene sets containing more than 1,000 genes relevant to cardiac architecture and function. These transcriptomic changes orchestrate cardiac architecture, excitation-contraction coupling, mitochondrial biogenesis, and oxidative phosphorylation capacity. Interestingly, the gene expression signature in p53-deficient hearts confers resistance to acute biomechanical stress. The data presented here demonstrate a role for p53, a previously unrecognized master regulator of the cardiac transcriptome. The complex contributions of p53 define a biological paradigm for the p53 regulator network in the heart under physiological conditions.

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“…These mice have multi-organ enlargement that includes the heart where there is prolonged proliferation of cardiac myocytes and a perturbation of cardiac myocyte hypertrophy (45). These data again underscore the possibility that specific targeting of certain cell regulatory molecules will enable the initiation of cell division in healthy cardiac myocyte that surround an injured area.…”

Section: Myocardial Infarctionmentioning

confidence: 78%