Two inhibitory systems and CKIs regulate cell cycle exit of mammalian cardiomyocytes after birth

Tane, Shoji; Okayama, Hitomi; Ikenishi, Aiko; Amemiya, Yuki; Nakayama, Keiichi I.; Takeuchi, Takashi

doi:10.1016/j.bbrc.2015.08.102

Cited by 17 publications

(11 citation statements)

References 16 publications

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“…However, no progression into M phase was observed due to a lack of Cdk1 activation. 56 In contrast, constitutive overexpression of cyclin A2 induced an increased number of cardiomyocytes in M phase as detected by phosphorylated histone H3. 57 While the loss of cell cycle inhibitors p27 58 or Meis1 59 has yielded promise through the indirect upregulation of multiple positive cell cycle regulators that become suppressed during terminal differentiation, the exact mechanism remains to be elucidated.…”

Section: Discussionmentioning

confidence: 99%

p53 and Mdm2 act synergistically to maintain cardiac homeostasis and mediate cardiomyocyte cell cycle arrest through a network of microRNAs

et al. 2017

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Defining the roadblocks responsible for cell cycle arrest in adult cardiomyocytes lies at the core of developing cardiac regenerative therapies. p53 and Mdm2 are crucial mediators of cell cycle arrest in proliferative cell types, however, little is known about their function in regulating homeostasis and proliferation in terminally differentiated cell types, like cardiomyocytes. To explore this, we generated a cardiac-specific conditional deletion of p53 and Mdm2 (DKO) in adult mice. Herein we describe the development of a dilated cardiomyopathy, in the absence of cardiac hypertrophy. In addition, DKO hearts exhibited a significant increase in cardiomyocyte proliferation. Further evaluation showed that proliferation was mediated by a significant increase in Cdk2 and cyclin E with downregulation of p21 and p27. Comparison of miRNA expression profiles from DKO mouse hearts and controls revealed 11 miRNAs that were downregulated in the DKO hearts and enriched for mRNA targets involved in cell cycle regulation. Knockdown of these miRNAs in neonatal rat cardiomyocytes significantly increased cytokinesis with an upregulation in the expression of crucial cell cycle regulators. These results illustrate the importance of the cooperative activities of p53 and Mdm2 in a network of miRNAs that function to impose a barrier against aberrant cardiomyocyte cell cycle re-entry to maintain cardiac homeostasis.

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Section: Discussionmentioning

confidence: 99%

p53 and Mdm2 act synergistically to maintain cardiac homeostasis and mediate cardiomyocyte cell cycle arrest through a network of microRNAs

et al. 2017

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“…There are two families of inhibitors that block the catalytic activity of cyclin-CDK complexes, namely inhibitor of CDK4 (INK4) family which only bind to CDK4/6, and KIP/CIP family including p21 WAF1/CIP1 and p27 KIP1 , which can inhibit all cyclin-CDK complexes [11, 27, 33, 34]. A gene knockout study in mice confirmed that p21 and p27 are important partners in mammalian cardiomyocyte [35]. p21 and p27 coordinately force the cell cycle exit by blocking all the phases of the cell cycle.…”

Section: Discussionmentioning

confidence: 99%

“…p21 and p27 coordinately force the cell cycle exit by blocking all the phases of the cell cycle. Both p21 and p27 inhibit G 1 phase entry, while p21 also plays a crucial role in the inhibition of M-phase entry [35-37]. In hypertrophied cardiomyocytes, increased expression of p21 can inhibit the activity of cyclin A-CDK1 complex in G 2 phase and cyclin B-CDK1 complex following cells arrest in G 2 /M phase [38, 39].…”

Section: Discussionmentioning

confidence: 99%

Cyclin-Dependent Kinase Inhibitor p21WAF1/CIP1 Facilitates the Development of Cardiac Hypertrophy

Tong

Wang

Ding

et al. 2017

Cell Physiol Biochem

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Background/Aims: Adult cardiomyocytes can re-enter cell cycle as stimulated by prohypertrophic factors although they withdraw from cell cycle soon after birth. p21^WAF1/CIP1, a cyclin-dependent kinase inhibitor, has been implicated in cardiac hypertrophy, however, its precise contribution to this process remains largely unclear. Methods: The gene expression profile in left ventricle (LV) of spontaneously hypertensive rats (SHR) and Wistar–Kyoto (WKY) rats was determined using quantitative PCR array and verified by real-time PCR and Western blotting. Hypertrophic response of H9c2 cells and neonatal rat ventricular myocytes (NRVM) were induced by angiotensin II (1 µmol/L). Cardiac hypertrophy of mice was elicited by isoproterenol (ISO) infusion (40 mg/kg per day for 14 days). p21-adenovirus and p21-siRNA were employed to transfect NRVM, and sterigmatocystin (STE, 3 mg/kg, ip, qd) was used to inhibit p21 activity. mRNA and protein expression levels of α- and β-myosin heavy chain (MHC), p21^WAF1/CIP1, calcineurin (CaN) and atrial natriuretic peptide (ANP) were assayed by realtime PCR and WB, respectively. Results: Sixteen genes showed two-fold or greater changes between SHR and WKY rats, in which the expression of p21^WAF1/CIP1 was upregulated by 4.15-fold (P=0.002) and reversed by losartan. Surface area, protein content, mRNA and protein expressions of β-MHC, ANP and p21^WAF1/CIP1 in H9c2 cells treated with AngII elevated significantly compared with control group. p21-Ad transfection markedly increased the surface area and β-MHC mRNA expression of normal NRVMs, and p21-siRNA transfection decreased them in AngII-treated NRVMs. STE treatment decreased HW/BW and cross-sectional area, expression levels of β-MHC, ANP and p21 significantly in ISO-treated mice. Conclusion: Our findings suggest that p21 facilitates the development of cardiac hypertrophy, and regulating the expression of p21 may be an approach to attenuate hypertrophic growth of cardiomyocytes.

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“…In adult mammalian cardiomyocytes, the complexes of cyclins/CDKs are constitutively inhibited by two families: the CIP/KIP family, including P21, P27, and P57; and the INK4 family, including p16, p15, p18, and p19. In general, upregulation of the CIP/KIP family and INK4 family arrests the cell cycle by blocking CDKs’ regulation of G1/S and G2/M checkpoints [ 16 , 18 , 19 ]. The CIP/KIP family members P21 and P27 block all phases of the cell cycle, forcing the postnatal cardiomyocytes to exit the cell cycle.…”

Section: Induction Of Cardiomyocyte Cell Cycle Entry Through Direct Cell Cycle Activationmentioning

confidence: 99%

Induced Cardiomyocyte Proliferation: A Promising Approach to Cure Heart Failure

Salama

Gebreil

Mohamed

et al. 2021

IJMS

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Unlike some lower vertebrates which can completely regenerate their heart, the human heart is a terminally differentiated organ. Cardiomyocytes lost during cardiac injury and heart failure cannot be replaced due to their limited proliferative capacity. Therefore, cardiac injury generally leads to progressive failure. Here, we summarize the latest progress in research on methods to induce cardiomyocyte cell cycle entry and heart repair through the alteration of cardiomyocyte plasticity, which is emerging as an effective strategy to compensate for the loss of functional cardiomyocytes and improve the impaired heart functions.

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Two inhibitory systems and CKIs regulate cell cycle exit of mammalian cardiomyocytes after birth

Cited by 17 publications

References 16 publications

p53 and Mdm2 act synergistically to maintain cardiac homeostasis and mediate cardiomyocyte cell cycle arrest through a network of microRNAs

p53 and Mdm2 act synergistically to maintain cardiac homeostasis and mediate cardiomyocyte cell cycle arrest through a network of microRNAs

Cyclin-Dependent Kinase Inhibitor p21WAF1/CIP1 Facilitates the Development of Cardiac Hypertrophy

Induced Cardiomyocyte Proliferation: A Promising Approach to Cure Heart Failure

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