Cyclin A2 Mediates Cardiomyocyte Mitosis in the Postmitotic Myocardium

Chaudhry, Hina W.; Dashoush, Nurin H.; Tang, Haiying; Zhang, Ling; Wang, Xiangyuan; Wu, Ed X.; Wolgemuth, Debra J.

doi:10.1074/jbc.m404975200

Cited by 189 publications

(163 citation statements)

References 42 publications

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“…Thus, overexpression of cyclin A2 is sufficient to promote ␤-cell proliferation. These findings are consistent with the observation that cyclin A2 is unique among the cyclins in that it regulates progression at both the G1/S and G2/M checkpoints of mitosis (25) and cyclin A2 overexpression alone in cardiomyocytes stimulates proliferation (26).…”

Section: Discussionsupporting

confidence: 91%

Exendin-4 Stimulation of Cyclin A2 in β-Cell Proliferation

et al. 2008

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OBJECTIVE-␤-Cell proliferation is an important mechanism underlying ␤-cell mass adaptation to metabolic demands. We have examined effects, in particular those mediated through intracellular cAMP signaling, of the incretin hormone analog exendin-4 on cell cycle regulation in ␤-cells.RESEARCH DESIGN AND METHODS-Changes in islet protein levels of cyclins and of two critical cell cycle regulators cyclin kinase inhibitor p27 and S-phase kinase-associated protein 2 (Skp2) were assessed in mice treated with exendin-4 and in a mouse model with specific upregulation of nuclear cAMP signaling exhibiting increased ␤-cell proliferation (CBP-S436A mouse). Because cyclin A2 was stimulated by cAMP, we assessed the role of cylcin A2 in cell cycle progression in Min6 and isolated islet ␤-cells.RESULTS-Mice treated with exendin-4 showed increased ␤-cell proliferation, elevated islet protein levels of cyclin A2 with unchanged D-type cyclins, elevated PDX-1 and Skp2 levels, and reduced p27 levels. Exendin-4 stimulated cyclin A2 promoter activity via the cAMP-cAMP response element binding protein pathway. CBP-S436A islets exhibited elevated cyclin A2, reduced p27, and no changes in D-type cyclins, PDX-1, or Skp2. In cultured islets, exendin-4 increased cyclin A2 and Skp2 and reduced p27. Cyclin A2 overexpression in primary islets increased proliferation and reduced p27. In Min6 cells, cyclin A2 knockdown prevented exendin-4 -stimulated proliferation. PDX-1 knockdown reduced exendin-4 -stimulated cAMP synthesis and cyclin A2 transcription.CONCLUSIONS-Cyclin A2 is required for ␤-cell proliferation, exendin-4 stimulates cyclin A2 expression via the cAMP pathway, and exendin-4 stimulation of cAMP requires PDX-1. Diabetes 57:2371-2381, 2008 P ancreatic ␤-cell mass is dynamic and responds to variations in metabolic demand on insulin production. The inability of the endocrine pancreas to adapt to changing insulin demand (inadequate ␤-cell mass) is found both in type 1 and type 2 diabetes. Increasing ␤-cell mass by regeneration may ameliorate or correct both type 1 and 2 diabetes (1). Within the pancreas, ␤-cells regenerate predominantly by ␤-cell replication (2,3). In this context, insight into the mechanisms underlying ␤-cell proliferation and cell cycle regulation, may provide potential targets for therapy in situations of inadequate ␤-cell mass.The incretin hormone glucagon-like peptide-1 (GLP-1) and its long-acting peptide analog exendin-4 stimulate ␤-cell proliferation in vitro and in vivo (4), leading to increased ␤-cell mass in rodents and amelioration of glucose metabolism in diabetic animal models and human diabetic subjects (4). Downstream effectors of the GLP-1 signaling to the cell nucleus include 1) the epidermal growth factor receptor-phosphoinositol 3-kinase (PI 3-kinase)-protein kinase B (PKB/Akt)-forkhead box transcription factor O1 (FoxO1) pathway (5) and 2) the cAMP-protein kinase A (PKA)-cAMP response element binding protein (CREB) pathway (4). Activation of the PI 3-kinase pathway results in phosphorylation and nuclear...

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Section: Discussionsupporting

confidence: 91%

Exendin-4 Stimulation of Cyclin A2 in β-Cell Proliferation

et al. 2008

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“…Both ECG-and respiratory-triggering was used during the entire in vivo CMR experiments. To measure LV function, FLASH cine sequence was used to obtain four short-axis slices covering the whole heart (34). The sequence parameters were as follows: TR ϭ 1 R-R interval, TE ϭ 2.3 ms, cardiac frames ϭ 12, matrix size ϭ 192 ϫ 192, flip angle ϭ 30°.…”

Section: In Vivo Cmr Imagingmentioning

confidence: 99%

MR study of postnatal development of myocardial structure and left ventricular function

2009

Magnetic Resonance Imaging

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Purpose: To investigate postnatal development of left ventricular (LV) cardiac function and myocardium structure. Materials and Methods:In vivo cardiac MR and ex vivo diffusion tensor imaging (DTI) were performed in normal Sprague-Dawley rats at postnatal day 2, 4, 7, 14, 21, 28, and 56 (N ϭ 6 per group). Results:Morphologically, LV size increased with age. Functionally, stroke volume and cardiac output increased. Heart rate increased gradually and became stable after day 14. On average, ejection fraction increased within the first 4 days, decreased at day 7, gradually increased until day 21, and became stable afterward. Structurally, double-helical myocardial structure was found as early as day 2. Myocardial fiber parameters, described by fractional anisotropy, mean apparent diffusion coefficient, and axial diffusivity, increased within the first 4 days. Then radial diffusivity increased until day 7 while other parameters decreased up to day 56. Conclusion:Postnatal heart development was documented by MRI. DTI findings are in agreement with the two known stages of early postnatal growth: hyperplasia and hypertrophy. These results can serve as the baselines for study of postnatal heart developmental abnormalities. They also demonstrate the ability of DTI to reveal microstructural alterations in myocardium.

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“…Transgenic overexpression of oncogenes/cell cycle promoters has led to cell cycle activation in adult cardiomyocytes but still failed to prove cell division. 27,[29][30][31][32][33] Recently, a major step forward was made by demonstrating that targeted expression of Cyclin D2 in cardiomyocytes leads to DNA synthesis in vivo and infarct regression. Although this study presents several indirect proofs for cardiomyocyte proliferation (increase in DNA synthesis, mitotic figures, and cell number based on mathematical calculations), the clear evidence that adult cardiomyocytes proliferate is still lacking.…”

Section: Can Adult Mammalian Cardiomyocytes Proliferate?mentioning

confidence: 99%

“…This might be the reason why most studies trying to induce cardiomyocyte proliferation have focused on inducers of proliferation, namely growth factors, cell cycle genes, and oncogenes. [27][28][29][30][31][32][33] However, these attempts were not successful. Based on the observation that cardiac tumors occur very rarely, this is not a surprising result.…”

Section: How Is Cardiomyocyte Proliferation Regulated?mentioning

confidence: 99%

Cardiomyocyte Proliferation: A Platform for Mammalian Cardiac Repair

Engel¹

2005

Cell Cycle

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Cyclin A2 Mediates Cardiomyocyte Mitosis in the Postmitotic Myocardium

Cited by 189 publications

References 42 publications

Exendin-4 Stimulation of Cyclin A2 in β-Cell Proliferation

Exendin-4 Stimulation of Cyclin A2 in β-Cell Proliferation

MR study of postnatal development of myocardial structure and left ventricular function

Cardiomyocyte Proliferation: A Platform for Mammalian Cardiac Repair

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