Myocyte DNA synthesis with aging: Correlation with ventricular loading in rats

Capasso, J. M.; Bruno, Silvia; Zhang, Xun; Darzynkiewicz, Zbigniew; Anversa, Piero

doi:10.1002/jcp.1041550320

Cited by 17 publications

(3 citation statements)

References 38 publications

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“…2). During senescence in dogs, the proportion of myocytes decreased from 87 to 54%, while the proportion of collagen and connective tissue cells increased [12], and similar changes occur in old rats [13], However, there is potential for heart growth even in old animals, as demonstrated by increased heart weight in old rats trained by treadmill running [14] and by hyper plasia due to enlargement of the left ventricle because of raised end-diastolic pressure [15].…”

Section: Heartmentioning

confidence: 99%

Postnatal Growth of the Heart and Its Blood Vessels

Hudlická

Brown²

1996

J Vasc Res

100

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Although rapid growth of the heart during early postnatal development ceases with maturation of the organism, the potential for cardiomyocyte growth is not lost and may be observed even in senescent hearts. Rapid developmental heart growth is accompanied by a proportional growth of capillaries but not always of larger vessels, and thus coronary vascular resistance gradually increases. Growth of adult hearts can be enhanced by thyroid hormones, catecholamines and the renin-angiotensin system hormones, but these do not always stimulate growth of coronary vessels. Likewise, chronic exposure to hypoxia leads to growth, mainly of the right ventricle and its vessels but without vascular growth elsewhere in the heart. On the other hand, ischaemia is a potent stimulus for the release of various growth factors involved in the development of collateral circulation. Heart hypertrophy develops in response to training, pressure or volume overload. Training usually leads to growth of larger coronary vessels but little growth of capillaries, except in young animals. However, growth of the capillary bed, but not the resistance vasculature capacity, can be induced by either increased coronary blood flow, bradycardia (electrically or pharmacologically induced) or increased inotropism, all of which are involved in the training stimulus. Thus, what actually promotes growth of larger vessels as opposed to capillaries in training is unclear. Pressure overload hypertrophy is mediated by both the renin-angiotensin system and the response of cardiomyocytes to stretch; both lead to activation of early oncogenes (c-fos, c-jun, c-myc) and angiotensin II activates several protein kinases involved in cell growth. In this condition, growth of larger vessels is inadequate, although some capillary growth may occur. Volume overload leads to cardiomyocyte hypertrophy and hyperplasia and some increase in vascular supply. Deficits in capillary supply in pressure or volume overload hypertrophy can be reversed by chronic administration of ACE inhibitors, dipyridamole, the bradycardic drug alinidine or pacing-induced bradycardia respectively, but in neither case is training effective. Mechanical and humoral factors are involved in growth of cardiomyocytes and vessels. For cardiomyocytes, stretch is most important, activating oncogenes, protein kinases and possibly the inositol phosphate pathway, but not ion channels, with regulation by the balance of angiotensin II, TGF-β1 and IGF-1, but not FGFs. For vessels, growth is stimulated by stretch and shear stress, possibly with involvement of VEGF. Increased shear stress disrupts the glycocalyx on the luminal side of vessels and releases plasminogen activator and metalloproteinases which disrupt the basement membrane and enable endothelial cell migration and proliferation. It also causes rearrangement of the endothelial cytoskeleton and transmission of mechanical signals to the abluminal side disturbing extracellular matrix and causing distortion of capillary basement membrane. Stretch acting from the ablum...

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Section: Heartmentioning

confidence: 99%

Postnatal Growth of the Heart and Its Blood Vessels

Hudlická

Brown²

1996

J Vasc Res

100

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“…Most researchers, however, agree that it is likely due to the biochemical inhibition of mitosis and DNA synthesis rather than the permanent physiological loss in their ability to proliferate. Observations of re-initiation of DNA synthesis and mitotic division of adult cardiac myocytes under certain conditions, such as ischemia , pressure overload [Capasso et al, 1993], anemia [Olivetti et al, 1992], phorbol ester treatment [Claycomb and Moses, 1988], and senescent heart in certain strains of rats [Anversa et al, 1991] substantiate this postulation.…”

mentioning

confidence: 96%

Expression of mitogen-activated protein kinase pathways during postnatal development of rat heart

Kim

Irwin²,

Katz

et al. 1998

J. Cell. Biochem.

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The loss of ability to proliferate (terminal differentiation) and reduction in capability to resist ischemia are key phenomena observed during postnatal development of the heart. Mitogen-activated protein kinases (MAPKs) mediate signaling pathways for cell proliferation/differentiation and stress responses such as ischemia. In this study, the expression of these kinases and their associated kinases were investigated in rat heart ventricle. Extracts of 1-, 10-, 20-, 50-, and 365-day-old rat heart ventricles were probed with specific antibodies and their immunoreactivities were quantified by densitometry. Most of the mitogenic protein kinases including Raf1, RafB, Mek1, Erk2, and Rsk1 were significantly down-regulated, whereas the stress signaling kinases, such as Mlk3, Mekkl, Sekl, Mkk3, and Mapkapk2 were up-regulated in expression during postnatal development. Most MAP kinases including Erk1, JNKs, p38 Hog, as well as Rsk2, however, did not exhibit postnatal changes in expression. The proto-oncogene-encoded kinases Mos and Cot/Tpl 2 were up-regulated up to two- and four-fold, respectively, during development. Pakl, which may be involved in the regulation of cytoskeleton as well as in stress signaling, was downregulated with age, but the Pak2 isoform increased only after 50 days. All of these proteins, except RafB, were also detected in the isolated adult ventricular myocytes at comparable levels to those found in adult ventricle. Tissue distribution studies revealed that most of the protein kinases that were up-regulated during heart development tended to be preferentially expressed in heart, whereas the downregulated protein kinases were generally expressed in heart at relatively lesser amounts than in most of other tissues.

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“…Even though the molecular mechanism(s) for the terminal differentiation is still unknown, it has become apparent that the cardiomyocytes are biochemically inhibited and do not permanently lose their ability to undergo mitotic cell divisions. Observations of reinitiation of DNA synthesis and mitotic division of adult cardiomyocytes under certain conditions such as pressure overload [Capasso et al, 1993], anemia [Olivetti et al, 1992], phorbol ester treatment [Claycomb and Moses, 1988], and senescent heart in certain strains of rats [Anversa et al, 1991] substantiate this theory. More clearly, the induction of hyperplasia of either the atria or the ventricle by SV40 large T-antigen oncoprotein which was expressed under the transcriptional control of the promoter regions of either atrial natriuretic factor or ␣-cardiac myosin heavy chain strongly supports the theory and may provide some clue to the mechanism of terminal differentiation [Field, 1988;Katz et al, 1992].…”

Section: Expression Of Cyclin-dependent Protein Kinases (Cdks)mentioning

confidence: 98%

Expression of second messenger- and cyclin- dependent protein kinases during postnatal development of rat heart

1998

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During early postnatal development, cardiomyocytes, which comprise about 80% of ventricular mass and volume, become phenotypically developed to facilitate their contractile functions and terminally differentiated to grow only in size but not in cell number. These changes are due to the expression of contractile proteins as well as the regulation of intracellular signal transduction proteins. In this study, the expression patterns of several protein kinases involved in various cardiac functions and cell-cycle control were analyzed by Western blotting of ventricular extracts from 1-, 10-, 20-, 50-, and 365-day-old rats. The expression level of cAMP-dependent protein kinase was slightly decreased (20%) over the first year, whereas no change was detected in cGMP-dependent protein kinase I. Calmodulin-dependent protein kinase II, which is involved in Ca2+ uptake into the sarcoplasmic reticulum, was increased as much as ten-fold. To the contrary, the expressions of protein kinase C-alpha and iota declined 77% with age. Cyclin-dependent protein kinases (CDKs) such as CDK1, CDK2, CDK4, and CDK5, which are required for cell-cycle progression, abruptly declined to almost undetectable levels after 10-20 days of age. In contrast, other CDK-related kinases, such as CDK8 or Kkialre, did not change significantly or increased up to 50% with age, respectively. Protein kinases implicated in CDK regulation such as CDK7 and Wee1 were either slightly increased in expression or did not change significantly. All of the proteins that were detected in ventricular extracts were also identified in isolated cardiac myocytes in equivalent amounts and analyzed for their relative expression in ten other adult rat tissues.

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Myocyte DNA synthesis with aging: Correlation with ventricular loading in rats

Cited by 17 publications

References 38 publications

Postnatal Growth of the Heart and Its Blood Vessels

Postnatal Growth of the Heart and Its Blood Vessels

Expression of mitogen-activated protein kinase pathways during postnatal development of rat heart

Expression of second messenger- and cyclin- dependent protein kinases during postnatal development of rat heart

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