Cardiac Terminal Differentiation Entails the Sequential Loss of Cell Proliferation Followed by Loss of DNA Synthesis

Although prevailing dogma holds that cardiac myocytes terminally differentiate soon after birth in mammals, little data exist that analyze this systematically. The most comprehensive study quantified cardiac myocyte DNA synthesis during murine development.6 In this model cardiac myocyte DNA synthesis occurs in two distinct phases. In utero, labeling indexes of 33% were observed, which rapidly tapered to near zero by postnatal day 1. During this phase, karyokinesis and cytokinesis were matched, resulting in cardiac myocyte proliferation. The second phase occurred early in the neonatal period, peaking 4-6 days after birth. However, in this phase, nuclear division occurred in the absence of myocyte cytokinesis, resulting in the hallmark binucleation of ventricular myocytes. Similar to temporal changes seen in skeletal muscle,7 as well as terminal differentiation in other lineages,8 cell cycle exit in ventricular muscle cells is accompanied by coordinated downregulation of positive-acting cell cycle regulators (e.g., cyclin dependent kinase [Cdk] 2, Cdc2 [Cdkl], Cyclins A and E) and upregulation of cell cycle inhibitors including the anti-oncogene Rb and the Cdk inhibitors p21 and p27.9 The results of multiple studies including our own are summarized in Table l,10-15 and the functional relationships among these proteins are shown schematically in Figure 1.

It has been suggested that adult cardiac myocytes from some species, including humans, retain a capacity for DNA synthesis, at least under pathophysiological conditions.16 Interestingly, although an increase in myocyte nucleation and ploidy is a well-described feature in human hypertrophied and failing hearts,17'18 analogous changes were not detected in several murine models of hypertrophy.19 Several points are worth emphasizing, with respect to this on-going controversy. First, even if DNA synthesis were reinitiated in ventricular myocytes after cell cycle exit, this need not culminate in cytokinesis. DNA synthesis could potentially lead merely to endoreduplication (increased DNA content per nucleus) or endomitosis (nuclear division without cytokinesis).20 Indeed, the specific steps remain to be defined that are responsible for uncoupling nuclear from cellular division early after birth, which results in cardiac myocyte binucleation. Second, one less appreciated action that is reported for Rb, and might be operative in any "post-mitotic" background where Rb expression is high, is its ability to suppress S phase progression even once it has begun (intra-S phase arrest).21 Finally, little if any of the available evidence from adult ventricular muscle excludes either of two additional alternative interpretations: abortive cell cycle reentry that culminates in apoptosis (cell death being associated with most of the states in which myocyte proliferation has been claimed),22 or the very different possibility that DNA synthesis in cells that possess cardiac-specific markers might, instead, reflect the recruitment of endogenous stem cells to a cardiac fate.23,24 For all of these reasons, the detection of DNA synthesis in terminally differentiated myocardium cannot be taken, by itself, as evidence for the resumption of proliferative growth.

Table 1. Synopsis of cell cycle regulators during cardiac maturation

Factor

fed

Neonatal

Adult

Cell cycle mediators

N-myc

++

+

-

c-myc

++

+

-

Cdc2

++

+

-

Cdk2

++

+

+/-

Cdk4

++

+

+/-

Cdk6

++

+

+/-

Cyclin D1

++

+

-

Cyclin D2

++

+

+/-

Cyclin D3

++

+

+/-

Cyclin E

++

+

-

Cyclin A

++

+

-

Cyclin B

++

+

-

E2F-1

++

+

-

E2F-4

-

+

++

E2F-5

-

+

++

Cell cycle inhibitors

p107

++

+

-

Rb

-

+

++

p130

+

++

+

p21

-

+

++

p27

-

+

++

p57

+

++

+

++, +, +/-, relative levels of expression; -, not detected. See text for details and references.

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Pregnancy Diet Plan

Pregnancy Diet Plan

The first trimester is very important for the mother and the baby. For most women it is common to find out about their pregnancy after they have missed their menstrual cycle. Since, not all women note their menstrual cycle and dates of intercourse, it may cause slight confusion about the exact date of conception. That is why most women find out that they are pregnant only after one month of pregnancy.

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