Cardiac muscle cells show two related but distinct modes of growth that are highly regulated during development and disease. Cardiomyocytes proliferate rapidly during fetal life but exit the cell cycle soon after birth, after which the predominant form of growth shifts from hyperplasia to hypertrophy.1,2
During postnatal development, cardiac growth in the human, the mouse, and the rat undergoes this shift, such that further increases in myocardial mass are not typically accompanied by cardiomyocyte proliferation.3
In humans, the capability to undergo mitosis and hyperplasia is lost 3–6 months postnatally.4
Previous studies suggested that most cardiac cells in the rat and mouse gradually cease to undergo DNA replication, which is a prerequisite for proliferation, within the first two weeks after birth.5–7
For this reason, further response to growth, injury, and increased workload is restricted to increasing the mass of existing myocytes, mainly by hypertrophy of mature cardiomyocytes.8,9
Differentiated mature myocytes are permanently withdrawn from the cell cycle and represent an irreversible commitment to the differentiated phenotype. The dogma was introduced that adult cardiomyocytes are terminally differentiated cells.4,10
However, the view that myocytes cannot re-enter the cell cycle in the adult heart has been challenged.11
Several factors including cell cycle regulators (cyclins, cyclin dependent kinases, and proliferating cell nuclear antigen) and oncogenes (c-myc and Rb) are reportedly involved in cardiac muscle cell cycle progression.1
However, the molecular mechanisms responsible for terminal differentiation in cardiomyocytes—in particular the cell cycle arrest—are still unclear. Furthermore, it is also controversial whether or not adult cardiomyocytes retain a limited capacity for cell cycle re-entry.10,11
The factors that drive the proliferative growth of embryonic myocardium in vivo and the mechanisms whereby adult cardiomyocytes hypertrophy in vivo are less clear.
If we could understand the molecular mechanisms involved in the blocking of mitosis in cardiomyocytes during postnatal life, this might facilitate the development of new treatment for cardiovascular injury or disease, based on enhancing the regeneration of the adult myocardium. To achieve this goal, it is essential to identify and characterise key molecules participating in the growth of the newborn heart.
Systematic studies of gene expression patterns using cDNA microarray analysis provide a powerful approach to the molecular dissection of cells and tissues by comparing expression levels of thousands of genes at one time.12–14
In the present study, we initiated a project to profile the gene expression in various postnatal cardiac developmental states using mouse cDNA microarray (6144 genes, including known regulatory genes and mouse expressed sequence tags (ESTs)), employing a colorimetric detection system.13,15
We identified many genes where expression was upregulated or downregulated during postnatal heart development. Some of these candidate genes may be involved in the control of proliferation, differentiation, and hypertrophy of the myocardium. An in vivo study showed the role of pleiotrophin (PTN) in cell growth regulation during postnatal development. Further studies are underway to characterise the exact function of the genes regulating cardiac development.