Intracellular Signaling and Genetic Reprogramming during Agonist‐Induced Hypertrophy of Cardiomyocytes a

Cardiac myocytes stop dividing shortly after birth and subsequently the heart grows by enlargement of individual cells, a process that can be observed in vitro as well.' However, growth of individual cardiomyocytes can also be observed in the adult heart, a process called hypertrophy. Chronic hernodynamic overload of the heart by, e.g. , infarction, hypertension or volume or pressure overload ultimately leads to hypertrophy of the left ventricular wall. The hypertrophy process involves induction of transcription of specific contractile as well as noncontractile protein genes resulting in growth as well as change in contractile function of the c a r d i o r n y o ~ y t e . ~ ~ ~ This allows the heart to maintain normal beat-to-beat volume under the circumstances mentioned above. Although only limited evidence was presented for their importance during in vivo development of hypertr~phy,~-' hormonal and mechanical stimuli are thought to be the initial signals that trigger the onset of cell growth. The evidence for the involvement of hormonal and mechanical signals in the induction of hypertrophy mainly comes from in vitro models employing cultured neonatal cardiomyocytes. Here it was shown that induction of hypertrophy is accompanied by activation of the phosphoinositide (PI) cycle and by rapid stimulation of transcription of so-called immediate early genes, transcription factors, ultimately leading to rearrangement of gene expression of structural proteins in the cardiomyocyte. Recently, studies of hypertrophy were also performed on cultured adult cardiomyocytes,8-'1 confirming results from the neonatal cardiomyocyte model. In this review we focus on the influence of these hormonal and mechanical signals that activate the PI cycle during development of hypertrophy in the model of cultured cardiomyocytes and the ultimate outcome