Cardiomyocytes - Tissue Functioning and Remodeling in the Circulatory and Ventilatory Systems - page 243

Protein kinase-C, protein kinase-D, and calmodulin-dependent kinase
phosphorylate histone deacetylases for translocation from the nucleus to the
cytoplasm. In the nucleus, HDAC2 is recruited to genes involved in the regulation
of cardiomyocyte growth. This enzyme prevents hypertrophy, as it inhibits myocyte
enhancer factor, whereas HDAC1 favors cardiac hypertrophy.

5.8.2.1 Hypertrophy Regulators and Calcium Signaling

Cardiomyocyte hypertrophy is induced by angiotensin-2, aldosterone, endothelin,
and noradrenaline. These hypertrophic substances can modify frequency, amplitude,
duration, and/or cellular location of Ca 2 + signaling.
Angiotensin-2 and endothelin generate Ca 2 + influx from stores via IP 3 agent.
Angiotensin-2 induces a moderate elevation in diastolic Ca 2 + concentration lasting
1 to 2 mn. This minor effect leads to long-term consequences by prolonged
occupancy of cognate receptors.
Catecholamines increase the frequency and amplitude of calcium transients.
Aldosterone affects time- and space-dependent calcium activity. Certain hyper-
trophic agents generate nuclear translocation of NFAT, thereby modulating the
frequency of spontaneous Ca 2 + oscillations in neonatal rat cardiomyocytes in
vitro. [ 413 ]. 72

5.8.2.2 Signaling Pathways

Signaling axes and mediators involved in cardiac hypertrophy include the

B activated
by G-protein-coupled receptors of endothelin-1 and angiotensin-2, or cytokine
receptors of TNF

PP3-NFAT, PI3K-PKB-GSK3, and MEF2-HDAC cascades, and NF κ

α and interleukin-1, with crosstalk at various levels.

This integrated signaling network regulates gene expression via many

transcription factors, such as NF B, MEF2, NFAT, and GATA4, as well as histone

deacetylases. Long-term inhibition of cGMP phosphodiesterase PDE5a deactivates
signaling pathways of cardiomyocyte hypertrophy.

κ

72 The small duration of spontaneous Ca 2 + oscillations (

200 ms) does not allow substantial
NFAT dephosphorylation and translocation into the nucleus. If the interval between 2 successive
Ca 2 + spikes is repeatedly shortened, dephosphorylated NFAT will tend to slowly accumulate.
In addition, repeated Ca 2 + spikes of higher amplitude can increase NFAT translocation. Each
Ca 2 + transient has a tiny effect, but integration over time produces a significant change. Near-
nucleus Ca 2 + increase also favors NFAT translocation. However, Ca 2 + sparks are observed
throughout the cytosol between Ca 2 + transients without increase in perinuclear Ca 2 + spark
frequency or spatial spreading of Ca 2 + sparks. Angiotensin-2, noradrenaline, and aldosterone (via
both mineralcorticoid receptor and AT1R) increase Ca 2 + oscillation frequency.

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