Title:Ca2+ Fluxes Involvement in Gene Expression During Cardiac Hypertrophy
Volume: 11
Issue: 4
Author(s): Ana M. Gomez, Gema Ruiz-Hurtado, Jean-Pierre Benitah and Alejandro Dominguez-Rodriguez
Affiliation:
Keywords:
Heart, calcium, excitation-transcription coupling, cardiac hypertrophy.
Abstract: Cardiac hypertrophy arises as a response of the heart to many different pathological stimuli that challenge its
work. Regardless of the initial pathologic cause, cardiac hypertrophy shares some characteristics resulting from a genetic
reprogramming of several proteins. Recent studies point to Ca2+ as a key signaling element in the initiation of this genetic
reprogramming. In fact, besides its important role in excitation-contraction coupling, Ca2+ regulates cardiac growth by activation
of Ca2+-dependent transcription factors. This mechanism has been termed excitation-transcription (ET) coupling.
Some information about cardiac ET coupling is being gathered from the analysis of cardiac hypertrophy development,
where two Ca2+ dependent enzymes are key actors: the Ca2+/calmodulin kinase II (CaMKII) and the phosphatase calcineurin,
both activated by Ca2+/Calmodulin. In this review we focus on some neurohormonal signaling pathways involved
in cardiac hypertrophy, which could be ascribed as activators of ET coupling, for instance, adrenergic stimulation
and the renin-angiotensin-aldosterone system. β-adrenergic receptor (β-AR) produces cAMP, which directly, (through
cAMP response element) or indirectly (through activating Epac) induces cardiac hypertrophy. α1 AR and angiotensin receptor
type 1 are Gq protein coupled receptors, which when activated, stimulate phospholipase C producing inositol 1,4,5
triphosphate (IP3) and diacylglycerol (DAG). IP3 promotes elevation of [Ca2+] in the nucleus, activating CaMKII/MEF2
(myocyte enhancer factor 2) pathway and may indirectly induce Ca2+ entry through transient receptor potential channels
(TRPC). Other TRPC channels are activated by DAG. Ca2+ entry activates calcineurin/NFAT hypertrophic signaling. By
promoting L-type Ca2+ channel expression, aldosterone may also have an important role in the genetic reprogramming
during hypertrophy.
