The small
guanine nucleotide-
binding protein Rac1 has emerged as an important molecule involved in cardiac myocyte
hypertrophy. Recently, we reported on apoptosis signal-regulating
kinase (ASK) 1 and a transcriptional factor,
nuclear factor-kappaB (
NF-kappaB), as novel signaling intermediates in cardiac myocyte
hypertrophy. The aim of the study presented here was to clarify the role of Rac1 in the ASK1-NF-kappaB signaling pathway.
Infection of isolated neonatal cardiac myocytes with an adenovirus expressing a constitutively active form of Rac1 (RacV12) enhanced the expression of a kappaB-dependent reporter gene construct and induced the degradation of
IkappaBalpha. Expression of a degradation-resistant mutant of
IkappaBalpha inhibited the RacV12-induced hypertrophic responses, including increases in
protein synthesis and
atrial natriuretic factor production and the enhancement of sarcomeric organization. An
immune complex kinase assay indicated that the expression of RacV12 activated ASK1. Expression of a dominant negative mutant of ASK1 eliminated the RacV12-induced
NF-kappaB activation and the biochemical and morphological hypertrophic responses, whereas expression of a dominant negative form of Rac1 attenuated
phenylephrine-induced activation of ASK1 and
NF-kappaB and cardiac myocyte
hypertrophy. These findings suggest that Rac1 induces cardiac myocyte
hypertrophy mediated through ASK1 and
NF-kappaB.