一氧化氮與內皮素之間於新生鼠心臟細胞的交互作用

Endothelin-1 (Et-1) treatment of cardiac
myocytes (CM) induces cardiac hypertrophy.
Cardiovascular release of nitric oxide (NO)
may play a role during cardiac hypertrophy.
The present study examined the protection
mechanism of endogenously released NO on
c-fos induction by Et-1 in neonatal rat CM.
CM exposed to Et-1 induced NO release. Et-1
stimulated nitric oxide synthase (NOS)
activity led to NO production that was
attenuated by treating CM with an antagonist
to endothelin B receptor. CM treated with a
NO donor, S-nitroso-N-acetylpenicillamine
(SNAP) or 3-morpholinosydnonimine (SIN-1),
inhibited Et-1–induced c-fos expression.
Conversely, CM treated with a NO scavenger,
2-phenyl-4,4,5,5,-tetramethyl-imidazoline-l-oxyl-
3-oxide (PTIO), augmented Et-1-induced
c-fos expression. The attenuation of
NO on c-fos expression was shown by
reducing either c-fos mRNA levels or c-fos
promoter activities using a chimera
containing the c-fos promoter region (-2.25
kb) ligated to a reporter gene CAT. In
contrast to the enhanced promoter activity in
CM after PTIO treatment, attenuated Et-1-induced
c-fos promoter activity was shown in
CM treated with a NO donor. CM
cotransfected with a dominant negative
mutant of Ras (RasN17), Raf-1 (Raf301), or
a catalytically inactive mutant of
extracellular signal–regulated kinase (ERK)–
2 (mERK) inhibited Et-1–induced c-fos
promoter activity, indicating Ras/Raf/ERK
pathway was involved. NO modulation of
this signaling pathway was shown by its
inhibitory effect on Et-1–induced ERK
activity. CM treated with NO resulted in a
decrease of Et-1-induced binding of nuclear
proteins to the AP-1 binding sequences.
Furthermore, CM treated with a NO donor
significantly suppressed Et-1-induced b-myosin
heavy chain promoter activities.
These results indicate that CM under Et-1
treatment increases NO levels and the
increased NO attenuated Et-1-induced c-fos
expression via the ERK signaling pathway.
These findings support the importance of NO
as a negative regulator in Et-1–induced gene
expression and cardiac hypertrophy.