Pq. Liang et al., MECHANICAL STRAIN INCREASES EXPRESSION OF THE BRAIN NATRIURETIC PEPTIDE GENE IN RAT CARDIAC MYOCYTES, The Journal of biological chemistry, 272(44), 1997, pp. 28050-28056
Using a device that applies cyclical strain (1 Hz) to ventricular card
iocytes cultured on collagen-coated silicone elastomer surfaces, we ha
ve demonstrated strain-dependent increases in brain natriuretic peptid
e (BNP) secretion, BNP mRNA levels, and expression of a transiently tr
ansfected -1595 human BNP-luciferase reporter. When actinomycin D (10
mu M) was introduced concomitantly with the strain stimulus, the strai
n-induced increase in BNP mRNA was eliminated, and the decay of transc
ripts was identical in the control and strained cells, indicating the
lack of independent effects on transcript stability. Strain-dependent
-1595 human BNP-luciferase activity was completely inhibited by cheler
ythrine, a-aminopurine, genistein, and W-7 and only partially or not a
t all by KN-62, wortmannin, and H-89. The effects of these individual
agents paralleled their effects on mitogen-activated protein kinase (M
APK) activity, but not c-Jun N-terminal kinase (JNK) activity, in the
cells. Overexpression of wild-type MAPK and, to a lesser extent, JNK i
ncreased strain-dependent BNP promoter activity, whereas dominant-nega
tive mutants of MAPK kinase, JNK kinase, or Ras completely blocked str
ain-dependent reporter activity. These findings provide the first demo
nstration that mechanical strain can increase myocardial gene expressi
on through a transcriptional mechanism and suggest important roles for
MAPK and JNK in mediating this effect.