© 1995 American Heart Association, Inc.
Articles |
Angiotensin II–Induced Growth Responses in Isolated Adult Rat Hearts
Evidence for Load-Independent Induction of Cardiac Protein Synthesis by Angiotensin II
From the Charles A. Dana Research Institute and Harvard-Thorndike Laboratory of Beth Israel Hospital, Department of Internal Medicine, Cardiovascular Division, Beth Israel Hospital, Harvard Medical School (J.S., Y.K., E.O.W., S.I., B.H.L.), Boston, Mass, and Medizinische Klinik II, University of Regensburg (Germany) (H.S., T.C., G.R.).
Abstract Cardiac myocyte hypertrophy often occurs in response
to both hemodynamic and neurohumoral factors. To study whether
activation of the renin-angiotensin system by itself may induce a
cardiac growth response, the acute effects of angiotensin II on cardiac
protein synthesis were studied in isolated rat hearts. New protein
synthesis in isolated buffer-perfused adult rat hearts was measured by
incorporation of [3H]phenylalanine into cardiac proteins
during a 3-hour perfusion protocol. Angiotensin II
(1x10-8 mol/L), administered alone or in combination with
the 
1-blocker prazosin (1x10-7 mol/L),
stimulated protein synthesis in both ventricles. The rate of
[3H]phenylalanine incorporation into cardiac proteins was
3.9-fold (P<.005) and 2.6-fold (P<.01) higher
in angiotensin II–perfused (n=6) than in vehicle-perfused (n=6) left
and right ventricles, respectively. The induction of new protein
synthesis by angiotensin II was blocked by the angiotensin II type 1
(AT1) receptor antagonist losartan (1x10-7
mol/L, n=5). To study the pathways of angiotensin signal transduction,
protein kinase C (PKC)-
as well as cardiac c-fos and
c-jun mRNA levels were analyzed. Angiotensin II
(1x10-8 mol/L, n=20) resulted in a transient
translocation of PKC- from the cytosol to the cellular membrane.
However, compared with phorbol ester stimulation (phorbol 12-myristate
13-acetate [PMA], 1x10-7 mol/L; n=20), angiotensin II
effects on PKC translocation were significantly less pronounced and
required a more prolonged stimulation. There was no effect of
angiotensin II in concentrations from 10-9 to
10-6 mol/L (n=22) on c-fos and c-jun
mRNA levels in intact adult rat hearts studied over a time course from
15 to 120 minutes of perfusion. In contrast, norepinephrine
(10-6 mol/L, n=6), phorbol ester (PMA, 10-7
mol/L; n=5), and calcium ionophore (A23187, 2.5x10-6
mol/L; n=5) infusion as well as elevated left ventricular systolic wall
stress (n=6) were all followed by a threefold to fourfold induction of
cardiac c-fos and c-jun mRNA levels
(P<.005) compared with respective angiotensin II–infused
or vehicle-infused rat hearts (n=12). In contrast, administration of
angiotensin II in concentrations >10-9 mol/L caused a
significant induction of c-fos in adult and neonatal cardiac
myocytes. In conclusion, angiotensin II acutely stimulates protein
synthesis in cultured adult isolated perfused rat hearts. Angiotensin
II–activated signal transduction appears to involve AT1
receptors and activation of PKC. However, further downstream signaling
mechanisms remain elusive, since angiotensin II may stimulate protein
synthesis in the adult intact heart without preceding c-fos
and c-jun proto-oncogene induction.
Key Words: angiotensin II • protein synthesis • c-fos • c-jun • proto-oncogenes
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A. I.M. Al-Shafei, R.G. Wise, G.A. Gresham, G. Bronns, T.A. Carpenter, L.D. Hall, and C. L.-H. Huang Non-invasive magnetic resonance imaging assessment of myocardial changes and the effects of angiotensin-converting enzyme inhibition in diabetic rats J. Physiol., December 3, 2001; (2001) 200101285. [Abstract] [PDF]
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B. V. Alvarez, J. Fujinaga, and J. R. Casey Molecular Basis for Angiotensin II-Induced Increase of Chloride/Bicarbonate Exchange in the Myocardium Circ. Res., December 7, 2001; 89(12): 1246 - 1253. [Abstract] [Full Text] [PDF]
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