(Hypertension. 1995;25:1252-1259.)
© 1995 American Heart Association, Inc.
Articles |
Angiotensin II Induces Cardiac Phenotypic Modulation and Remodeling In Vivo in Rats
From the Department of Pharmacology, Osaka City University Medical School, Osaka, Japan.
Abstract Cardiac phenotypic modulation and remodeling appear
to be involved in the pathophysiology of cardiac hypertrophy and heart
failure. We undertook this study to examine whether angiotensin II (Ang
II) in vivo, independent of blood pressure, contributes to cardiac
phenotypic modulation and remodeling. A low dose (200 ng/kg per minute)
of Ang II was continuously infused into rats by osmotic minipump for 24
hours or 3 or 7 days to examine the effects on the expression of
cardiac phenotype–related or fibrosis-related genes. This Ang II dose
caused a small and gradual increase in blood pressure over 7 days. Left
ventricular mRNAs for skeletal 
-actin, ß-myosin heavy chain,
atrial natriuretic polypeptide, and fibronectin were already increased
by 6.9-, 1.8-, 4.8-, and 1.5-fold, respectively, after 24 hours of Ang
II infusion and by 6.9-, 3.3-, 7.5-, and 2.5-fold, respectively, after
3 days, whereas ventricular -myosin heavy chain and smooth muscle
-actin mRNAs were not significantly altered by Ang II infusion.
Ventricular transforming growth factor-ß1 and types I and III
collagen mRNA levels did not increase at 24 hours and began to increase
by 1.4-, 2.8-, and 2.1-fold, respectively, at 3 days. An increase in
left ventricular weight occurred 3 days after Ang II infusion.
Treatment with TCV-116 (3 mg/kg per day), a nonpeptide selective
angiotensin type 1 receptor antagonist, completely inhibited the
above-mentioned Ang II–induced increases in ventricular gene
expressions and weight. Hydralazine (10 mg/kg per day), which
completely normalized blood pressure, did not block cardiac hypertrophy
or increased cardiac gene expressions by Ang II. This study
demonstrates that Ang II in vivo, via the type 1 receptor, directly
induces a shift to the fetal phenotype of cardiac myocytes and cardiac
remodeling independent of blood pressure elevation. Thus, Ang II may
play an important role in the modulation of cardiac performance in
pathological cardiac hypertrophy.
Key Words: heart hypertrophy • actins • collagen • fibronectin • transforming growth factor-ß1 • receptors, angiotensin
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