To identify genes that are differentially expressed during the transition f
rom compensated hypertrophy to failure, myocardial mRNA from spontaneously
hypertensive rats (SBR) with heart failure (SHR-F) was compared with that f
rom age-matched SHR with compensated hypertrophy (SHR-NF) and normotensive
Wistar-Kyoto rats (WKY) by differential display reverse transcriptase-polym
erase chain reaction. Characterization of a transcript differentially expre
ssed in SHR-F yielded a cDNA with homology to the extracellular matrix prot
ein osteopontin. Northern analysis showed low levels of osteopontin mRNA in
left ventricular myocardium from WKY and SHR-NF but a markedly increased (
approximate to 10-fold) level in SHR-F. In myocardium from WKY and SHR-NF,
in situ hybridization showed only scant osteopontin mRNA, primarily in arte
riolar cells. In SHR-F, in situ hybridization revealed abundant expression
of osteopontin mRNA, primarily in nonmyocytes in the interstitial and periv
ascular space. Similar findings for osteopontin protein were observed in th
e midwall region of myocardium from the SHR-F group. Consistent with the fi
ndings in SHR, osteopontin mRNA was minimally increased (approximate to 1.9
-fold) in left ventricular myocardium from nonfailing aortic-banded rats wi
th pressure-overload hypertrophy but was markedly increased (approximate to
8-fold) in banded rats with failure. Treatment with captopril starting bef
ore or after the onset of failure in the SHR reduced the increase in left v
entricular osteopontin mRNA levels. Thus, osteopontin expression is markedl
y increased in the heart coincident with the development of heart failure,
The source of osteopontin in SHR-F is primarily nonmyocytes, and its induct
ion is inhibited by an angiotensin-converting enzyme inhibitor, suggesting
a role for angiotensin II. Given the known biological activities of osteopo
ntin, including cell adhesion and regulation of inducible nitric oxide synt
hase gene expression, these data suggest that it could play a role in the p
athophysiology of heart failure.