Myocardial osteopontin expression coincides with the development of heart failure

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.