ANTISENSE INHIBITION OF ANGIOTENSINOGEN IN HEPATOMA-CELL CULTURE IS ENHANCED BY CATIONIC LIPOSOME DELIVERY

Abnormalities in expression of renin angiotensin system components, in cluding angiotensinogen, have been implicated in the development and m aintenance of hypertension in the spontaneously hypertensive rat model of hypertension. Antisense compounds are being used as physiological tools to provide information on cardiovascular function and hypertensi on and also show great potential for development as therapeutic agents . We have previously shown that peripheral administration of antisense oligonucleotides to angiotensinogen in vivo decreases hypertensive bl ood pressures with concomitant changes in angiotensinogen protein and angiotensin II. However, studies using naked phosphorothioated oligonu cleotide targeted to the same region did not produce changes in angiot ensinogen mRNA in vivo or in cell culture. We now provide data which s how that enhanced oligonucleotide delivery utilizing cationic liposome s significantly increases the attenuation of angiotensinogen protein a nd decreases mRNA in a dose dependent manner. These data provide an un derstanding of the mechanism of action of the antisense oligonucleotid e and also establish optimal conditions and doses for further studies. (C) 1997 Academic Press