Antisense inhibition of angiotensinogen in hepatoma cell culture is enhanced by cationic liposome delivery.
Abnormalities in expression of renin angiotensin system components, including angiotensinogen, have been implicated in the development and maintenance 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 hypertension 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 blood pressures with concomitant changes in angiotensinogen protein and angiotensin II. However, studies using naked phosphorothioated oligonucleotide targeted to the same region did not produce changes in angiotensinogen mRNA in vivo or in cell culture. We now provide data which show that enhanced oligonucleotide delivery utilizing cationic liposomes significantly increases the attenuation of angiotensinogen protein and decreases mRNA in a dose dependent manner. These data provide an understanding of the mechanism of action of the antisense oligonucleotide and also establish optimal conditions and doses for further studies.
Wielbo
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Department of Medicinal Chemistry, University of Florida, Gainesville 32610-0485, USA.
Shi
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Sernia
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D000808:Angiotensinogen / Q000037:antagonists & inhibitors* / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D001483:Base Sequence; D002412:Cations; D004305:Dose-Response Relationship, Drug; D008081:Liposomes; D008114:Liver Neoplasms, Experimental / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012334:RNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D051381:Rats; D012084:Renin-Angiotensin System / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D014407:Tumor Cells, Cultured
D002412:Cations; D008081:Liposomes; D016376:Oligonucleotides, Antisense; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D000808:Angiotensinogen