title: Antisense oligodeoxynucleotides directed against a novel angiotensinogen mRNA-stabilizing protein reduce blood pressure in spontaneously hypertensive rats.
abstract: We have previously reported that hypertension in the young spontaneously hypertensive rat (SHR) is associated with an elevation in tissue angiotensinogen and a novel polysomal protein known to stabilize angiotensinogen mRNA. In our current study we determined the role of the mRNA-stabilizing protein in the regulation of tissue angiotensinogen expression and mean arterial pressure (MAP) in the SHR utilizing antisense oligodeoxynucleotide (AON) inhibition. Three AONs (RNASTAAS1, position 31-50; RNASTAAS2, position 21-40; RNASTAAS3, position 143-162 of the cDNA coding for the polysomal protein) were administered intravenously (dose 450, 900, and 1,800 microg/kg; 1 dosage/day over 3 days) in conscious, chronically instrumented male SHRs at the age of 7 wk. Control SHRs received corresponding scrambled oligodeoxynucleotide sequences (SCR1, SCR2, SCR3). Each animal received the increasing dose schedule. RNASTAAS2 resulted in a reduced expression of the polysomal protein to 21% (liver), 12% (brain), 27% (heart), 18% (renal cortex), and 22% (renal medulla) of control. Angiotensinogen expression was inhibited to 54% (liver), 41% (brain), 68% (heart), 52% (renal cortex), and 74% (renal medulla) compared with control SHRs. Decreases in plasma concentrations of angiotensinogen and plasma renin activities were associated with a significant decrease in MAP from 147 +/- 6 mmHg (after SCR2) to 106 +/- 4 mmHg after RNASTAAS2. The effects of the two other AONs on MAP were less (RNASTAAS1, -31 mmHg; RNASTAAS3, -16 mmHg) with corresponding decreases in mRNAs coding for angiotensinogen and the polysomal protein. A significant decrease in intracellular concentrations of the polysomal protein accompanied AON inhibition. The magnitude of effects (-15 to -41 mmHg) was comparable to the effects of captopril (100 mg x kg(-1) x day(-1) for 3 days: -32 mmHg) and an AT(1) receptor antagonist (L-158809, 1.5 mg x kg(-1) x day(-1) for 3 days: -36 mmHg). These data suggest an important role of the mRNA-stabilizing protein for hepatic and extrahepatic angiotensinogen expression and MAP in the SHR.
authors.affiliation: Department of Physiology and Biophysics, University of Mississippi Medical Center, 2500 N. State St., Jackson, MS 39216, USA. cklett@physiology.umsmed.edu
authors.forename: Christoph P R
authors.initials: CP
authors.lastname: Klett
authors.forename: Dock
authors.initials: D
authors.lastname: Anderson
authors.forename: Myssara
authors.initials: M
authors.lastname: Sholook
authors.forename: Joey P
authors.initials: JP
authors.lastname: Granger
mesh_terms: D047228:Angiotensin II Type 1 Receptor Blockers; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000808:Angiotensinogen / Q000097:blood / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects*; D002216:Captopril / Q000494:pharmacology; D006973:Hypertension / Q000503:physiopathology*; D007093:Imidazoles / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D016376:Oligonucleotides, Antisense / Q000494:pharmacology*; D020871:RNA Stability / Q000187:drug effects / Q000235:genetics*; D012333:RNA, Messenger / Q000737:chemistry*; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D012083:Renin / Q000097:blood; D013777:Tetrazoles / Q000494:pharmacology
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D000806:Angiotensin-Converting Enzyme Inhibitors; D000959:Antihypertensive Agents; D007093:Imidazoles; D016376:Oligonucleotides, Antisense; D012333:RNA, Messenger; D013777:Tetrazoles; D000808:Angiotensinogen; C070967:L 158809; D002216:Captopril; D012083:Renin