Modulation of angiotensin II and norepinephrine-induced plasminogen activator inhibitor-1 expression by AT1a receptor deficiency.
Angiotensin (Ang) II stimulates plasminogen activator inhibitor-1 (PAI-1) expression in many cell types by mechanisms that are cell-type specific. We measured effects of Ang II or norepinephrine on PAI-1 expression in wild type (WT) and Ang type-1a receptor knockout mice (AT(1a)-/-) in the presence or absence of the non-specific AT(1) antagonist losartan. Ang II and norepinephrine increased systolic blood pressure equally, whereas losartan decreased the pressor response of the former but not the latter in WT mice. In AT(1a)-/- mice, baseline systolic blood pressure was lower with no effect of Ang II, norepinephrine, or losartan. Ang II stimulated PAI-1 expression in the heart, aorta, and kidney and markedly in the liver of WT mice. In AT(1a)-/- mice, Ang II-stimulated PAI-1 was significantly attenuated compared with the WT in the heart and aorta but significantly enhanced in the kidney. Losartan decreased the induction in the aorta and liver of WT, and in the kidney and liver of AT(1a)-/- mice. Norepinephrine increased PAI-1 expression in WT heart and aorta, and in AT(1a)-/- heart, kidney, and liver with no effect of losartan. Renal PAI-1 expression correlated with AT(1b) receptor mRNA. We conclude that Ang II stimulates PAI-1 expression in part through the AT(1b) receptor in the kidney and liver. Further, norepinephrine induces PAI-1 expression in vivo with AT(1a) receptor deficiency modulating the effect.
Brown
N J
NJ
Vanderbilt University Medical Center, Nashville, Tennessee 37232-6602, USA. nancy.j.brown@vanderbilt.edu
Bradford
J
J
Wang
Z
Z
Lea
W
W
Ma
L
L
Ma
J
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Vaughan
D E
DE
Fogo
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D000804:Angiotensin II / Q000494:pharmacology*; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D019808:Losartan / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009206:Myocardium / Q000378:metabolism; D009638:Norepinephrine / Q000494:pharmacology*; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011897:Random Allocation; D044140:Receptor, Angiotensin, Type 1 / Q000235:genetics / Q000378:metabolism*; D014662:Vasoconstrictor Agents / Q000494:pharmacology*
D047228:Angiotensin II Type 1 Receptor Blockers; D017395:Plasminogen Activator Inhibitor 1; D012333:RNA, Messenger; D044140:Receptor, Angiotensin, Type 1; D014662:Vasoconstrictor Agents; D000804:Angiotensin II; D019808:Losartan; D009638:Norepinephrine