Role of the angiotensin AT(1) receptor in rat aortic and cardiac PAI-1 gene expression.
Although the renin-angiotensin system has been implicated in increasing plasminogen activator inhibitor-1 (PAI-1) expression, the role of the angiotensin type 1 (AT(1)) receptor is controversial. This report examines the effects of angiotensin peptides, angiotensin-converting enzyme inhibition, and AT(1) antagonism on rat aortic and cardiac PAI-1 gene expression. In vitro, angiotensin (Ang) I, Ang II, and angiotensin Arg(2)-Phe(8) (Ang III) were potent agonists of PAI-1 mRNA expression in rat aortic smooth muscle cells (RASMCs), and stimulation of PAI-1 by these peptides was blocked by the AT(1) antagonist candesartan. Angiotensin Val(3)-Phe(8) (Ang IV) and angiotensin Asp(1)-Pro(7) (Ang [1-7]) did not affect PAI-1 expression in RASMCs. In neonatal rat cardiomyocytes, Ang II increased PAI-1 mRNA expression by 4-fold (P<0.01), and this response was completely blocked by AT(1) receptor antagonism. Continuous intrajugular infusion of Ang II into Sprague-Dawley rats for 3 hours increased aortic and cardiac PAI-1 mRNA expression by 17- and 9 fold, respectively, and these Ang II responses were completely blocked by coinfusion with candesartan. Aortic and cardiac PAI-1 expressions were compared in spontaneously hypertensive rats and Wistar-Kyoto rats. PAI-1 expression in the aorta and heart from spontaneously hypertensive rats was 5.8-fold and 2-fold higher, respectively, than in control Wistar-Kyoto rats (P<0.05). Candesartan treatment for 1 week reduced aortic and cardiac PAI-1 expression in spontaneously hypertensive rats by 94% and 72%, respectively (P<0.05), but did not affect vascular PAI-1 levels in Wistar-Kyoto rats. These results demonstrate a role for the AT(1) receptor in mediating the effects of Ang II on aortic and cardiac PAI-1 gene expression.
Chen
H C
HC
Research Division, Joslin Diabetes Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.
Bouchie
J L
JL
Perez
A S
AS
Clermont
A C
AC
Izumo
S
S
Hampe
J
J
Feener
E P
EP
D000804:Angiotensin II / Q000494:pharmacology; D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D000959:Antihypertensive Agents / Q000494:pharmacology; D001011:Aorta / Q000187:drug effects / Q000378:metabolism*; D001562:Benzimidazoles / Q000494:pharmacology; D001713:Biphenyl Compounds; D002478:Cells, Cultured; D015870:Gene Expression / Q000187:drug effects; D006352:Heart Ventricles / Q000187:drug effects; D007262:Infusions, Intravenous; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism*; D017395:Plasminogen Activator Inhibitor 1 / Q000096:biosynthesis* / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis / Q000096:biosynthesis; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin / Q000378:metabolism*; D013777:Tetrazoles / Q000494:pharmacology
D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors; D000959:Antihypertensive Agents; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D017395:Plasminogen Activator Inhibitor 1; D012333:RNA, Messenger; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin; D013777:Tetrazoles; D000804:Angiotensin II; C081643:candesartan