Angiotensin induction of PAI-1 expression in endothelial cells is mediated by the hexapeptide angiotensin IV.

Kerins, David M.; Qin, Hao; Vaughan, Douglas E.

doi:10.1172/jci118312

Cited by 293 publications

(167 citation statements)

References 30 publications

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“…AT 1a and AT 1b exhibit similar ligand binding and signal transduction properties, and cannot be distinguished pharmacologically, but differ in their tissue distribution. 3 In addition to Ang II, shorter Ang metabolites, such as Ang IV 4,5 and Ang-(1-7), [6][7][8] demonstrate potent biological activity. The heptapeptide Ang-(1-7) is an Ang metabolite of special interest because it can often counteract the detrimental effects of Ang II, for example, its vasoconstrictive properties.…”

Section: Introductionmentioning

confidence: 99%

Hemodynamic effects of vasorelaxant compounds in mice lacking one, two or all three angiotensin II receptors

et al. 2012

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The renin-angiotensin system (RAS) has a vital role in regulating the cardiovascular system. The primary effector of the RAS is the octapeptide angiotensin (Ang) II, a potent regulator of blood pressure and water homeostasis. Ang II mediates its functions through the stimulation of two distinct receptors, AT 1 (two subtypes in rodents (AT 1a and AT 1b )) and AT 2 . It was shown that in addition to Ang II, shorter fragments of Ang are also biologically active. Ang-(1-7) came into focus because it opposes many of the detrimental effects of Ang II. However, it is still controversial whether Ang II receptors are involved in Ang-(1-7)-mediated signaling. To characterize the impacts of Ang II receptors on Ang-(1-7)-stimulated vascular relaxation, the effects of acute infusion of the three vasorelaxant compounds, that is, Ang-(1-7), bradykinin (BK) and acetylcholine (ACh), on heart rate (HR) and mean arterial pressure (MAP) were investigated in mice deficient for one, two or all three Ang II receptors. Ang-(1-7) and BK reduced MAP in wild-type, AT 1a /AT 1b -deficient and AT 2 -deficient mice. Although the change in absolute MAP values in the hypotensive triple knockouts (KO) could not be further reduced by both peptides, the percent change in MAP was comparable between the triple KO and wild-type mice. Both peptides did not alter the HR in all four genotypes. ACh significantly reduced absolute MAP values in all four genotypes with a similar percentage of reduction. In contrast to Ang-(1-7) and BK, ACh significantly reduced HR without genotypic differences. Our results generate proof that Ang-(1-7)-induced effects on MAP are mediated by a receptor that is independent of AT 1 and AT 2 .

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Section: Introductionmentioning

confidence: 99%

Hemodynamic effects of vasorelaxant compounds in mice lacking one, two or all three angiotensin II receptors

et al. 2012

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“…9 In contrast, other reports have suggested that the AT 1 receptor does not mediate Ang II-stimulated PAI-1 expression. 24,25 Establishing the role of the AT 1 receptor in the regulation of PAI-1 expression may have important clinical significance related to potential differences between ACE inhibitors and AT 1 antagonists on the fibrinolytic system.…”

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confidence: 99%

Role of the Angiotensin AT ₁ Receptor in Rat Aortic and Cardiac PAI-1 Gene Expression

Chen¹,

Bouchie²,

Perez³

et al. 2000

ATVB

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Abstract-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 (PϽ0.01), 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 (PϽ0.05). Candesartan treatment for 1 week reduced aortic and cardiac PAI-1 expression in spontaneously hypertensive rats by 94% and 72%, respectively (PϽ0.05), 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. Key Words: angiotensin II Ⅲ plasminogen activator inhibitor Ⅲ hypertension Ⅲ aorta Ⅲ vascular smooth muscle cells P lasminogen activator inhibitor-1 (PAI-1) is the major inhibitor of tissue and urokinase plasminogen activators and thereby reduces the conversion of plasminogen to plasmin, an extracellular protease that mediates fibrinolysis and activates matrix metalloproteinases. 1-3 An elevated level of PAI-1, which occurs in diabetes, insulin resistance, obesity, and hypertension, has been implicated as a contributing risk factor for cardiovascular disease. 4 -7 Recent studies suggest that the renin-angiotensin system (RAS) may exert an important role in the regulation of circulating and vascular PAI-1 expression and may thereby affect the fibrinolytic balance. Reports from our laboratory and others have demonstrated that angiotensin II (Ang II) is a potent stimulator of PAI-1 mRNA and protein expression in both cultured endothelial and vascular smooth muscle cells. 8 -11 The physiological importance of the RAS in modulating PAI-1 levels is supported by in vivo studies, which have demonstrated that treatment of rats with the angiotensin-converting enzyme (ACE) inhibitor captopril suppresses the induction of PAI-1 expression in the aortic neointima induced by b...

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“…10,11 The dissimilar effects of imidapril and candesartan on PAI-1 could have been due in part to increased PAI-1 expression by the hexapeptide Ang II metabolite Ang IV and to stimulation of AT4 receptor, as reported in vitro in human endothelial cells. 52 These effects could have increased PAI-1 antigen concentration after short-term AT1 receptor blockade and after 2 week AT1 blockade, when AT4 receptors may be upregulated. 53 This mechanism is difficult to determine in a clinical setting and remains undetermined in the present study.…”

Section: Discussionmentioning

confidence: 99%

Fibrinolysis and insulin sensitivity in imidapril and candesartan (FISIC study) recipients with hypertension

et al. 2010

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The aim of this study was to evaluate the effects of imidapril and candesartan on fibrinolysis and insulin sensitivity in normoweight hypertensive patients. After a 2-week wash-out period, 61 patients with mild-to-moderate hypertension were randomized to imidapril or candesartan for 12 weeks. Blood pressure (BP), plasma tissue plasminogen activator (t-PA) and plasminogen activator inhibitor-1 (PAI-1) antigen activities were evaluated at baseline and during treatment. The patients underwent a euglycemic-hyperinsulinemic clamp (insulin sensitivity was evaluated as glucose infusion rate during the last 30 min) and a desmopressin test (with desmopressin infusion in the brachial artery) to evaluate endothelial ability to release t-PA. Imidapril and candesartan induced similar systolic/diastolic BP reductions (À16/12.6 and À16.1/12.2 mm Hg, respectively, Po0.001 vs. baseline). Imidapril increased glucose infusion rate (+1.1 mg min À1 per kg, Po0.02), whereas candesartan did not change it. Both drugs decreased PAI-1 antigen activity after 4 weeks of treatment; subsequently, only the decreasing effect of imidapril was sustained throughout the 12 weeks, whereas candesartan increased PAI-1 activity at week 12 (Po0.05 vs. baseline, Po0.01 vs. imidapril). Activity of t-PA decreased with candesartan (from 0.48 ± 0.16 to 0.43 ± 0.14 IU ml À1 , Po0.05) but not with imidapril. Activity of t-PA in response to desmopressin was increased more by imidapril (+4.45 IU ml À1 ) than by candesartan (+2.73 IU ml À1 , Po0.01 vs. imidapril). These results indicate that in normoweight hypertensive patients, despite similar BP reduction, imidapril but not candesartan improved the fibrinolytic balance, suggesting that mechanisms other than Ang II inhibition, possibly including bradykinin-mediated effects on insulin sensitivity and endothelial function, may be responsible for these different effects.

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Angiotensin induction of PAI-1 expression in endothelial cells is mediated by the hexapeptide angiotensin IV.

Cited by 293 publications

References 30 publications

Hemodynamic effects of vasorelaxant compounds in mice lacking one, two or all three angiotensin II receptors

Hemodynamic effects of vasorelaxant compounds in mice lacking one, two or all three angiotensin II receptors

Role of the Angiotensin AT ₁ Receptor in Rat Aortic and Cardiac PAI-1 Gene Expression

Fibrinolysis and insulin sensitivity in imidapril and candesartan (FISIC study) recipients with hypertension

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Angiotensin induction of PAI-1 expression in endothelial cells is mediated by the hexapeptide angiotensin IV.

Cited by 293 publications

References 30 publications

Hemodynamic effects of vasorelaxant compounds in mice lacking one, two or all three angiotensin II receptors

Hemodynamic effects of vasorelaxant compounds in mice lacking one, two or all three angiotensin II receptors

Role of the Angiotensin AT 1 Receptor in Rat Aortic and Cardiac PAI-1 Gene Expression

Fibrinolysis and insulin sensitivity in imidapril and candesartan (FISIC study) recipients with hypertension

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Role of the Angiotensin AT ₁ Receptor in Rat Aortic and Cardiac PAI-1 Gene Expression