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. 1995 Mar;95(3):1353–1362. doi: 10.1172/JCI117786

Angiotensin II induces plasminogen activator inhibitor-1 and -2 expression in vascular endothelial and smooth muscle cells.

E P Feener 1, J M Northrup 1, L P Aiello 1, G L King 1
PMCID: PMC441475  PMID: 7883982

Abstract

Angiotensin II (AII)- and Arg8-vasopressin (AVP)-regulated gene expression in vascular cells has been reported to contribute to vascular homeostasis and hypertrophy. In this report, AVP-induced expression of plasminogen activator inhibitor (PAI)-2 mRNA in rat microvessel endothelial (RME) cells was identified using differential mRNA display. Further characterization of vasoactive peptide effects on PAI expression revealed that AII stimulated a 44.8 +/- 25.2-fold and a 12.4 +/- 3.2-fold increase in PAI-2 mRNA in RME cells and rat aortic smooth muscle cells (RASMC), respectively. AII also stimulated a 10- and 48-fold increase in PAI-1 mRNA in RME cells and RASMC, respectively. These AII effects were inhibited by either Sar1, Ile8-angiotensin or the AT1 antagonist DuP 735, but were not significantly altered in the presence of the AT2 antagonist PD123319. AII stimulation of RASMC and RME cells also significantly increased both PAI-1 protein and PAI activity released to the culture medium. Inhibition of protein kinase C completely blocked PMA-stimulated induction of PAI-2 mRNA in both cell types and inhibited the AII-stimulated increase in RASMC by 98.6 +/- 2.8%. In contrast, protein kinase C inhibition only partially decreased the AII-stimulated PAI-2 expression in RME cells by 68.8 +/- 11.1%, suggesting that a protein kinase C-independent mechanism contributes to a 6.9 +/- 1.5-fold AII induction of PAI-2 expression in endothelial cells. AII and PMA also stimulated protein tyrosine phosphorylation in RME cells, and the tyrosine kinase inhibitor genistein partially blocked their induction of PAI-2 mRNA. These findings suggest that AII may regulate plasminogen activation in the vasculature by inducing both PAI-1 and PAI-2 expression.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Akiyama T., Ishida J., Nakagawa S., Ogawara H., Watanabe S., Itoh N., Shibuya M., Fukami Y. Genistein, a specific inhibitor of tyrosine-specific protein kinases. J Biol Chem. 1987 Apr 25;262(12):5592–5595. [PubMed] [Google Scholar]
  2. Bell L., Luthringer D. J., Madri J. A., Warren S. L. Autocrine angiotensin system regulation of bovine aortic endothelial cell migration and plasminogen activator involves modulation of proto-oncogene pp60c-src expression. J Clin Invest. 1992 Jan;89(1):315–320. doi: 10.1172/JCI115578. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Bell L., Madri J. A. Influence of the angiotensin system on endothelial and smooth muscle cell migration. Am J Pathol. 1990 Jul;137(1):7–12. [PMC free article] [PubMed] [Google Scholar]
  4. Berk B. C., Vekshtein V., Gordon H. M., Tsuda T. Angiotensin II-stimulated protein synthesis in cultured vascular smooth muscle cells. Hypertension. 1989 Apr;13(4):305–314. doi: 10.1161/01.hyp.13.4.305. [DOI] [PubMed] [Google Scholar]
  5. Braunwald E. ACE inhibitors--a cornerstone of the treatment of heart failure. N Engl J Med. 1991 Aug 1;325(5):351–353. doi: 10.1056/NEJM199108013250508. [DOI] [PubMed] [Google Scholar]
  6. Bruzdzinski C. J., Riordan-Johnson M., Nordby E. C., Suter S. M., Gelehrter T. D. Isolation and characterization of the rat plasminogen activator inhibitor-1 gene. J Biol Chem. 1990 Feb 5;265(4):2078–2085. [PubMed] [Google Scholar]
  7. Cambien F., Poirier O., Lecerf L., Evans A., Cambou J. P., Arveiler D., Luc G., Bard J. M., Bara L., Ricard S. Deletion polymorphism in the gene for angiotensin-converting enzyme is a potent risk factor for myocardial infarction. Nature. 1992 Oct 15;359(6396):641–644. doi: 10.1038/359641a0. [DOI] [PubMed] [Google Scholar]
  8. Carmeliet P., Stassen J. M., Schoonjans L., Ream B., van den Oord J. J., De Mol M., Mulligan R. C., Collen D. Plasminogen activator inhibitor-1 gene-deficient mice. II. Effects on hemostasis, thrombosis, and thrombolysis. J Clin Invest. 1993 Dec;92(6):2756–2760. doi: 10.1172/JCI116893. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Caulfield M., Lavender P., Farrall M., Munroe P., Lawson M., Turner P., Clark A. J. Linkage of the angiotensinogen gene to essential hypertension. N Engl J Med. 1994 Jun 9;330(23):1629–1633. doi: 10.1056/NEJM199406093302301. [DOI] [PubMed] [Google Scholar]
  10. Cousin E., Medcalf R. L., Bergonzelli G. E., Kruithof E. K. Regulatory elements involved in constitutive and phorbol ester-inducible expression of the plasminogen activator inhibitor type 2 gene promoter. Nucleic Acids Res. 1991 Jul 25;19(14):3881–3886. doi: 10.1093/nar/19.14.3881. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Delafontaine P., Lou H. Angiotensin II regulates insulin-like growth factor I gene expression in vascular smooth muscle cells. J Biol Chem. 1993 Aug 5;268(22):16866–16870. [PubMed] [Google Scholar]
  12. Doria A., Warram J. H., Krolewski A. S. Genetic predisposition to diabetic nephropathy. Evidence for a role of the angiotensin I--converting enzyme gene. Diabetes. 1994 May;43(5):690–695. doi: 10.2337/diab.43.5.690. [DOI] [PubMed] [Google Scholar]
  13. Erickson L. A., Fici G. J., Lund J. E., Boyle T. P., Polites H. G., Marotti K. R. Development of venous occlusions in mice transgenic for the plasminogen activator inhibitor-1 gene. Nature. 1990 Jul 5;346(6279):74–76. doi: 10.1038/346074a0. [DOI] [PubMed] [Google Scholar]
  14. Force T., Kyriakis J. M., Avruch J., Bonventre J. V. Endothelin, vasopressin, and angiotensin II enhance tyrosine phosphorylation by protein kinase C-dependent and -independent pathways in glomerular mesangial cells. J Biol Chem. 1991 Apr 5;266(10):6650–6656. [PubMed] [Google Scholar]
  15. Griendling K. K., Rittenhouse S. E., Brock T. A., Ekstein L. S., Gimbrone M. A., Jr, Alexander R. W. Sustained diacylglycerol formation from inositol phospholipids in angiotensin II-stimulated vascular smooth muscle cells. J Biol Chem. 1986 May 5;261(13):5901–5906. [PubMed] [Google Scholar]
  16. Hachiya H. L., Takayama S., White M. F., King G. L. Regulation of insulin receptor internalization in vascular endothelial cells by insulin and phorbol ester. J Biol Chem. 1987 May 5;262(13):6417–6424. [PubMed] [Google Scholar]
  17. Hu K. Q., Backer J. M., Sahagian G., Feener E. P., King G. L. Modulation of the insulin growth factor II/mannose 6-phosphate receptor in microvascular endothelial cells by phorbol ester via protein kinase C. J Biol Chem. 1990 Aug 15;265(23):13864–13870. [PubMed] [Google Scholar]
  18. Imai T., Hirata Y., Emori T., Yanagisawa M., Masaki T., Marumo F. Induction of endothelin-1 gene by angiotensin and vasopressin in endothelial cells. Hypertension. 1992 Jun;19(6 Pt 2):753–757. doi: 10.1161/01.hyp.19.6.753. [DOI] [PubMed] [Google Scholar]
  19. Ito H., Hirata Y., Adachi S., Tanaka M., Tsujino M., Koike A., Nogami A., Murumo F., Hiroe M. Endothelin-1 is an autocrine/paracrine factor in the mechanism of angiotensin II-induced hypertrophy in cultured rat cardiomyocytes. J Clin Invest. 1993 Jul;92(1):398–403. doi: 10.1172/JCI116579. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Itoh H., Mukoyama M., Pratt R. E., Gibbons G. H., Dzau V. J. Multiple autocrine growth factors modulate vascular smooth muscle cell growth response to angiotensin II. J Clin Invest. 1993 May;91(5):2268–2274. doi: 10.1172/JCI116454. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Jeunemaitre X., Soubrier F., Kotelevtsev Y. V., Lifton R. P., Williams C. S., Charru A., Hunt S. C., Hopkins P. N., Williams R. R., Lalouel J. M. Molecular basis of human hypertension: role of angiotensinogen. Cell. 1992 Oct 2;71(1):169–180. doi: 10.1016/0092-8674(92)90275-h. [DOI] [PubMed] [Google Scholar]
  22. King G. L., Goodman A. D., Buzney S., Moses A., Kahn C. R. Receptors and growth-promoting effects of insulin and insulinlike growth factors on cells from bovine retinal capillaries and aorta. J Clin Invest. 1985 Mar;75(3):1028–1036. doi: 10.1172/JCI111764. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Ko Y., Stiebler H., Nickenig G., Wieczorek A. J., Vetter H., Sachinidis A. Synergistic action of angiotensin II, insulin-like growth factor-I, and transforming growth factor-beta on platelet-derived growth factor-BB, basic fibroblastic growth factor, and epidermal growth factor-induced DNA synthesis in vascular smooth muscle cells. Am J Hypertens. 1993 Jun;6(6 Pt 1):496–499. doi: 10.1093/ajh/6.6.496. [DOI] [PubMed] [Google Scholar]
  24. Krishnamurti C., Alving B. M. Plasminogen activator inhibitor type 1: biochemistry and evidence for modulation of fibrinolysis in vivo. Semin Thromb Hemost. 1992 Jan;18(1):67–80. doi: 10.1055/s-2007-1002412. [DOI] [PubMed] [Google Scholar]
  25. Kruithof E. K. Plasminogen activator inhibitors--a review. Enzyme. 1988;40(2-3):113–121. doi: 10.1159/000469153. [DOI] [PubMed] [Google Scholar]
  26. Laborda J. 36B4 cDNA used as an estradiol-independent mRNA control is the cDNA for human acidic ribosomal phosphoprotein PO. Nucleic Acids Res. 1991 Jul 25;19(14):3998–3998. doi: 10.1093/nar/19.14.3998. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Lenz T., Sealey J. E., Lappe R. W., Carilli C., Oshiro G. T., Baxter J. D., Laragh J. H. Infusion of recombinant human prorenin into rhesus monkeys. Effects on hemodynamics, renin-angiotensin-aldosterone axis and plasma testosterone. Am J Hypertens. 1990 Apr;3(4):257–261. doi: 10.1093/ajh/3.4.257. [DOI] [PubMed] [Google Scholar]
  28. Lewis E. J., Hunsicker L. G., Bain R. P., Rohde R. D. The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. The Collaborative Study Group. N Engl J Med. 1993 Nov 11;329(20):1456–1462. doi: 10.1056/NEJM199311113292004. [DOI] [PubMed] [Google Scholar]
  29. Liang P., Pardee A. B. Differential display of eukaryotic messenger RNA by means of the polymerase chain reaction. Science. 1992 Aug 14;257(5072):967–971. doi: 10.1126/science.1354393. [DOI] [PubMed] [Google Scholar]
  30. Marre M., Bernadet P., Gallois Y., Savagner F., Guyene T. T., Hallab M., Cambien F., Passa P., Alhenc-Gelas F. Relationships between angiotensin I converting enzyme gene polymorphism, plasma levels, and diabetic retinal and renal complications. Diabetes. 1994 Mar;43(3):384–388. doi: 10.2337/diab.43.3.384. [DOI] [PubMed] [Google Scholar]
  31. Mawatari M., Okamura K., Matsuda T., Hamanaka R., Mizoguchi H., Higashio K., Kohno K., Kuwano M. Tumor necrosis factor and epidermal growth factor modulate migration of human microvascular endothelial cells and production of tissue-type plasminogen activator and its inhibitor. Exp Cell Res. 1991 Feb;192(2):574–580. doi: 10.1016/0014-4827(91)90078-9. [DOI] [PubMed] [Google Scholar]
  32. Naftilan A. J., Pratt R. E., Dzau V. J. Induction of platelet-derived growth factor A-chain and c-myc gene expressions by angiotensin II in cultured rat vascular smooth muscle cells. J Clin Invest. 1989 Apr;83(4):1419–1424. doi: 10.1172/JCI114032. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Niiya K., Takeuchi T., Kobayashi M., Miyoshi I., Hayashi T., Sakuragawa N. Dexamethasone and phorbol ester, but not cytokines, increase the production of plasminogen activator inhibitor type-2 in the PL-21 human promyelocytic leukemia cell line. Thromb Haemost. 1991 Aug 1;66(2):232–238. [PubMed] [Google Scholar]
  34. Nishio Y., Aiello L. P., King G. L. Glucose induced genes in bovine aortic smooth muscle cells identified by mRNA differential display. FASEB J. 1994 Jan;8(1):103–106. doi: 10.1096/fasebj.8.1.8299882. [DOI] [PubMed] [Google Scholar]
  35. Oliver F. J., de la Rubia G., Feener E. P., Lee M. E., Loeken M. R., Shiba T., Quertermous T., King G. L. Stimulation of endothelin-1 gene expression by insulin in endothelial cells. J Biol Chem. 1991 Dec 5;266(34):23251–23256. [PubMed] [Google Scholar]
  36. Pfeffer M. A., Braunwald E., Moyé L. A., Basta L., Brown E. J., Jr, Cuddy T. E., Davis B. R., Geltman E. M., Goldman S., Flaker G. C. Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction. Results of the survival and ventricular enlargement trial. The SAVE Investigators. N Engl J Med. 1992 Sep 3;327(10):669–677. doi: 10.1056/NEJM199209033271001. [DOI] [PubMed] [Google Scholar]
  37. Powell J. S., Clozel J. P., Müller R. K., Kuhn H., Hefti F., Hosang M., Baumgartner H. R. Inhibitors of angiotensin-converting enzyme prevent myointimal proliferation after vascular injury. Science. 1989 Jul 14;245(4914):186–188. doi: 10.1126/science.2526370. [DOI] [PubMed] [Google Scholar]
  38. Raynolds M. V., Bristow M. R., Bush E. W., Abraham W. T., Lowes B. D., Zisman L. S., Taft C. S., Perryman M. B. Angiotensin-converting enzyme DD genotype in patients with ischaemic or idiopathic dilated cardiomyopathy. Lancet. 1993 Oct 30;342(8879):1073–1075. doi: 10.1016/0140-6736(93)92061-w. [DOI] [PubMed] [Google Scholar]
  39. Reilly C. F., McFall R. C. Platelet-derived growth factor and transforming growth factor-beta regulate plasminogen activator inhibitor-1 synthesis in vascular smooth muscle cells. J Biol Chem. 1991 May 25;266(15):9419–9427. [PubMed] [Google Scholar]
  40. Ridker P. M., Gaboury C. L., Conlin P. R., Seely E. W., Williams G. H., Vaughan D. E. Stimulation of plasminogen activator inhibitor in vivo by infusion of angiotensin II. Evidence of a potential interaction between the renin-angiotensin system and fibrinolytic function. Circulation. 1993 Jun;87(6):1969–1973. doi: 10.1161/01.cir.87.6.1969. [DOI] [PubMed] [Google Scholar]
  41. Schleuning W. D., Medcalf R. L., Hession C., Rothenbühler R., Shaw A., Kruithof E. K. Plasminogen activator inhibitor 2: regulation of gene transcription during phorbol ester-mediated differentiation of U-937 human histiocytic lymphoma cells. Mol Cell Biol. 1987 Dec;7(12):4564–4567. doi: 10.1128/mcb.7.12.4564. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Schunkert H., Hense H. W., Holmer S. R., Stender M., Perz S., Keil U., Lorell B. H., Riegger G. A. Association between a deletion polymorphism of the angiotensin-converting-enzyme gene and left ventricular hypertrophy. N Engl J Med. 1994 Jun 9;330(23):1634–1638. doi: 10.1056/NEJM199406093302302. [DOI] [PubMed] [Google Scholar]
  43. Schunkert H., Ingelfinger J. R., Hirsch A. T., Tang S. S., Litwin S. E., Talsness C. E., Dzau V. J. Evidence for tissue-specific activation of renal angiotensinogen mRNA expression in chronic stable experimental heart failure. J Clin Invest. 1992 Oct;90(4):1523–1529. doi: 10.1172/JCI116020. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Simonson M. S., Herman W. H. Protein kinase C and protein tyrosine kinase activity contribute to mitogenic signaling by endothelin-1. Cross-talk between G protein-coupled receptors and pp60c-src. J Biol Chem. 1993 May 5;268(13):9347–9357. [PubMed] [Google Scholar]
  45. Taubman M. B., Berk B. C., Izumo S., Tsuda T., Alexander R. W., Nadal-Ginard B. Angiotensin II induces c-fos mRNA in aortic smooth muscle. Role of Ca2+ mobilization and protein kinase C activation. J Biol Chem. 1989 Jan 5;264(1):526–530. [PubMed] [Google Scholar]
  46. Taubman M. B., Marmur J. D., Rosenfield C. L., Guha A., Nichtberger S., Nemerson Y. Agonist-mediated tissue factor expression in cultured vascular smooth muscle cells. Role of Ca2+ mobilization and protein kinase C activation. J Clin Invest. 1993 Feb;91(2):547–552. doi: 10.1172/JCI116234. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Timmermans P. B., Wong P. C., Chiu A. T., Herblin W. F., Benfield P., Carini D. J., Lee R. J., Wexler R. R., Saye J. A., Smith R. D. Angiotensin II receptors and angiotensin II receptor antagonists. Pharmacol Rev. 1993 Jun;45(2):205–251. [PubMed] [Google Scholar]
  48. Toullec D., Pianetti P., Coste H., Bellevergue P., Grand-Perret T., Ajakane M., Baudet V., Boissin P., Boursier E., Loriolle F. The bisindolylmaleimide GF 109203X is a potent and selective inhibitor of protein kinase C. J Biol Chem. 1991 Aug 25;266(24):15771–15781. [PubMed] [Google Scholar]
  49. Ullian M. E., Linas S. L. Angiotensin II surface receptor coupling to inositol trisphosphate formation in vascular smooth muscle cells. J Biol Chem. 1990 Jan 5;265(1):195–200. [PubMed] [Google Scholar]
  50. Vassalli J. D., Sappino A. P., Belin D. The plasminogen activator/plasmin system. J Clin Invest. 1991 Oct;88(4):1067–1072. doi: 10.1172/JCI115405. [DOI] [PMC free article] [PubMed] [Google Scholar]
  51. Yang S. G., Saifeddine M., Laniyonu A., Hollenberg M. D. Distinct signal transduction pathways for angiotensin-II in guinea pig gastric smooth muscle: differential blockade by indomethacin and tyrosine kinase inhibitors. J Pharmacol Exp Ther. 1993 Feb;264(2):958–966. [PubMed] [Google Scholar]
  52. Yusuf S., Pepine C. J., Garces C., Pouleur H., Salem D., Kostis J., Benedict C., Rousseau M., Bourassa M., Pitt B. Effect of enalapril on myocardial infarction and unstable angina in patients with low ejection fractions. Lancet. 1992 Nov 14;340(8829):1173–1178. doi: 10.1016/0140-6736(92)92889-n. [DOI] [PubMed] [Google Scholar]

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