Skip to main content
PMC home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1995 Aug;96(2):1059–1065. doi: 10.1172/JCI118092

Natriuretic peptides inhibit angiotensin II-induced proliferation of rat cardiac fibroblasts by blocking endothelin-1 gene expression.

H Fujisaki 1, H Ito 1, Y Hirata 1, M Tanaka 1, M Hata 1, M Lin 1, S Adachi 1, H Akimoto 1, F Marumo 1, M Hiroe 1
PMCID: PMC185295  PMID: 7635942

Abstract

The present study was aimed to test the role of endothelin-1 (ET-1) as a possible autocrine/paracrine growth factor for cardiac fibroblasts, and to examine its interaction with cardiac natriuretic hormones. Expression of preproET-1 (ppET-1) mRNA by cultured cardiac fibroblasts from neonatal rats was demonstrated by Northern blot analysis using cDNA for rat ppET-1 as a probe. Angiotensin II (ANG II) and ET-1 transiently (30 min) increased steady-state ppET-1 mRNA levels in cardiac fibroblasts. Both ET-1 and ANG II significantly stimulated [3H] thymidine incorporation into cardiac fibroblasts, whose effects were dose-dependently inhibited by an ETA receptor antagonist (BQ123), BQ123 also inhibited both ET-1- and ANG II-induced ppET-1 mRNA expression. Both atrial and brain natriuretic peptides (ANP, BNP), which activate particulate guanylate cyclase, inhibited ppET-1 mRNA expression and [3H]thymidine incorporation stimulated by ANG II and ET-1. Sodium nitroprusside, a soluble guanylate cyclase activator, and 8-bromocyclic GMP, a membrane-permeable cGMP derivative, similarly inhibited ppET-1 mRNA expression and [3H]-thymidine incorporation. BNP was more potent than ANP to inhibit ANG II- and ET-1-stimulated DNA synthesis, whereas BNP and ANP were almost equipotent in stimulating cGMP generation in cardiac fibroblasts. Our data demonstrated that ANG II and ET-1 upregulate ET-1 gene expression in rat cardiac fibroblasts partly via cyclic GMP-dependent mechanism, and that natriuretic peptides inhibit ANG II-stimulated proliferation of cardiac fibroblasts, possibly by inhibiting ET-1 gene expression. Our data suggest the possible role of endogenous ET-1 as an autocrine/paracrine growth factor for cardiac fibroblasts and its close interaction with natriuretic peptides in the regulation of cardiac fibrosis.

Full text

PDF

Images in this article

1061Image
on p.1061
1061Image
on p.1061
1061Image
on p.1061
1062Image
on p.1062
1062Image
on p.1062
1062Image
on p.1062
1062Image
on p.1062

Selected References

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

  1. Aceto J. F., Baker K. M. [Sar1]angiotensin II receptor-mediated stimulation of protein synthesis in chick heart cells. Am J Physiol. 1990 Mar;258(3 Pt 2):H806–H813. doi: 10.1152/ajpheart.1990.258.3.H806. [DOI] [PubMed] [Google Scholar]
  2. Anversa P., Olivetti G., Melissari M., Loud A. V. Morphometric study of myocardial hypertrophy induced by abdominal aortic stenosis. Lab Invest. 1979 Mar;40(3):341–349. [PubMed] [Google Scholar]
  3. Baker K. M., Chernin M. I., Wixson S. K., Aceto J. F. Renin-angiotensin system involvement in pressure-overload cardiac hypertrophy in rats. Am J Physiol. 1990 Aug;259(2 Pt 2):H324–H332. doi: 10.1152/ajpheart.1990.259.2.H324. [DOI] [PubMed] [Google Scholar]
  4. Brilla C. G., Janicki J. S., Weber K. T. Cardioreparative effects of lisinopril in rats with genetic hypertension and left ventricular hypertrophy. Circulation. 1991 May;83(5):1771–1779. doi: 10.1161/01.cir.83.5.1771. [DOI] [PubMed] [Google Scholar]
  5. Bühler F. R., Amstein R., Fetkovska N. Serotonin and preactivated platelets in essential hypertension. J Cardiovasc Pharmacol. 1987;10 (Suppl 3):S32–S34. [PubMed] [Google Scholar]
  6. Chirgwin J. M., Przybyla A. E., MacDonald R. J., Rutter W. J. Isolation of biologically active ribonucleic acid from sources enriched in ribonuclease. Biochemistry. 1979 Nov 27;18(24):5294–5299. doi: 10.1021/bi00591a005. [DOI] [PubMed] [Google Scholar]
  7. Dostal D. E., Baker K. M. Angiotensin II stimulation of left ventricular hypertrophy in adult rat heart. Mediation by the AT1 receptor. Am J Hypertens. 1992 May;5(5 Pt 1):276–280. doi: 10.1093/ajh/5.5.276. [DOI] [PubMed] [Google Scholar]
  8. Emori T., Hirata Y., Imai T., Eguchi S., Kanno K., Marumo F. Cellular mechanism of natriuretic peptides-induced inhibition of endothelin-1 biosynthesis in rat endothelial cells. Endocrinology. 1993 Dec;133(6):2474–2480. doi: 10.1210/endo.133.6.8243267. [DOI] [PubMed] [Google Scholar]
  9. Feinberg A. P., Vogelstein B. A technique for radiolabeling DNA restriction endonuclease fragments to high specific activity. Anal Biochem. 1983 Jul 1;132(1):6–13. doi: 10.1016/0003-2697(83)90418-9. [DOI] [PubMed] [Google Scholar]
  10. Frank J. S., Langer G. A. The myocardial interstitium: its structure and its role in ionic exchange. J Cell Biol. 1974 Mar;60(3):586–601. doi: 10.1083/jcb.60.3.586. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Hahn A. W., Resink T. J., Scott-Burden T., Powell J., Dohi Y., Bühler F. R. Stimulation of endothelin mRNA and secretion in rat vascular smooth muscle cells: a novel autocrine function. Cell Regul. 1990 Aug;1(9):649–659. doi: 10.1091/mbc.1.9.649. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Hirata Y., Tomita M., Takata S., Inoue I. Specific binding sites for atrial natriuretic peptide (ANP) in cultured mesenchymal nonmyocardial cells from rat heart. Biochem Biophys Res Commun. 1985 Aug 30;131(1):222–229. doi: 10.1016/0006-291x(85)91792-9. [DOI] [PubMed] [Google Scholar]
  13. Hirata Y., Yoshimi H., Takaichi S., Yanagisawa M., Masaki T. Binding and receptor down-regulation of a novel vasoconstrictor endothelin in cultured rat vascular smooth muscle cells. FEBS Lett. 1988 Oct 24;239(1):13–17. doi: 10.1016/0014-5793(88)80536-2. [DOI] [PubMed] [Google Scholar]
  14. Hisa H., Tomura Y., Yamagata T., Satoh S. Atrial natriuretic peptide suppresses renal vasoconstriction induced by angiotensin II and norepinephrine in dogs. Eur J Pharmacol. 1992 Nov 10;222(2-3):265–271. doi: 10.1016/0014-2999(92)90865-2. [DOI] [PubMed] [Google Scholar]
  15. Ihara M., Noguchi K., Saeki T., Fukuroda T., Tsuchida S., Kimura S., Fukami T., Ishikawa K., Nishikibe M., Yano M. Biological profiles of highly potent novel endothelin antagonists selective for the ETA receptor. Life Sci. 1992;50(4):247–255. doi: 10.1016/0024-3205(92)90331-i. [DOI] [PubMed] [Google Scholar]
  16. Inoue A., Yanagisawa M., Takuwa Y., Mitsui Y., Kobayashi M., Masaki T. The human preproendothelin-1 gene. Complete nucleotide sequence and regulation of expression. J Biol Chem. 1989 Sep 5;264(25):14954–14959. [PubMed] [Google Scholar]
  17. 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]
  18. Ito H., Hirata Y., Hiroe M., Tsujino M., Adachi S., Takamoto T., Nitta M., Taniguchi K., Marumo F. Endothelin-1 induces hypertrophy with enhanced expression of muscle-specific genes in cultured neonatal rat cardiomyocytes. Circ Res. 1991 Jul;69(1):209–215. doi: 10.1161/01.res.69.1.209. [DOI] [PubMed] [Google Scholar]
  19. Ito H., Hiroe M., Hirata Y., Tsujino M., Adachi S., Shichiri M., Koike A., Nogami A., Marumo F. Insulin-like growth factor-I induces hypertrophy with enhanced expression of muscle specific genes in cultured rat cardiomyocytes. Circulation. 1993 May;87(5):1715–1721. doi: 10.1161/01.cir.87.5.1715. [DOI] [PubMed] [Google Scholar]
  20. Itoh H., Pratt R. E., Ohno M., Dzau V. J. Atrial natriuretic polypeptide as a novel antigrowth factor of endothelial cells. Hypertension. 1992 Jun;19(6 Pt 2):758–761. doi: 10.1161/01.hyp.19.6.758. [DOI] [PubMed] [Google Scholar]
  21. Jalil J. E., Doering C. W., Janicki J. S., Pick R., Shroff S. G., Weber K. T. Fibrillar collagen and myocardial stiffness in the intact hypertrophied rat left ventricle. Circ Res. 1989 Jun;64(6):1041–1050. doi: 10.1161/01.res.64.6.1041. [DOI] [PubMed] [Google Scholar]
  22. Koller K. J., Goeddel D. V. Molecular biology of the natriuretic peptides and their receptors. Circulation. 1992 Oct;86(4):1081–1088. doi: 10.1161/01.cir.86.4.1081. [DOI] [PubMed] [Google Scholar]
  23. Nunez D. J., Dickson M. C., Brown M. J. Natriuretic peptide receptor mRNAs in the rat and human heart. J Clin Invest. 1992 Nov;90(5):1966–1971. doi: 10.1172/JCI116075. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Sadoshima J., Xu Y., Slayter H. S., Izumo S. Autocrine release of angiotensin II mediates stretch-induced hypertrophy of cardiac myocytes in vitro. Cell. 1993 Dec 3;75(5):977–984. doi: 10.1016/0092-8674(93)90541-w. [DOI] [PubMed] [Google Scholar]
  25. Schorb W., Booz G. W., Dostal D. E., Conrad K. M., Chang K. C., Baker K. M. Angiotensin II is mitogenic in neonatal rat cardiac fibroblasts. Circ Res. 1993 Jun;72(6):1245–1254. doi: 10.1161/01.res.72.6.1245. [DOI] [PubMed] [Google Scholar]
  26. Shubeita H. E., McDonough P. M., Harris A. N., Knowlton K. U., Glembotski C. C., Brown J. H., Chien K. R. Endothelin induction of inositol phospholipid hydrolysis, sarcomere assembly, and cardiac gene expression in ventricular myocytes. A paracrine mechanism for myocardial cell hypertrophy. J Biol Chem. 1990 Nov 25;265(33):20555–20562. [PubMed] [Google Scholar]
  27. Sugimoto T., Kikkawa R., Haneda M., Shigeta Y. Atrial natriuretic peptide inhibits endothelin-1-induced activation of mitogen-activated protein kinase in cultured rat mesangial cells. Biochem Biophys Res Commun. 1993 Aug 31;195(1):72–78. doi: 10.1006/bbrc.1993.2011. [DOI] [PubMed] [Google Scholar]
  28. Suzuki T., Hoshi H., Mitsui Y. Endothelin stimulates hypertrophy and contractility of neonatal rat cardiac myocytes in a serum-free medium. FEBS Lett. 1990 Jul 30;268(1):149–151. doi: 10.1016/0014-5793(90)80995-u. [DOI] [PubMed] [Google Scholar]
  29. Villarreal F. J., Kim N. N., Ungab G. D., Printz M. P., Dillmann W. H. Identification of functional angiotensin II receptors on rat cardiac fibroblasts. Circulation. 1993 Dec;88(6):2849–2861. doi: 10.1161/01.cir.88.6.2849. [DOI] [PubMed] [Google Scholar]
  30. Weber K. T., Brilla C. G. Pathological hypertrophy and cardiac interstitium. Fibrosis and renin-angiotensin-aldosterone system. Circulation. 1991 Jun;83(6):1849–1865. doi: 10.1161/01.cir.83.6.1849. [DOI] [PubMed] [Google Scholar]
  31. Yanagisawa M., Kurihara H., Kimura S., Tomobe Y., Kobayashi M., Mitsui Y., Yazaki Y., Goto K., Masaki T. A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature. 1988 Mar 31;332(6163):411–415. doi: 10.1038/332411a0. [DOI] [PubMed] [Google Scholar]
  32. Zak R. Cell proliferation during cardiac growth. Am J Cardiol. 1973 Feb;31(2):211–219. doi: 10.1016/0002-9149(73)91034-5. [DOI] [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES