Skip to main content
SpringerLink
Log in

Effects of Olmesartan, an Angiotensin II Receptor Blocker, on Mechanically-Modulated Genes in Cardiac Myocytes

  • Published:
Cardiovascular Drugs and Therapy Aims and scope Submit manuscript

Abstract

Background: Angiotensin II plays an important role in cardiac hypertrophy or remodeling. Angiotensin II receptor blockers (ARB) are clinically useful for the treatment of hypertension and heart failure. However, the molecular effects of ARB in the mechanically-stressed myocardium have not been completely defined. We investigated the effects of ARB on mechanically-modulated genes in cardiac myocytes.

Methods: We used powerful DNA microarray technology to study the effects of the ARB, CS-886 (olmesartan), on genes modulated in neonatal rat cardiac myocytes using mechanical stimuli. Mechanical deformation was applied to a thin and transparent membrane on which neonatal rat cardiac myocytes were cultured in the presence or absence of RNH-6270, an active metabolite of CS-886. Expression profiles of 8000 rat genes using the Affymetrix GeneChip (Rat Genome U34A) were investigated with mRNA obtained from the samples above.

Results: Nine genes induced under 4% mechanical strain were significantly suppressed by RNH-6270 in rat cardiac myocytes: monoamine oxidase B, neuromedine B receptor, olfactory receptor, synaptotagmin XI, retinol-binding protein, and 4 expressed sequence tags (ESTs). In contrast, 21 genes suppressed under mechanical strain were significantly restored by RNH-6270: major acute phase alpha 1-protein, Sp-1, Bcl-Xalpha, JAK2, 2 genes encoding detoxification, few genes for receptor, structure, metabolism or ion channel, and 10 ESTs.

Conclusions: As some of these genes may be involved in promoting or modulating cardiac remodeling, these findings suggest that ARB may affect cardiovascular morbidity and mortality partially via these molecular alterations.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. The CONSENSUS Trial Study Group. Effects of enalapril on mortality in severe congestive heart failure. N Engl J Med 1987;316:1429-1435.

    Google Scholar 

  2. The SOLVD Investigators. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. N Engl J Med 1991;325:293-302.

    Google Scholar 

  3. Pfeffer MA, Braunwald E, Moye LA, et al. 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;327:669-677.

    Google Scholar 

  4. Israili ZH, Hall WD. Cough and angioneurotic edema associated with angiotensin-converting enzyme inhibitor therapy. A review of the literature and pathophysiology. Ann Intern Med 1992;117:234-242.

    Google Scholar 

  5. Goodfriend TL, Elliott ME, Catt KJ. Angiotensin receptors and their antagonists. N Engl J Med 1996;334:1649-1654.

    Google Scholar 

  6. Cohn JN, Tognoni G; Valsartan Heart Failure Trial Investigators. A randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure. N Engl J Med 2001;345:1667-1675.

    Google Scholar 

  7. Yanagisawa H, Amemiya Y, Kanazaki T, et al. Nonpeptide angiotensin II receptor antagonists: synthesis, biological activities, and structure-activity relationships of imidazole-5-carboxylic acids bearing alkyl, alkenyl, and hydroxyalkyl substituents at the 4-position and their related compounds. J Med Chem 1996;39:323-338.

    Google Scholar 

  8. Mizuno M, Sada T, Ikeda M, et al. Pharmacology of CS-866, a novel nonpeptide angiotensin II receptor antagonist. Eur J Pharmacol 1995;285:181-188.

    Google Scholar 

  9. Iyer VR, Eisen MB, Ross DT, et al. The transcriptional program in the response of human fibroblasts to serum. Science 1999;283:83-87.

    Google Scholar 

  10. Stanton LW, Garrard LJ, Damm D, et al. Altered patterns of gene expression in response to myocardial infarction. Circ Res 2000;86:939-945.

    Google Scholar 

  11. Friddle CJ, Koga T, Rubin EM, Bristow J. Expression pro-filing reveals distinct sets of genes altered during induction and regression of cardiac hypertrophy. Proc Natl Acad Sci USA 2000;97:6745-6750.

    Google Scholar 

  12. Yang J, Moravec CS, Sussman MA, et al. Decreased SLIM1 expression and increased gelsolin expression in failing human hearts measured by high-density oligonucleotide arrays. Circulation 2000;102:3046-3052.

    Google Scholar 

  13. Springhorn JP, Claycomb WC. Preproenkephalin mRNA expression in developing rat heart and in cultured ventricular cardiac muscle cells. Biochem J 1989;258:73-78.

    Google Scholar 

  14. Cheng GC, Briggs WH, Gerson DS, et al. Mechanical strain tightly controls fibroblast growth factor-2 release from cultured human vascular smooth muscle cells. Circ Res 1997;80:28-36.

    Google Scholar 

  15. Lockhart DJ, Dong H, Byrne MC, et al. Expression monitoring by hybridization to high-density oligonucleotide arrays. Nat Biotechnol 1996;14:1675-1680.

    Google Scholar 

  16. Heid CA, Stevens J, Livak KJ, et al. Real time quantitative PCR. Genome Res 1996;6:986-994.

    Google Scholar 

  17. Kruse N, Pette M, Toyka K, et al. Quantification of cytokine mRNA expression by RT PCR in samples of previously frozen blood. J Immunol Methods 1997;210:195-203.

    Google Scholar 

  18. Lockhart DJ, Dong H, Byrne MC, et al. Expression monitoring by hybridization to high-density oligonucleotide arrays. Nat Biotechnol 1996;14:1675-1680.

    Google Scholar 

  19. Cole T, Inglis AS, Roxburgh CM, Howlett GJ, Schreiber G. Major acute phase alpha 1-protein of the rat is homologous to bovine kininogen and contains the sequence for bradykinin: its synthesis is regulated at the mRNA level. FEBS Lett 1985;182:57-61.

    Google Scholar 

  20. Minamino N, Kangawa K, Matsuo H. Neuromedin B: A novel bombesin-like peptide identified in porcine spinal cord. Biochem Biophy Res Commun 1983;114:541-548.

    Google Scholar 

  21. Cuttitta F, Carney DN, Mulshine J, et al. Bombesin-like peptides can function as autocrine growth factors in human small cell lung cancer. Nature 1985;316:823-825.

    Google Scholar 

  22. Moody TW, Jensen RT, Garcia L, Leyton J. Nonpeptide neuromedin B receptor antagonists inhibit the proliferation of C6 cells. Eur J Pharmacol 2000;409:133-142.

    Google Scholar 

  23. Snyder MJ, Mulder EP. Environmental endocrine disruption in decapod crustacean larvae: hormone titers, cytochrome P450, and stress protein responses to heptachlor exposure. Aquat Toxicol 2001;55:177-190.

    Google Scholar 

  24. Rodrigues-Lima F, Delomenie C, Goodfellow GH, Grant DM, Dupret JM. Homology modelling and structural analysis of human arylamine N-acetyltransferase NAT1: Evidence for the conservation of a cysteine protease catalytic domain and an active-site loop. Biochem J 2001;356:327-334.

    Google Scholar 

  25. Ling S, Deng G, Ives HE, et al. Estrogen inhibits mechanical strain-induced mitogenesis in human vascular smooth muscle cells via down-regulation of Sp-1. Cardiovasc Res 2001;50:108-114.

    Google Scholar 

  26. Pan J, Fukuda K, Saito M, et al. Mechanical stretch activates the JAK/STAT pathway in rat cardiomyocytes. Circ Res 1999;84:1127-1136.

    Google Scholar 

  27. Boise LH, Gonzalez-Garcia M, Postema CE, et al. bcl-x, a bcl-2-related gene that functions as a dominant regulator of apoptotic cell death. Cell 1993;74:597-608.

    Google Scholar 

  28. Shiraiwa N, Inohara N, Okada S, Yuzaki M, Shoji S, Ohta S. An additional form of rat Bcl-x, Bcl-xbeta, generated by an unspliced RNA, promotes apoptosis in promyeloid cells. J Biol Chem 1996;271:13258-13265.

    Google Scholar 

  29. Pitt B, Poole-Wilson PA, Segal R, et al. Effect of losartan compared with captopril on mortality in patients with symptomatic heart failure: Randomised trial-the Losartan Heart Failure Survival Study ELITE II. Lancet 2000;355:1582-1587.

    Google Scholar 

  30. Schwocho LR, Masonson HN. Pharmacokinetics of CS-866, a new angiotensin II receptor blocker, in healthy subjects. J Clin Pharmacol 2001;41:515-527.

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Cardiovascular Medicine, Jichi Medical School, Minamikawachi-Machi, Tochigi, Japan, 329-0498

    Ruri Ohki, Keiji Yamamoto, Shuichi Ueno, Uichi Ikeda & Kazuyuki Shimada

  2. Division of Functional Genomics, Jichi Medical School, Minamikawachi-Machi, Tochigi, Japan, 329-0498

    Hiroyuki Mano

Authors
  1. Ruri Ohki
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Keiji Yamamoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Shuichi Ueno
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hiroyuki Mano
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Uichi Ikeda
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Kazuyuki Shimada
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ohki, R., Yamamoto, K., Ueno, S. et al. Effects of Olmesartan, an Angiotensin II Receptor Blocker, on Mechanically-Modulated Genes in Cardiac Myocytes. Cardiovasc Drugs Ther 17, 231–236 (2003). https://doi.org/10.1023/A:1026120123461

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1026120123461

Search

Navigation