Advertisement

Critical role of farnesyltransferase inhibitor in protective myocardial function after endotoxemia in rat model

 
crossMark
doi: 10.18081/2333-5106/014-07/827-839
American Journal of BioMedicine Volume 2, Issue 7, pages 827-839
Published: July 26, 2014

Richard Durum; John F. Memon; Thomas N. Mackall; Catherine A. Mencacci; Ronald J. Venet; Kevin Deback; Terry H. Peterson; Michel Herndon

Abstract

Farnesyltransferase (FTase) is one of the three enzymes in the prenyltransferase group that catalyzes most prenylation reactions and has been proposed as one component of acute inflammation. Endotoxemia was induced in male Wistar rats weighing 300-340 g by lipopolysaccharide (LPS) injection (10 mg/kg BW IV rout via the rat tail vein). Hemodynamic evaluation was performed 4-6 h post-LPS injection by measuring left ventricular end-diastolic pressure, dP/dtmax and myocardial tissue was histologically assessed to analyze macrophage infiltration and cellular damage. Left ventricular function was significantly impaired in the LPS-treated rats, as demonstrated by dP/dtmax (5579±213 vs. 2929±246 mmHg, ctrl vs. LPS; P=0.002) and ejection fraction (61% vs. 23%, ctrl vs. LPS; P=0.0035). LPS was significantly correlated with prominent myocardial cell injury characterized by the increased plasma cardiac troponin-I (cTn-I) and upregulation of proinflammatory cytokines. Furthermore, rats pretreated with FTase inhibitor (Tipifarnib 15 mg/kg BW, IV rout via the rat tail vein) shortly before LPS administration improved myocardial function, dP/dtmax (2929±246 vs. 4125±126 mmHg, LPS vs. Tipifarnib; P<0.05) and ejection fraction (23% vs. 41%, LPS vs. Tipifarnib; P<0.05). The proinflammatory cytokines level, cTn-I level and macrophage accumulation are reduced after neutralized the LPS by FTase inhibitor P<0.05. These data suggest that FTase is a new potential molecular target to improved myocardial function in sepsis.

Keywords: Farnesyltransferase; Endotoxemia; Myocardial function; LPS; FTase inhibitorn

Copyright © 2014 by The American Society for BioMedicine and BM-Publisher, Inc.

Article citationReferencesFull-Text/PDFFeedback
The citation data is computed by the following citation measuring services:

Google scholarcitedby

References

1. Gao F, Linhartova L, Johnston AM, Thickett DR. Statins and sepsis. Br J Anaesth 2008;100:288–298. [PubMed]

2. Ando H, Takamura T, Ota T, Nagai Y, Kobayashi K. Cerivastatin improves survival of mice with lipopolysaccharide-induced sepsis. J Pharmacol Exp Ther 2000;294:1043–1046. [PubMed]

3. Ruocco A, Santillo M, Cicale M, et al. Farnesyl transferase inhibitors induce neuroprotection by inhibiting Ha-Ras signalling pathway. Eur J Neurosci 2007;26:3261–3266. [PubMed]

4. Aoshiba K, Onizawa S, Tsuji T, Nagai A. Therapeutic effects of erythropoietin in murine models of endotoxin shock. Crit Care Med 2009;37:889–898. [PubMed]

5. Efron PA, Tinsley K, Minnich DJ, et al. Increased lymphoid tissue apoptosis in baboons with bacteremic shock. Shock 2004;21:566–571. [PubMed]

6. Zeni F, Freeman B, Natanson C. Anti-inflammatory therapies to treat sepsis and septic shock: a reassessment. Crit Care Med 1997;25:1095–1100. [PubMed]

7. Yun Y; Zheng X; Chen L; Su Y; Kim CF; Zhao M. Expression of ATF3 in mouse protects the liver against sepsis via inhibiting HMGB expression. American Journal of BioMedicine  2014;2(3):337–349. [Abstract/Full-Text]

8. Felmet KA, Hall MW, Clark RS, Jaffe R, Carcillo JA. Prolonged lymphopenia, lymphoid depletion, and hypoprolactinemia in children with nosocomial sepsis and multiple organ failure. J Immunol 2005;174:3765–3772. [PubMed]

9. Cox AD, Der CJ. Farnesyltransferase inhibitors and cancer treatment: targeting simply Ras? Biochim Biophys Acta 1997;1333:F51–F71. [PubMed]

10. Cao P, Hanai J, Tanksale P, Imamura S, Sukhatme VP, Lecker SH. Statin-induced muscle damage and atrogin-1 induction is the result of a geranylgeranylation defect. FASEB J 2009;9:2844–2854. [PubMed]

11. Yang W, Yamada M, Tamura Y, Chang K, Mao J, Zou L, Feng Y, Kida K. Farnesyltransferase inhibitor FTI-277 reduces mortality of septic mice along with improved bacterial clearance. J Pharmacol Exp Ther 2011;339(3):832-41. [ PubMed ]

12. Almog Y, Shefer A, Novack V, et al. Prior statin therapy is associated with a decreased rate of severe sepsis. Circulation 2004;110:880–885. [Abstract/Full-Text]

13. Zhang R, Singh S, Ha X, et al. American Journal of BioMedicine 2014;2:80–93. [Abstract/Full-Text]

14. Mullen MJ, Wright D, Donald AE, Thorne S, Thomson H, Deanfield JE. Atorvastatin but not L-arginine improves endothelial function in type I diabetes mellitus: a double-blind study. J Am Coll Cardiol 2000;36:410–416. [Abstract/Full-Text]

15. Kleemann R, Princen HM, Emeis JJ, et al. Rosuvastatin reduces atherosclerosis development beyond and independent of its plasma cholesterol-lowering effect in APOE*3-Leiden transgenic mice: evidence for antiinflammatory effects of rosuvastatin. Circulation 2003;108:1368–1374. [Abstract/Full-Text]

16. Austin EW, Yousif NG, Ao L, Cleveland JC, Fullerton DA, Meng X. Ghrelin reduces myocardial injury following global ischemia and reperfusion via suppression of myocardial inflammatory response. American Journal of BioMedicine 2013;1:38-48. [Abstract/Full-Text]

17. George J, Afek A, Keren P, et al. Functional inhibition of Ras by S-trans, trans-farnesyl thiosalicylic acid attenuates atherosclerosis in apolipoprotein E knockout mice. Circulation 2002; 105: 2416–2422. [Abstract/Full-Text]

18. Yang W, Del Villar K, Urano J, Mitsuzawa H, Tamanoi F. Advances in the development of farnesyltransferase inhibitors: substrate recognition by protein farnesyltransferase. J Cell Biochem Suppl 1997; 27: 12–19. [Abstract/Full-Text]

19. Yousif NG. Novel therapeutic role of siglec-E in down-regulation TLR4-mediated inflammatory response after global myocardial ischemia and reperfusion. Cardiovascular research 2014;103:S90-S90. [Abstract/Full-Text]

20. Munier ML, Kelleher AD. Acutely dysregulated, chronically disabled by the enemy within: T-cell responses to HIV-1 infection. Immunol. Cell Biol 2007; 85:6–15. [PubMed]

21. Felmet KA, Hall MW, Clark RS, Jaffe R, Carcillo JA. Prolonged lymphopenia, lymphoid depletion, and hypoprolactinemia in children with nosocomial sepsis and multiple organ failure. J Immunol 2005;174:3765-72. [Abstract/Full-Text]

22. Hotchkiss RS,Tinsley KW, Swanson PE, et al. Sepsis-induced apoptosis causes progressive profound depletion of B and CD4+ T lymphocytes in humans. J Immunol 2001;166:6952-63. [Abstract/Full-Text]

23. Remick DG. Pathophysiology of sepsis. Am J Pathol 2007;170:1435-44. [PubMed]

24. Almog Y, Shefer A, Novack V, et al. Prior statin therapy is associated with a decreased rate of severe sepsis. Circulation 2004;110:880–885. [Abstract/Full-Text]

25.  Yousif NG,  Al-amran FG. Novel Toll-like receptor-4 deficiency attenuates trastuzumab (Herceptin) induced cardiac injury in mice. BMC cardiovascular disorders 2011;11(1):62. [Abstract/Full-Text]

26. Ayyadurai S, Lepidi H, Nappez C, Raoult D, Drancourt M. Lovastatin protects against experimental plague in mice. PLoS One 2010;5:e10928. [PubMed]

27. Kwak B, Mulhaupt F, Myit S, Mach F. Statins as a newly recognized type of immunomodulator. Nat Med 2000; 6:1399–1402. [PubMed]

28. Briegel J, Weis F, Kilger E. Anti-inflammatory therapy in sepsis. Chirurg 2003 ;74(6):590-1. [PubMed]

29. Müller-Werdan U, Buerke M, Werdan K. Progress in therapy of infection. Internist (Berl) 2003;44(12):1531-40. [PubMed]

30. Kasten KR, Prakash PS, Unsinger J, et al. Interleukin-7 (IL-7) treatment accelerates neutrophil recruitment through gamma delta T-cell IL-17 production in a murine model of sepsis. Infect Immun 2010;78:4714-22. [Abstract/Full-Text]

31. Unsinger J, Herndon JM, Davis CG, Muenzer JT, Hotchkiss RS, Ferguson TA. The role of TCR engagement and activation-induced cell death in sepsis-induced T cell apoptosis. J Immunol 2006;177:7968-73. [Abstract/Full-Text]

READ THE FULL ARTICLE

limited access

1. Access this article  through your login credentials or your institution

Get Access

2. Access this article through OpenAthens/Sign in

3. Purchase this article at rate $55.00 and received Full-Text/PDF
You will have online immediate access to article following the completion of this purchase and you may download and print a copy of each article for your personal use. Use the coding below to purchase your article as PDF by credit card, debit card, payball will be asked to supply your billing card information. Before continue with your purchase please read carefully the AJBM terms and conditions of purchase.

Purchase Article

 For any technique error please contact us and will be response to sending purchase article by email.

Thank you for visiting American Journal of BioMedicine.  * = Required fields

[gravityform id=”6″ name=”Feedback”]

American Journal of Biomedicine © 2017 Frontier Theme
%d bloggers like this: