Cardiovascular Drugs and Therapy

, Volume 21, Issue 6, pp 415–422 | Cite as

Effect of Long-term Monotherapy with the Aldosterone Receptor Blocker Eplerenone on Cytoskeletal Proteins and Matrix Metalloproteinases in Dogs with Heart Failure

  • Sharad Rastogi
  • Sudhish Mishra
  • Valerio Zacà
  • Issa Alesh
  • Ramesh C. Gupta
  • Sidney Goldstein
  • Hani N. Sabbah
Article

Abstract

Purpose

Long-term monotherapy with the aldosterone receptor blocker eplerenone in dogs with HF was previously shown to improve LV systolic and diastolic function. This study examined the effects of long-term monotherapy with the aldosterone receptor blocker eplerenone on mRNA and protein expression of the cytoskeletal proteins titin, tubulin, fibronectin and vimentin, the matrix metalloproteinases (MMPs)-1, -2 and -9, and the tissue inhibitors of MMPs (TIMPs)-1 and -2 in left ventricular (LV) myocardium of dogs with heart failure (HF).

Methods

HF was produced in 12 dogs by intracoronary microembolizations. Dogs were randomized to 3 months oral therapy with eplerenone (10 mg/kg twice daily, n = 6) or to no therapy at all (HF-control, n = 6). LV tissue from six normal dogs was used for comparison. mRNA expression was measured using reverse-transcriptase polymerase chain reaction (RT-PCR) and protein expression using Western blots.

Results

Compared to NL dogs, control dogs showed upregulation of mRNA and protein expression for tubulin, fibronectin, MMP-1, -2 and -9, and down-regulation of mRNA and protein expression for total titin. Normalization of mRNA and protein expression for all these genes was seen after treatment with eplerenone. N2BA/N2B-titin mRNA expression ratio increased significantly in dogs with HF treated with eplerenone. No differences in expression for vimentin, TIMP-1 and -2 were observed among groups.

Conclusions

In dogs with HF, long-term eplerenone therapy normalizes mRNA and protein expression of key cytoskeletal proteins and MMPs. Reversal of these molecular maladaptations may partly explain the improvement in LV diastolic function seen after long-term therapy with eplerenone.

Key words

titin heart failure cytoskeletal proteins reverse remodeling 

Notes

Acknowledgments

This study was supported, in part, by grants from the National Heart, Lung, and Blood Institute PO1 HL074237-04.

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Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  • Sharad Rastogi
    • 1
  • Sudhish Mishra
    • 1
  • Valerio Zacà
    • 1
  • Issa Alesh
    • 1
  • Ramesh C. Gupta
    • 1
  • Sidney Goldstein
    • 1
  • Hani N. Sabbah
    • 1
    • 2
  1. 1.Department of Medicine, Division of Cardiovascular MedicineHenry Ford Health SystemDetroitUSA
  2. 2.Cardiovascular ResearchHenry Ford HospitalDetroitUSA

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