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Effect of long-term monotherapy with the aldosterone receptor blocker eplerenone on cytoskeletal proteins and matrix metalloproteinases in dogs with heart failure.
Cardiovasc Drugs Ther. 2007 Dec; 21(6):415-22.CD

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.

Authors+Show Affiliations

Department of Medicine, Division of Cardiovascular Medicine, Henry Ford Health System, Detroit, MI 48202, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

17940859

Citation

Rastogi, Sharad, et al. "Effect of Long-term Monotherapy With the Aldosterone Receptor Blocker Eplerenone On Cytoskeletal Proteins and Matrix Metalloproteinases in Dogs With Heart Failure." Cardiovascular Drugs and Therapy, vol. 21, no. 6, 2007, pp. 415-22.
Rastogi S, Mishra S, Zacà V, et al. Effect of long-term monotherapy with the aldosterone receptor blocker eplerenone on cytoskeletal proteins and matrix metalloproteinases in dogs with heart failure. Cardiovasc Drugs Ther. 2007;21(6):415-22.
Rastogi, S., Mishra, S., Zacà, V., Alesh, I., Gupta, R. C., Goldstein, S., & Sabbah, H. N. (2007). Effect of long-term monotherapy with the aldosterone receptor blocker eplerenone on cytoskeletal proteins and matrix metalloproteinases in dogs with heart failure. Cardiovascular Drugs and Therapy, 21(6), 415-22.
Rastogi S, et al. Effect of Long-term Monotherapy With the Aldosterone Receptor Blocker Eplerenone On Cytoskeletal Proteins and Matrix Metalloproteinases in Dogs With Heart Failure. Cardiovasc Drugs Ther. 2007;21(6):415-22. PubMed PMID: 17940859.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Effect of long-term monotherapy with the aldosterone receptor blocker eplerenone on cytoskeletal proteins and matrix metalloproteinases in dogs with heart failure. AU - Rastogi,Sharad, AU - Mishra,Sudhish, AU - Zacà,Valerio, AU - Alesh,Issa, AU - Gupta,Ramesh C, AU - Goldstein,Sidney, AU - Sabbah,Hani N, PY - 2007/10/18/pubmed PY - 2008/2/19/medline PY - 2007/10/18/entrez SP - 415 EP - 22 JF - Cardiovascular drugs and therapy JO - Cardiovasc Drugs Ther VL - 21 IS - 6 N2 - 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. SN - 0920-3206 UR - https://www.unboundmedicine.com/medline/citation/17940859/Effect_of_long_term_monotherapy_with_the_aldosterone_receptor_blocker_eplerenone_on_cytoskeletal_proteins_and_matrix_metalloproteinases_in_dogs_with_heart_failure_ L2 - https://doi.org/10.1007/s10557-007-6057-8 DB - PRIME DP - Unbound Medicine ER -