Effect of long-term monotherapy with the aldosterone receptor blocker eplerenone on cytoskeletal proteins and matrix metalloproteinases in dogs with heart failure.
OBJECTIVE
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.
Rastogi
Sharad
S
Department of Medicine, Division of Cardiovascular Medicine, Henry Ford Health System, Detroit, MI 48202, USA.
Mishra
Sudhish
S
Zacà
Valerio
V
Alesh
Issa
I
Gupta
Ramesh C
RC
Goldstein
Sidney
S
Sabbah
Hani N
HN
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use; D000818:Animals; D003598:Cytoskeletal Proteins / Q000235:genetics*; D004285:Dogs; D000077545:Eplerenone; D006333:Heart Failure / Q000188:drug therapy* / Q000378:metabolism; D020782:Matrix Metalloproteinases / Q000235:genetics; D000451:Mineralocorticoid Receptor Antagonists / Q000494:pharmacology*; D012333:RNA, Messenger / Q000032:analysis; D013148:Spironolactone / Q000031:analogs & derivatives* / Q000494:pharmacology; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000235:genetics
D000806:Angiotensin-Converting Enzyme Inhibitors; D003598:Cytoskeletal Proteins; D000451:Mineralocorticoid Receptor Antagonists; D012333:RNA, Messenger; D019715:Tissue Inhibitor of Metalloproteinase-1; D019716:Tissue Inhibitor of Metalloproteinase-2; D013148:Spironolactone; D000077545:Eplerenone; D020782:Matrix Metalloproteinases