Adrenoceptor blockade alters plasma gelatinase activity in patients with heart failure and MMP-9 promoter activity in a human cell line (ECV304).
This study assessed the effects of short-term adrenoceptor blockade on plasma matrix metalloproteinase (MMP) activity in patients with heart failure, and the ability of adrenoceptor stimulation to modulate matrix metalloproteinase-9 (MMP-9) promoter activity in vitro. Patients with heart failure received standard therapy or standard therapy plus carvedilol. Plasma MMP activity was determined by zymography and tissue inhibitor (TIMP-1) expression was measured by immunoblotting. MMP-9 promoter activity was assessed in transfected ECV304 cells following exposure to isoprenaline or phenylephrine in the absence or presence of either propranolol or prazosin. In patients with heart failure, carvedilol attenuated the increase in proMMP-9 activity observed at 4 and 12 weeks in non-beta-blocker-treated patients (44.0 +/- 4.9 AU versus 60.8 +/- 6.7 AU; P < 0.05). Although TIMP-1 expression was unaltered, the MMP-9:TIMP-1 ratio was lower in those receiving carvedilol at 4 and 12 weeks (0.54 +/- 0.07 versus 1.04 +/- 0.17; P < 0.05). Isoprenaline transiently increased MMP-9 promoter activity after 4 h exposure (80.6 +/- 14.8-fold; P < 0.001) before returning to baseline. The response to isoprenaline was prevented by propranolol (P < 0.01). Phenylephrine caused a biphasic increase in MMP-9 promoter activity, with the greatest increase occurring at 24 h (23 +/- 3.7-fold) compared to baseline. This response was unaffected by co-incubation with prazosin. In conclusion, treatment with a mixed alpha1/beta-adrenoceptor antagonist attenuates MMP activity and tips the degradative balance to a less degradative phenotype in heart failure patients. Furthermore, adrenoceptor stimulation increases MMP-9 promoter activity, which is inhibited by beta- but not alpha-adrenoceptor blockade. Therefore, mixed adrenoceptor blockade may reduce remodeling in heart failure as a direct consequence of a beta-adrenoceptor-mediated reduction in MMP-9 transcription.
Institute of Molecular Medicine, Trinity College Dublin, Dublin, Ireland.
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G
Song
M
M
Hennessy
Y L
YL
Zhao
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Q
Li
W D
WD
Han
Y
Y
Qi
W N
WN
Zhao
B
B
Silke
M
M
Barry
R
R
Doyle
J P
JP
Spiers
D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology*; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000368:Aged; D000369:Aged, 80 and over; D002227:Carbazoles / Q000494:pharmacology*; D000077261:Carvedilol; D002374:Catalase / Q000378:metabolism; D002460:Cell Line; D005260:Female; D018093:Gelatinases / Q000097:blood; D006333:Heart Failure / Q000378:metabolism*; D006801:Humans; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000235:genetics; D008875:Middle Aged; D011401:Promoter Regions, Genetic; D011412:Propanolamines / Q000494:pharmacology*; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000097:blood
D000317:Adrenergic alpha-Antagonists; D000319:Adrenergic beta-Antagonists; D002227:Carbazoles; D011412:Propanolamines; D019715:Tissue Inhibitor of Metalloproteinase-1; D000077261:Carvedilol; D002374:Catalase; D018093:Gelatinases; D020780:Matrix Metalloproteinase 9