TNF-alpha and myocardial matrix metalloproteinases in heart failure: relationship to LV remodeling.
The cytokine tumor necrosis factor (TNF)-alpha has been causally linked to left ventricular (LV) remodeling, but the molecular basis for this effect is unknown. Matrix metalloproteinases (MMPs) have been implicated in cardiac remodeling and can be regulated by TNF-alpha. This study tested the central hypothesis that administration of a TNF-alpha blocking protein would prevent the induction of MMPs and alter the course of myocardial remodeling in developing LV failure. Adult dogs were randomly assigned to the following groups: 1) chronic pacing (250 beats/min, 28 days, n = 12), 2) chronic pacing with concomitant administration of a TNF-alpha blocking protein (TNF block) using a soluble p75 TNF receptor fusion protein (TNFR:Fc; administered at 0.5 mg/kg twice a week subcutaneously, n = 7), and 3) normal controls (n = 10). LV end-diastolic volume increased from control with chronic pacing (83 +/- 12 vs. 118 +/- 10 ml, P < 0.05) and was reduced with TNF block (97 +/- 9 ml, P < 0.05). MMP zymographic levels (92 kDa, pixels) increased from control with chronic pacing (36,848 +/- 9,593 vs. 87,247 +/- 12,912, P < 0.05) and was normalized by TNF block. Myocardial MMP-9 and MMP-13 levels by immunoblot increased with chronic pacing relative to controls (130 +/- 10% and 118 +/- 6%, P < 0.05) and was normalized by TNF block. These results provide evidence to suggest that TNF-alpha contributes to the myocardial remodeling process in evolving heart failure through the local induction of specific MMPs.
Bradham
William S
WS
Medical University of South Carolina, Charleston, South Carolina 29425, USA.
Moe
Gordon
G
Wendt
Katherine A
KA
Scott
Amelia A
AA
Konig
Andrea
A
Romanova
Marina
M
Naik
George
G
Spinale
Francis G
FG
D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D004195:Disease Models, Animal; D004285:Dogs; D006333:Heart Failure / Q000503:physiopathology*; D006339:Heart Rate / Q000502:physiology; D007527:Isoenzymes / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020784:Matrix Metalloproteinase 8 / Q000378:metabolism; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D009206:Myocardium / Q000201:enzymology; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism; D019714:Tissue Inhibitor of Metalloproteinases / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000502:physiology*; D016277:Ventricular Function, Left / Q000502:physiology*; D000097792:Tissue Inhibitor of Metalloproteinase-4
D000906:Antibodies; D007527:Isoenzymes; D020778:Matrix Metalloproteinase 2; D020784:Matrix Metalloproteinase 8; D020782:Matrix Metalloproteinases; D019715:Tissue Inhibitor of Metalloproteinase-1; D019714:Tissue Inhibitor of Metalloproteinases; D014409:Tumor Necrosis Factor-alpha; D000097792:Tissue Inhibitor of Metalloproteinase-4