Targeted deletion of caspase-1 reduces early mortality and left ventricular dilatation following myocardial infarction.
Objective. - Mice with targeted deletion of caspase-1 (interleukin-1beta (IL-1beta)-converting enzyme) lack the active forms of IL-1beta and IL-18, two cytokines implicated in maladaptive ventricular remodeling following cardiac injury. We, therefore, investigated the extent of ventricular dilation in caspase-1-knockout (KO) mice. Methods and results. - Transthoracic echocardiography was performed at days 1, 4, and 9 following left anterior descending artery ligation in caspase-1-KO and wild-type (WT) control animals, including M-mode and short-axis imaging at both mid-papillary and apical levels. Although initial post-operative mortality was lower in KO than in WT animals (21.4% WT, 12.0% KO, P < 0.001), there was no difference in mortality between 24 h and 9 d (P = n.s.). Caspase-1 KOs exhibited significantly less mid-papillary ventricular dilatation at days 4 and 9 compared to day 1 post-myocardial infarction (MI) (P < 0.05). Caspase-1 KOs also had a marked (50%) reduction in the level of matrix metalloproteinase 3 (MMP-3), although no significant changes occurred in other MMPs or in tissue inhibitors of metalloproteinase 1 levels by immunoblot analysis. Although IL-beta plasma levels were not detectable, both IL-18 levels and the rate of apoptosis in remodeling, non-infarcted muscle were significantly higher in WT compared to caspase-1-KO animals.Conclusion. - Mice lacking caspase-1 exhibited both improved peri-infarct survival and a decreased rate of ventricular dilatation, possibly due in part to a decrease in MMP-3 activity, IL-18 production, and a reduction in the rate of apoptosis after experimental MI.
Frantz
Stefan
S
Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, MA 02115, Boston, USA. S.frantz@mail.uni-uerzburg.de
Ducharme
Anique
A
Sawyer
Douglas
D
Rohde
Luis E
LE
Kobzik
Lester
L
Fukazawa
Ryuji
R
Tracey
Daniel
D
Allen
Hamish
H
Lee
Richard T
RT
Kelly
Ralph A
RA
D000818:Animals; D017209:Apoptosis; D006690:Bisbenzimidazole / Q000494:pharmacology; D015152:Blotting, Northern; D015153:Blotting, Western; D020170:Caspase 1 / Q000235:genetics*; D003094:Collagen / Q000378:metabolism; D004396:Coloring Agents / Q000494:pharmacology; D004452:Echocardiography; D004797:Enzyme-Linked Immunosorbent Assay; D017353:Gene Deletion; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D007375:Interleukin-1 / Q000235:genetics; D020382:Interleukin-18 / Q000235:genetics; D020781:Matrix Metalloproteinase 1 / Q000235:genetics; D019278:Matrix Metalloproteinase 3 / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D016297:Mutagenesis, Site-Directed; D009203:Myocardial Infarction / Q000235:genetics / Q000473:pathology*; D009206:Myocardium / Q000166:cytology; D013997:Time Factors; D016277:Ventricular Function, Left
D004396:Coloring Agents; D007375:Interleukin-1; D020382:Interleukin-18; D003094:Collagen; D020170:Caspase 1; D019278:Matrix Metalloproteinase 3; D020781:Matrix Metalloproteinase 1; D006690:Bisbenzimidazole