Targeted deletion of p53 prevents cardiac rupture after myocardial infarction in mice.
OBJECTIVE
Apoptosis may play an important role in cardiac remodeling after myocardial infarction (MI). p53 is a well-known proapoptotic factor. However, its pathophysiological significance in these conditions remains unclear. We thus examined the effects of target deletion of the p53 gene on post-MI hearts.


METHODS
Anterior MI was created in male heterozygous p53-deficient (p53(+/-); n = 28) mice and sibling wild-type (p53(+/+); n = 29) mice by ligating the left coronary artery.


RESULTS
By day 7, p53(+/-) mice had significantly better survival rate than p53(+/+) mice (89% vs. 69%, P < 0.05). Notably, p53(+/-) mice had a significantly lower incidence of left ventricular (LV) rupture (7% vs. 28%, P < 0.05) despite comparable infarct size (60 +/- 2% vs. 59 +/- 2%, P = NS), heart rate (488 +/- 15 vs. 489 +/- 17 bpm, P = NS), or mean arterial blood pressure (80 +/- 2 vs. 78 +/- 3 mm Hg, P = NS). The extent of infiltrating interstitial cells including macrophages into the post-MI hearts was not altered by the deletion of p53. Further, collagen deposition as well as the zymographic MMP-2 and -9 activities were comparable between p53(+/-) and p53(+/+) mice with MI. However, the p53(+/-) mice had a significantly thicker infarct wall. The number of TUNEL-positive cells in the infarct area was significantly lower in p53(+/-) mice than in p53(+/+) mice (423+/-86 vs. 1330 +/- 275/10(5) cells, P < 0.01).


CONCLUSIONS
p53 is involved in cardiac rupture after MI, probably via the induction of a proapoptotic pathway. The inhibition of p53 may be a potentially useful therapeutic strategy to manage post-MI patients.
Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Hidenori
H
Matsusaka
Tomomi
T
Ide
Shouji
S
Matsushima
Masaki
M
Ikeuchi
Toru
T
Kubota
Kenji
K
Sunagawa
Shintaro
S
Kinugawa
Hiroyuki
H
Tsutsui
D000818:Animals; D017209:Apoptosis; D004452:Echocardiography; D005260:Female; D017353:Gene Deletion; D006342:Heart Rupture, Post-Infarction / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D006579:Heterozygote; D008297:Male; D020782:Matrix Metalloproteinases / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D023421:Models, Animal; D009203:Myocardial Infarction / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000503:physiopathology; D051058:Oncogene Protein v-akt / Q000378:metabolism; D013997:Time Factors; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism; D018487:Ventricular Dysfunction, Left / Q000000981:diagnostic imaging / Q000503:physiopathology; D020257:Ventricular Remodeling
D016159:Tumor Suppressor Protein p53; D051058:Oncogene Protein v-akt; D020782:Matrix Metalloproteinases