Targeted deletion of p53 prevents cardiac rupture after myocardial infarction in mice

doi:10.1016/j.cardiores.2006.02.001

Cardiovascular Research 2006 70(3):457-465; doi:10.1016/j.cardiores.2006.02.001

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Targeted deletion of p53 prevents cardiac rupture after myocardial infarction in mice

Hidenori Matsusaka^a, Tomomi Ide^a, Shouji Matsushima^a, Masaki Ikeuchi^a, Toru Kubota^a, Kenji Sunagawa^a, Shintaro Kinugawa^b and Hiroyuki Tsutsui^b^,*

^aDepartment of Cardiovascular Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
^bDepartment of Cardiovascular Medicine, Hokkaido University Graduate School of Medicine, Kita-15, Nishi-7, Kita-ku, Sapporo 060-8638, Japan

^* Corresponding author. Tel.: +81 11 706 6970; fax: +81 11 706 7874. Email address: htsutsui{at}med.hokudai.ac.jp

Objective Apoptosis may play an important role in cardiac remodelingafter myocardial infarction (MI). p53 is a well-known proapoptoticfactor. However, its pathophysiological significance in theseconditions remains unclear. We thus examined the effects oftarget 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 bettersurvival rate than p53^+/+ mice (89% vs. 69%, P<0.05). Notably,p53^{+/ –} mice had a significantly lower incidence of leftventricular (LV) rupture (7% vs. 28%, P<0.05) despite comparableinfarct size (60±2% vs. 59±2%, P=NS), heart rate(488±15 vs. 489±17 bpm, P=NS), or mean arterialblood pressure (80±2 vs. 78±3 mm Hg, P=NS). Theextent of infiltrating interstitial cells including macrophagesinto the post-MI hearts was not altered by the deletion of p53.Further, collagen deposition as well as the zymographic MMP-2and -9 activities were comparable between p53^{+/ –} andp53^+/+ mice with MI. However, the p53^{+/ –} mice had a significantlythicker infarct wall. The number of TUNEL-positive cells inthe infarct area was significantly lower in p53^{+/ –} micethan in p53^+/+ mice (423±86 vs. 1330±275/10⁵ cells,P<0.01).

Conclusions p53 is involved in cardiac rupture after MI, probablyvia the induction of a proapoptotic pathway. The inhibitionof p53 may be a potentially useful therapeutic strategy to managepost-MI patients.

KEYWORDS Apoptosis; Extracellular matrix; Infarction; Myocytes; Remodeling

Time for primary review 43 days

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