METHODS AND RESULTS: Left ventricular (LV) structure, function, apoptosis,
fibrosis, and
protein levels of apoptosis- and
fibrosis-related
proteins were examined in wild-type (WT) and ATM heterozygous knockout (hKO) mice 7 days post-MI.
Infarct sizes were similar in both MI groups. However,
infarct thickness was higher in hKO-MI group. Two dimensional M-mode echocardiography revealed decreased percent fractional shortening (%FS) and ejection fraction (EF) in both MI groups when compared to their respective
sham groups. However, the decrease in %FS and EF was significantly greater in WT-MI vs hKO-MI. LV end systolic and diastolic diameters were greater in WT-MI vs hKO-MI.
Fibrosis, apoptosis, and α-smooth muscle actin staining was significantly higher in hKO-MI vs WT-MI. MMP-2
protein levels and activity were increased to a similar extent in the
infarct regions of both groups. MMP-9
protein levels were increased in the non-
infarct region of WT-MI vs WT-
sham. MMP-9
protein levels and activity were significantly lower in the
infarct region of WT vs hKO.
TIMP-2 protein levels similarly increased in both MI groups, whereas TIMP-4
protein levels were significantly lower in the
infarct region of hKO group. Phosphorylation of p53
protein was higher, while
protein levels of
manganese superoxide dismutase were significantly lower in the
infarct region of hKO vs WT. In vitro, inhibition of ATM using
KU-55933 increased oxidative stress and apoptosis in cardiac myocytes.