The prolonged production of
reactive oxygen species due to
ischemia-reperfusion (I/R) is a potential cause of the pathological remodeling that frequently precedes
heart failure. We tested the ability of a potent
dithiol antioxidant,
bucillamine, to protect against the long-term consequences of I/R injury in a murine model of
myocardial infarction. After transiently occluding the left anterior descending coronary artery for 30 min, saline or
bucillamine (10 microg/g body wt) was injected intravenously as a bolus within the first 5 min of reperfusion. The
antioxidant treatment continued with daily
subcutaneous injections for 4 wk. There were no differences in
infarct sizes between
bucillamine- and saline-treated animals. After 4 wk of reperfusion,
cardiac hypertrophy was decreased by
bucillamine treatment (ventricular weight-to-
body weight ratios: I/R + saline, 4.5 +/- 0.2 mg/g
vs. I/R +
bucillamine, 4.2 +/- 0.1 mg/g; means +/- SE; P < 0.05). Additionally, the hearts of
bucillamine-treated mice had improved contractile function (echocardiographic measurement of fractional shortening) relative to saline controls: I/R + saline, 32 +/- 3%, versus I/R +
bucillamine, 41 +/- 4% (P < 0.05). Finally, I/R-induced injury in the saline-treated mice was accompanied by a fetal pattern of gene expression determined by
ribonuclease protection assay that was consistent with pathological
cardiac hypertrophy and remodeling [increased
atrial natriuretic peptide,
beta-myosin heavy chain (MHC), skeletal
alpha-actin; decreased sarco(endo)plasmic reticulum
Ca2+ ATPase 2a, and alpha-MHC-to-beta-MHC ratio]. These changes in gene expression were significantly attenuated by
bucillamine. Therefore, treatment with a
dithiol antioxidant for 4 wk after I/R preserved ventricular function and prevented the abnormal pattern of gene expression associated with pathological cardiac remodeling.