Prolonged administration of a dithiol antioxidant protects against ventricular remodeling due to ischemia-reperfusion in mice.
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.
Ambler
S Kelly
SK
Division of Cardiology, University of Colorado Denver, Aurora, USA.
Hodges
Yvonne K
YK
Jones
Gayle M
GM
Long
Carlin S
CS
Horwitz
Lawrence D
LD
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D001835:Body Weight / Q000502:physiology; D003545:Cysteine / Q000031:analogs & derivatives* / Q000494:pharmacology; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D005260:Female; D005333:Fetus / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D006334:Heart Function Tests; D051379:Mice; D008810:Mice, Inbred C57BL; D009200:Myocardial Contraction / Q000187:drug effects; D009203:Myocardial Infarction / Q000473:pathology; D015428:Myocardial Reperfusion Injury / Q000473:pathology*; D009206:Myocardium / Q000378:metabolism; D023282:Nuclease Protection Assays; D009929:Organ Size / Q000502:physiology; D011247:Pregnancy; D018487:Ventricular Dysfunction, Left / Q000503:physiopathology / Q000517:prevention & control; D020257:Ventricular Remodeling / Q000187:drug effects*
D000975:Antioxidants; D016207:Cytokines; D003545:Cysteine; C026535:bucillamine