Prolonged administration of a dithiol antioxidant protects against ventricular remodeling due to ischemia-reperfusion in mice

Am J Physiol Heart Circ Physiol. 2008 Sep;295(3):H1303-H1310. doi: 10.1152/ajpheart.01143.2007. Epub 2008 Aug 8.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antioxidants / pharmacology*
  • Body Weight / physiology
  • Cysteine / analogs & derivatives*
  • Cysteine / pharmacology
  • Cytokines / biosynthesis
  • Cytokines / genetics
  • Female
  • Fetus / metabolism
  • Gene Expression / drug effects
  • Heart Function Tests
  • Mice
  • Mice, Inbred C57BL
  • Myocardial Contraction / drug effects
  • Myocardial Infarction / pathology
  • Myocardial Reperfusion Injury / pathology*
  • Myocardium / metabolism
  • Nuclease Protection Assays
  • Organ Size / physiology
  • Pregnancy
  • Ventricular Dysfunction, Left / physiopathology
  • Ventricular Dysfunction, Left / prevention & control
  • Ventricular Remodeling / drug effects*

Substances

  • Antioxidants
  • Cytokines
  • Cysteine
  • bucillamine