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PRECLINICAL STUDY

Haptoglobin Genotype Determines Myocardial Infarct Size in Diabetic Mice

Shany Blum, MD, MSc^_*, Roy Asaf^_*, Julia Guetta, PhD^_*, Rachel Miller-Lotan, PhD^_*, Rabea Asleh, MSc^_*, Ran Kremer, MD^_*, Nina S. Levy, PhD^_*, Franklin G. Berger, MD, PhD, Doron Aronson, MD, Xiaoming Fu, PhD, Renliang Zhang, PhD, Stanley L. Hazen, MD, PhD and Andrew P. Levy, MD, PhD, FACC^_*,1,_*

^_* Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel
Department of Biological Sciences, University of South Carolina, Columbia, South Carolina
Department of Cardiology, Rambam Medical Center, Haifa, Israel
Department of Cardiovascular Medicine and Center for Cardiovascular Diagnostics and Prevention, Cleveland Clinic Foundation, Cleveland, Ohio.

Manuscript received June 5, 2006; revised manuscript received July 26, 2006, accepted August 8, 2006.

^_* Reprint requests and correspondence: Dr. Andrew P. Levy, Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel. (Email: alevy{at}tx.technion.ac.il).

This paper, presented in abstract form, was awarded first place in the young investigator award competition of the 2006 Scientific Session of the American College of Cardiology.

OBJECTIVES: We sought to understand the importance of oxidative stress in explaining why the haptoglobin (Hp) genotype determines myocardial infarction (MI) size in diabetes mellitus (DM).

BACKGROUND: Two common alleles (1 and 2) exist at the Hp locus in humans. The Hp 2 allele is associated with increased MI size in individuals with DM. In vitro, the Hp 2 protein is associated with increased generation of oxidatively active iron, whereas the Hp 1 protein is associated with increased production of the antioxidant cytokine interleukin (IL)-10.

METHODS: Myocardial infarction was produced by myocardial ischemia-reperfusion (IR) in DM C57BL/6 mice carrying the Hp 1 or Hp 2 allele. Myocardial oxidative stress after IR was assessed using electrospray ionization mass spectrometry. Redox active iron and IL-10 were measured in the serum after IR.

RESULTS: Myocardial infarction size was significantly larger in Hp 2 mice as compared with Hp 1 mice (44.3 ± 9.3% vs. 21.0 ± 4.0%, p = 0.03), and these larger infarctions were associated with a significant increase in a panel of hydroxyl-eicosatetraenoic acids. Redox active iron was greater in Hp 2 mice (0.45 ± 0.11 µmol/l vs. 0.14 ± 0.05 µmol/l, p = 0.02), whereas IL-10 was greater in Hp 1 mice (85.8 ± 12.9 pg/µl vs. 46.7 ± 10.8 pg/µl, p = 0.04) after IR. Administration of an antioxidant (BXT-51072) to Hp 2 mice reduced myocardial injury after IR by more than 80% (p = 0.003), but no myocardial protection was provided by the antioxidant to Hp 1 mice.

CONCLUSIONS: The increased MI size in DM Hp 2 mice occurring after IR may be due to increased oxidative stress.

Abbreviations and Acronyms   DM = diabetes mellitus   Hb = hemoglobin   Hp = haptoglobin   IA = infarct area   IL = interleukin   IR = ischemia-reperfusion   LAD = left anterior descending coronary artery   LPI = labile plasma iron   LV = left ventricle/ventricular   MI = myocardial infarction   RA = risk area

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