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The Rappaport Institute looks forward to continuing to make substantial future contributions in biomedical research"

Professor Karl Skorecki

Haptoglobin Genotype Determines Myocardial Infarct Size in Diabetic Mice

14 March, 2007

The Rappaport Family Institute for Research in the Medical Sciences is happy to announce the publication of two papers co-authored by Prof. Andrew Levy and Dr. Shany Blum. The first paper, “Haptoglobin Genotype Determines Myocardial Infarct Size in Diabetic Mice” was published in the January 2007 issue (Vol 49, No.1, 2007) of  the Journal of the American College of Cardiology (JACC) and the second paper, “BXT-51072 and the prevention of myocardial ischemia-reperfusion injury” was published in the March 2007 Issue of Letters in Drug Design and Discovery (2007;4:160-162). Both papers detail the extensive research conducted by Prof. Levy and Dr. Blum, on the antioxidant, BXT-51072, a glutathione peroxidase (GPx) mimic and its ability to prevent myocardial ischemia-reperfusion injury in Hp 2 mice. Prof. Levy is also from the Technion Faculty of Medicine, Technion-Israel Institute of Technology, Haifa. 

The Hp 2 genotype is associated with an increased myocardial infarction size in diabetic (DM) mice and humans, when compared to the Hp 1 genotype. Therefore, the findings from their research are very exciting because they may lead to the development of improved treatment for diabetes related cardiovascular disease.

Oxidative stress increases in a setting of ischemia reperfusion in Hp 2, due to an increased production of hemoglobin (Hb) derived reactive oxygen species (ROS). This may then cause membrane lipid peroxidation and myocardial injury. Administration of  BXT blocks the membrane lipid peroxidation and has been shown to provide profound protection against myocardial injury due to ischemia and reperfusion in Hp 2 diabetic mice.

Oxidative stress is responsible for myocardial injury occurring after ischemia and reperfusion (IR). Oxidative stress has also been shown to be modulated by the Haptoglobin (Hp) genotype. BXT – 51072 provides protection against IR injury in an Hp genotype dependent fashion.  

Myocardial ischemia and reperfusion (IR) plays a major role in determining the extent of myocardial injury in acute coronary syndromes. IR generates highly reactive oxygen species (ROS) which can mediate myocardial damage, both directly, by promoting peroxidation of membrane phospholipids and indirectly, by promoting an exaggerated inflammatory reaction.(1)   Moreover, the dramatic increase in ROS associated with IR in individuals with diabetes mellitus, can account for the significantly greater number of infarctions that occur in this population.

Prof. Levy used BXT-51072 on mice to test his theory that a polymorphism in the Haptoglobin (Hp) gene can determine the amount of lipid peroxidation and myocardial injury in acute coronary syndromes, in both human diabetic patients and in diabetic transgenic mice. His research findings show  that reducing lipid peroxidation in this setting may limit myocardial injury. GPx was chosen because it is an intracellular enzyme that is expressed in all tissues. While the chief function of Hp is to protect against lipid peroxidation by extracorpuscular (free) hemoglobin (Hb), GPx is the primary mechanism used by red blood cells to protect the cell membrane from lipid peroxidation, by the extraordinarily high Hb concentrations found within the cell.

The level of GPx is known to decrease in a diabetic setting. In-vitro and in-vivo studies with BXT have shown that it is capable of protecting cells against ROS, catabolizing lipid peroxides, and inhibiting inflammation. 

Since the Hp 2 allele exists only in humans, mice were genetically modified by introducing the human Hp 2 allele as a transgene, causing them to change their status from Hp1 to Hp2. 

After myocardial IR was induced in the mice, a comparison of the two groups was made to test the effectiveness of administering the BXT-51072. They found that the administration of BXT to Hp 2 mice resulted in a greater than 80% reduction in myocardial injury. Myocardial protection was observed with doses as low as 0.5mg/kg. However, no beneficial effect from BXT was found in Hp 1 mice.

Discussion

While reperfusion after occlusion of a coronary artery is essential in order to restore the delivery of oxygen to the myocardium, it is well recognized that reactive oxygen species, generated during the reperfusion process, can induce a considerable amount of myocardial injury Despite the well recognized importance of oxidative stress in reperfusion injury, various antioxidant therapies have failed to show clinical benefit in reducing infarction size after ischemia and reperfusion.

Oxidative stress and myocardial injury are markedly increased in individuals and mice subjected to IR with the Hp 2 allele.   Accordingly, strategies designed to decrease oxidative stress in Hp 2 would be expected to reduce myocardial injury.  Administering the drug BXT-51072 shows the promise of providing dramatic myocardial protection for HP2 individuals.

Antioxidant therapy has failed to show a cardioprotective effect in multiple pre-clinical and clinical studies. Prof. Levy feels that his team’s findings suggest that a pharmacogenomic approach, whereby antioxidant therapy is dictated by the patient's Hp genotype, may be a clinically useful strategy that merits investigation.

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