Haptoglobin genotype is a determinant of survival and cardiac remodeling after myocardial infarction in diabetic mice.
BACKGROUND
We have recently demonstrated in man that a functional allelic polymorphism in the Haptoglobin (Hp) gene plays a major role in determining survival and congestive heart failure after myocardial infarction (MI). We sought to recapitulate the effect of Hp type on outcomes and cardiac remodeling after MI in transgenic mice.


METHODS
The Hp 2 allele exists only in man. Wild type C57Bl/6 mice carry the Hp 1 allele with high homology to the human Hp 1 allele. We genetically engineered a murine Hp 2 allele and targeted its insertion by homologous recombination to the murine Hp locus to create Hp 2 mice. Diabetes Mellitus (DM) was induced with streptozotocin. MI was produced by occlusion of the left anterior descending artery in DM C57Bl/6 mice carrying the Hp 1 or Hp 2 allele. MI size was determined with TTC staining. Left ventricular (LV) function and dimensions were assessed by 2-dimensional echocardiography.


RESULTS
In the absence of DM, Hp 1-1 and Hp 2-2 mice had similar LV dimensions and LV function. MI size was similar in DM Hp 1-1 and 2-2 mice 24 hours after MI (50.2 +/- 2.1%and 46.9 +/- 5.5%, respectively, p = 0.6). However, DM Hp 1-1 mice had a significantly lower mortality rate than DM Hp 2-2 mice 30 days after MI (HR 0.41, 95% CI (0.19-0.95), p = 0.037 by log rank). LV chamber dimensions were significantly increased in DM Hp 2-2 mice compared to DM Hp 1-1 mice 30 days after MI (0.196 +/- 0.01 cm2 vs. 0.163 +/- 0.01 cm2, respectively; p = 0.029).


CONCLUSIONS
In DM mice the Hp 2-2 genotype is associated with increased mortality and more severe cardiac remodeling 30 days after MI.
Asaf
Roy
R
Department of Anatomy and Cell Biology, Rappaport Faculty of Medicine, Technion Israel Institute of Technology, Haifa, Israel. royasaf@tx.technion.ac.il
Blum
Shany
S
Roguin
Ariel
A
Kalet-Litman
Shiri
S
Kheir
Jad
J
Frisch
Avi
A
Miller-Lotan
Rachel
R
Levy
Andrew P
AP
D000483:Alleles; D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000235:genetics*; D004195:Disease Models, Animal; D005838:Genotype; D006242:Haptoglobins / Q000235:genetics*; D006333:Heart Failure / Q000209:etiology / Q000235:genetics; D006352:Heart Ventricles / Q000473:pathology; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009203:Myocardial Infarction / Q000150:complications / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D018487:Ventricular Dysfunction, Left / Q000235:genetics
D006242:Haptoglobins