SR-BI and apo E knockout animals and use thereof as models for atherosclerosis and heart attack

Abstract

Transgenic animals that do not express functional SR-BI and ApoE develop severe atherosclerosis, by age four weeks in transgenic mice. Moreover, these animals exhibit progressive heart block by age four weeks, and die by age nine weeks. Pathology shows extensive fibrosis of the heart and occlusion of coronary arteries. The occlusion appears to be due to clotting, since fat deposition is in the walls. These animals are good models for the following diseases, and for screening of drugs useful in the treatment and/or prevention of these disorders: cardiac fibrosis, myocardial infarction, defects in electrical conductance, atherosclerosis, unstable plaque, and stroke. In contrast to other known models for atherosclerosis, these animals do not have to be fed extreme diets for long periods before developing atherosclerosis. No other known model for heart attacks and stroke is known.

We claim:  
     
         1 . A method for screening for compounds having an effect on disorders selected from the group consisting of cardiac fibrosis, myocardial infarction, defects in electrical conductance, atherosclerosis, unstable plaque, stroke and diseases associated with abnormal cardiac structure or function or elevated cholesterol or lipoprotein levels comprising administering the compound to an animal which is deficient in active SR-BI and apolipoprotein and determining the effect on the animals relative to control animals not treated with compound.  
     
     
         2 . The method of  claim 1  wherein the apolipoprotein is Apo E.  
     
     
         3 . The method of  claim 1  wherein the animal does not express SR-BI.  
     
     
         4 . The method of  claim 1  wherein the animal does not express active SR-BI.  
     
     
         5 . The method of  claim 2  wherein the animal is an SR-BI and Spo E knockout.  
     
     
         6 . The method of  claim 1  wherein the animal is a rodent.  
     
     
         7 . The method of  claim 6  wherein the animal is a mouse, rat, hamster or gerbil.  
     
     
         8 . The method of  claim 1  wherein the animal is treated with a compound which lowers the level of SR-BI.  
     
     
         9 . The method of  claim 1  wherein the animal is treated with a compound which lowers the level of apolipoprotein.  
     
     
         10 . The method of  claim 1  wherein the animals are screened for alterations in levels of cholesterol or lipoproteins.  
     
     
         11 . A transgenic animal which is deficient in active SR-BI and apolipoprotein.  
     
     
         12 . The animal of  claim 11  wherein the apolipoprotein is Apo E.  
     
     
         13 . The animal of  claim 11  which is a rodent.  
     
     
         14 . The animal of  claim 13  which is a mouse, rat, hamster or gerbil.  
     
     
         15 . The animal of  claim 11  wherein the animal is an SR-BI and Apo E knockout.