Rosiglitazone (PPARgamma-agonist) attenuates atherogenesis with no effect on hyperglycaemia in a combined diabetes-atherosclerosis mouse model.
BACKGROUND
The administration of peroxisome proliferator-activated receptor gamma (PPARgamma) agonists to low-density lipoprotein (LDL)-receptor-deficient mice resulted in a reduction in the atherosclerotic lesion area in male mice, but not in female mice. The male mice also exhibited reduction in insulin resistance while the female mice did not. To further examine the relationship between PPARgamma agonists, insulin resistance and atherosclerosis, we used the model of accelerated atherosclerosis in male apolipoprotein E (apoE)-deficient mice rendered diabetic by low-dose streptozotocin (STZ).


METHODS
Male, apoE-deficient mice (n = 48) were randomly divided into four groups. To induce diabetes, two groups received low-dose STZ and two groups served as controls. After diabetes induction, rosiglitazone (a PPARgamma agonist) was administered by oral gavage to one of the diabetic and one of the non-diabetic groups.


RESULTS
Rosiglitazone reduced significantly the atherosclerotic aortic plaque area in both diabetic and non-diabetic apoE-deficient mice: 340 +/- 54 vs. 201 +/- 27 micromol2 (p = 0.001) in diabetic mice; 243 +/- 22 vs. 158 +/- 27 micromol2 (p = 0.001) in non-diabetic mice. Also, rosiglitazone reduced the correlation coefficient between plasma glucose and the degree of atherosclerosis (p < 0.0025) without affecting plasma glucose levels. The rosiglitazone-treated mice, both diabetic and non-diabetic, had higher lipid levels.


CONCLUSIONS
Rosiglitazone-treated animals showed less atherosclerosis despite higher lipid levels and similar glucose levels. These data suggest a direct anti-atherogenic effect of rosiglitazone on the arterial wall.
Levi
Z
Z
Institute of Atherosclerosis and Lipid Research, Sheba Medical Center, Tel-Hashomer, Israel.
Shaish
A
A
Yacov
N
N
Levkovitz
H
H
Trestman
S
S
Gerber
Y
Y
Cohen
H
H
Dvir
A
A
Rhachmani
R
R
Ravid
M
M
Harats
D
D
D000818:Animals; D001018:Aortic Diseases / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D001057:Apolipoproteins E / Q000172:deficiency; D001161:Arteriosclerosis / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D002784:Cholesterol / Q000097:blood; D003921:Diabetes Mellitus, Experimental / Q000097:blood; D003925:Diabetic Angiopathies / Q000097:blood / Q000188:drug therapy*; D005343:Fibrinolytic Agents / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists; D000077154:Rosiglitazone; D013844:Thiazoles / Q000627:therapeutic use*; D045162:Thiazolidinediones; D014157:Transcription Factors / Q000819:agonists; D014280:Triglycerides / Q000097:blood
D001057:Apolipoproteins E; D001786:Blood Glucose; D005343:Fibrinolytic Agents; D018160:Receptors, Cytoplasmic and Nuclear; D013844:Thiazoles; D045162:Thiazolidinediones; D014157:Transcription Factors; D014280:Triglycerides; D000077154:Rosiglitazone; D002784:Cholesterol