The HMG-CoA reductase inhibitor rosuvastatin and the angiotensin receptor antagonist candesartan attenuate atherosclerosis in an apolipoprotein E-deficient mouse model of diabetes via effects on advanced glycation, oxidative stress and inflammation.
OBJECTIVE
We evaluated the anti-atherosclerotic effect of the 3-hydroxy-3-methylglutaryl CoA reductase inhibitor, rosuvastatin, and the angiotensin II receptor blocker (ARB), candesartan, alone and in combination, in the streptozotocin-induced diabetic apolipoprotein E-deficient (Apoe (-/-)) mouse.


METHODS
Control and streptozotocin-induced diabetic Apoe (-/-) mice received rosuvastatin (5 mg kg(-1) day(-1)), candesartan (2.5 mg kg(-1) day(-1)), dual therapy or no treatment for 20 weeks. Aortic plaque deposition was assessed by Sudan IV staining and subsequent visual quantification. The abundance of proteins was measured using immunohistochemistry.


RESULTS
Diabetes was associated with a fourfold increase in total plaque area. Rosuvastatin attenuated plaque area in diabetic mice in the absence of lipid-lowering effects. The anti-atherosclerotic effect of rosuvastatin was comparable to that observed with candesartan. A similar beneficial effect was seen with dual therapy, although it was not superior to monotherapy. Rosuvastatin treatment was associated with attenuated accumulation of AGE and AGE receptor (RAGE) in plaques. Similar beneficial effects on markers of oxidative stress were seen with the ARB and statin. Candesartan was more effective at reducing macrophage accumulation and collagen I abundance in plaques compared with rosuvastatin. The combined effect of candesartan and rosuvastatin was superior in reducing macrophage infiltration, monocyte chemoattractant protein-1 level, vascular AGE accumulation and RAGE abundance in the vascular wall. Furthermore, the combination tended to be more effective in reducing smooth muscle cell infiltration and connective tissue growth factor abundance in plaques.


CONCLUSIONS
Rosuvastatin has direct anti-atherosclerotic effects in diabetic macrovascular disease. These effects are independent of effects on lipids and comparable to the effects observed with candesartan.
Calkin
A C
AC
Diabetes Complications Laboratory, Baker Heart Research Institute, P.O. Box 6492, St Kilda Rd Central, Melbourne 8008, Victoria, Australia.
Giunti
S
S
Sheehy
K J
KJ
Chew
C
C
Boolell
V
V
Rajaram
Y S
YS
Cooper
M E
ME
Jandeleit-Dahm
K A
KA
D047228:Angiotensin II Type 1 Receptor Blockers / Q000627:therapeutic use*; D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency*; D001562:Benzimidazoles / Q000627:therapeutic use*; D001713:Biphenyl Compounds; D001808:Blood Vessels / Q000187:drug effects / Q000473:pathology; D003920:Diabetes Mellitus / Q000188:drug therapy* / Q000473:pathology; D004195:Disease Models, Animal; D005464:Fluorobenzenes / Q000627:therapeutic use*; D017127:Glycation End Products, Advanced / Q000378:metabolism*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use*; D007249:Inflammation / Q000517:prevention & control*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018384:Oxidative Stress / Q000187:drug effects*; D011743:Pyrimidines / Q000627:therapeutic use*; D000068718:Rosuvastatin Calcium; D013449:Sulfonamides / Q000627:therapeutic use*; D013777:Tetrazoles / Q000627:therapeutic use*
D047228:Angiotensin II Type 1 Receptor Blockers; D001057:Apolipoproteins E; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D005464:Fluorobenzenes; D017127:Glycation End Products, Advanced; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011743:Pyrimidines; D013449:Sulfonamides; D013777:Tetrazoles; D000068718:Rosuvastatin Calcium; C081643:candesartan