Irbesartan but not amlodipine suppresses diabetes-associated atherosclerosis.
BACKGROUND
It remains controversial whether specific blockade of the renin-angiotensin system confers superior antiatherosclerotic effects over other antihypertensive agents in diabetes. Therefore, the aim of this study was to compare equihypotensive doses of the angiotensin II subtype 1 (AT1) receptor blocker irbesartan with the calcium antagonist amlodipine on diabetes-induced plaque formation in the apolipoprotein E (apoE)-null mouse and to explore molecular and cellular mechanisms linked to vascular protection.


RESULTS
Diabetes was induced by injection of streptozotocin in 6-week-old apoE-null mice. Diabetic animals were randomized to no treatment, irbesartan, or amlodipine for 20 weeks. Diabetes was associated with an increase in plaque area and complexity in the aorta in association with a significant increase in aortic AT1 receptor expression, cellular proliferation, collagen content, macrophage- and alpha-smooth muscle actin-positive cell infiltration, as well as an increased expression of platelet-derived growth factor-B (PDGF-B), monocyte chemoattractant protein-1 (MCP-1), and vascular cell adhesion molecule-1 (VCAM-1). Irbesartan but not amlodipine treatment attenuated the development of atherosclerosis, collagen content, cellular proliferation, and macrophage infiltration as well as diabetes-induced AT1 receptor, PDGF-B, MCP-1, and VCAM-1 overexpression in the aorta despite similar blood pressure reductions by both treatments.


CONCLUSIONS
Diabetes-associated atherosclerosis is ameliorated by AT1 receptor blockade but not by calcium channel antagonism, providing further evidence for the vascular renin-angiotensin system playing a pivotal role in the development and acceleration of atherosclerosis in diabetes.
Candido
Riccardo
R
Vascular Division, Baker Heart Research Institute, PO Box 6492, Melbourne 8008, Victoria, Australia.
Allen
Terri J
TJ
Lassila
Markus
M
Cao
Zemin
Z
Thallas
Vicki
V
Cooper
Mark E
ME
Jandeleit-Dahm
Karin A
KA
D017311:Amlodipine / Q000494:pharmacology / Q000627:therapeutic use*; D047228:Angiotensin II Type 1 Receptor Blockers; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001018:Aortic Diseases / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D001161:Arteriosclerosis / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D001713:Biphenyl Compounds / Q000494:pharmacology / Q000627:therapeutic use*; D002121:Calcium Channel Blockers / Q000494:pharmacology / Q000627:therapeutic use*; D002455:Cell Division; D018932:Chemokine CCL2 / Q000096:biosynthesis / Q000235:genetics; D003094:Collagen / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000150:complications*; D004353:Drug Evaluation, Preclinical; D005786:Gene Expression Regulation / Q000187:drug effects; D000077405:Irbesartan; D008264:Macrophages / Q000187:drug effects; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D020574:Proto-Oncogene Proteins c-sis / Q000096:biosynthesis / Q000235:genetics; D044140:Receptor, Angiotensin, Type 1 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D012084:Renin-Angiotensin System / Q000187:drug effects / Q000502:physiology; D013311:Streptozocin; D013777:Tetrazoles / Q000494:pharmacology / Q000627:therapeutic use*; D019010:Vascular Cell Adhesion Molecule-1 / Q000096:biosynthesis / Q000235:genetics
D047228:Angiotensin II Type 1 Receptor Blockers; D000959:Antihypertensive Agents; D001057:Apolipoproteins E; D001713:Biphenyl Compounds; D002121:Calcium Channel Blockers; D018932:Chemokine CCL2; D020574:Proto-Oncogene Proteins c-sis; D044140:Receptor, Angiotensin, Type 1; D013777:Tetrazoles; D019010:Vascular Cell Adhesion Molecule-1; D017311:Amlodipine; D013311:Streptozocin; D003094:Collagen; D000077405:Irbesartan