title: Renin inhibition by aliskiren prevents atherosclerosis progression: comparison with irbesartan, atenolol, and amlodipine.
abstract: Hypertension is associated with increased risk of cardiovascular diseases. Antihypertensive treatment, particularly blockade of the renin-angiotensin system, contributes to prevent atherosclerosis-mediated cardiovascular events. Direct comparison of different antihypertensive treatments on atherosclerosis and particularly plaque stabilization is sparse. ApoE(-/-) mice with vulnerable (2-kidney, 1-clip renovascular hypertension model) or stable (1-kidney, 1-clip renovascular hypertension model) atherosclerotic plaques were used. Mice were treated with aliskiren (renin inhibitor), irbesartan (angiotensin-receptor blocker), atenolol (beta-blocker), or amlodipine (calcium channel blocker). Atherosclerosis characteristics were assessed. Hemodynamic and hormonal parameters were measured. Aliskiren and irbesartan significantly prevented atherosclerosis progression in 2-kidney, 1-clip mice. Indeed, compared with untreated animals, plaques showed thinner fibrous cap (P<0.05); smaller lipid core (P<0.05); decreased media degeneration, layering, and macrophage content (P<0.05); and increased smooth muscle cell content (P<0.05). Interestingly, aliskiren significantly increased the smooth muscle cell compared with irbesartan. Despite similar blood pressure lowering, only partial plaque stabilization was attained by atenolol and amlodipine. Amlodipine increased plaque smooth muscle cell content (P<0.05), whereas atenolol decreased plaque inflammation (P<0.05). This divergent effect was also observed in 1-kidney, 1-clip mice. Normalizing blood pressure by irbesartan increased the plasma renin concentration (5932+/-1512 ng/mL per hour) more than normalizing it by aliskiren (16085+/-5628 ng/mL per hour). Specific renin-angiotensin system blockade prevents atherosclerosis progression. First, evidence is provided that direct renin inhibition mediates atherosclerotic plaque stabilization. In contrast, beta-blocker and calcium channel blocker treatment only partially stabilize plaques differently influencing atherogenesis. Angiotensin II decisively mediates plaque vulnerability. The plasma renin concentration measurement by an indirect method did not confirm the excessive increase of plasma renin concentration reported in the literature during aliskiren compared with irbesartan or amlodipine treatment.
authors.affiliation: Service of Vascular Medicine, Department of Medicine, Lausanne University Hospital, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.
authors.forename: Jürg
authors.initials: J
authors.lastname: Nussberger
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Aubert
authors.forename: Karima
authors.initials: K
authors.lastname: Bouzourene
authors.forename: Maxime
authors.initials: M
authors.lastname: Pellegrin
authors.forename: Daniel
authors.initials: D
authors.lastname: Hayoz
authors.forename: Lucia
authors.initials: L
authors.lastname: Mazzolai
mesh_terms: D000577:Amides / Q000494:pharmacology / Q000627:therapeutic use*; D017311:Amlodipine / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001057:Apolipoproteins E / Q000378:metabolism; D001262:Atenolol / Q000494:pharmacology / Q000627:therapeutic use*; D050197:Atherosclerosis / Q000097:blood / Q000473:pathology / Q000517:prevention & control*; D001713:Biphenyl Compounds / Q000494:pharmacology / Q000627:therapeutic use*; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D002784:Cholesterol / Q000097:blood; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D005650:Fumarates / Q000494:pharmacology / Q000627:therapeutic use*; D006339:Heart Rate / Q000187:drug effects / Q000502:physiology; D000077405:Irbesartan; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012084:Renin-Angiotensin System / Q000187:drug effects / Q000502:physiology; D013777:Tetrazoles / Q000494:pharmacology / Q000627:therapeutic use*; D000092502:Renin Inhibitors
chemical_list: D000577:Amides; D017311:Amlodipine; D000959:Antihypertensive Agents; D001057:Apolipoproteins E; D001262:Atenolol; D001713:Biphenyl Compounds; D002784:Cholesterol; D005650:Fumarates; D000077405:Irbesartan; D013777:Tetrazoles; D000092502:Renin Inhibitors; C446481:aliskiren