Angiotensin II promotes aortic valve thickening independent of elevated blood pressure in apolipoprotein-E deficient mice

BackgroundValvular aortic stenosis (AS) is not an infrequent condition in the aged population. Activation of renin-angiotensin system (RAS) is presumed to be involved in the development of AS; however, direct evidence seems to be limited. We herein examined the effect of the administration of angiotensin II (Ang II) on the development of aortic valve thickening in apolipoprotein-E (ApoE)-deficient mice.Methods and ResultsMale ApoE-deficient mice were divided into three groups: control (saline, n = 8), mice that were administered low-dose Ang II (500 ng/kg/min, n = 11), and those with high-dose Ang II (1000 ng/kg/min, n = 11) administration for 4 weeks. Administration of high-dose, but not low-dose, Ang II significantly induced aortic valve thickening. It was found that in the aortic valve leaflets of high-dose Ang II group, integrity of endothelial cells was impaired and the number of myofibroblasts was increased. These phenomena induced by high-dose Ang II were suppressed by Ang II type 1 receptor blocker olmesartan (n = 15), but not by the dilatator, hydralazine (n = 13). Olmesartan also suppressed dilatation of aortic diameter, although it did not significantly affect the plaque area, in the abdominal aorta in ApoE-deficient mice.ConclusionAdministration of Ang II to genetically hyperlipidemic mice induced aortic valve thickening by a pressor-independent mechanism. Role of RAS activation in the development of AS in dyslipidemic patients should further be investigated.

► Ang II infusion induces aortic valve thickness in ApoE-deficient mice. ► Loss of endothelial integrity and accumulating myofibroblasts are in aortic valve. ► Olmesartan, but not hydralazine, inhibits Ang II-induced aortic valve remodeling. ► Ang II-induced aortic remodeling seems to be in a pressor-independent manner.