Inverse Agonist Activity of Angiotensin II Receptor Blocker Is Crucial for Prevention of Progressive Aortic Dilatation in Marfan Syndrome

BACKGROUND: Marfan syndrome is an inherited disorder caused by FBN1 gene mutations, which can lead to thoracic aortic aneurysm and dissection. Selective AT 1 (angiotensin II type 1) receptor blockade is a preventive option against Marfan syndrome aortopathy, and recent clinical studies demonstrated that the inhibitory effect of an ARB (AT 1 receptor blocker) losartan on aortic aneurysm growth is equivalent to that of β-blockers. At present, several ARBs are clinically available, and they have drug-specific differences in pharmacological properties. Especially, inverse agonism of ARBs has potential benefits for cardiovascular protection, but its impact on Marfan syndrome aortopathy remains poorly understood. METHODS: Candesartan-7H is a candesartan derivative that lacks the carboxyl group critical for inverse agonist activity and works as a neutral antagonist for the AT 1 receptor. Candesartan cilexetil (1 mg/kg per day), candesartan-7H (1 or 20 mg/kg per day), or vehicle was administered to Fbn1 C1041G/+ mice, and aortic dilatation was analyzed using echocardiography, histological staining, and in situ MMP (matrix metalloproteinase) assay. Activation of TGF-β (transforming growth factor β) signaling and mechanosensitive signaling was studied using Western blot and immunohistochemical analysis. RESULTS: Candesartan cilexetil (1 mg/kg per day) and candesartan-7H (20 mg/kg per day) lowered blood pressures equally in Fbn1 C1041G/+ mice. Progressive dilatation of the aorta in association with aortic wall thickening, degeneration of elastic fibers, deposition of collagen, MMP activation, and TGF-β signaling activation in Fbn1 C1041G/+ mice was significantly suppressed by treatment with candesartan cilexetil (1 mg/kg per day), but not by candesartan-7H, even at 20 mg/kg per day. In addition, candesartan cilexetil, but not candesartan-7H, suppressed activation of mechanosensitive signaling involving focal adhesion kinase, p38 mitogen-activated protein kinase, and early growth response-1 in the ascending aorta of Fbn1 C1041G/+ mice. CONCLUSIONS: Our findings support a crucial role of inverse agonist activity of ARB for the prevention of mechanical stress-induced AT 1 receptor activation and aortic aneurysm progression in Marfan syndrome mice.