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 AT1 (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 (AT1 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 AT1 receptor. Candesartan cilexetil (1 mg/kg per day), candesartan-7H (1 or 20 mg/kg per day), or vehicle was administered to Fbn1C1041G/+ 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 Fbn1C1041G/+ 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 Fbn1C1041G/+ 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 Fbn1C1041G/+ mice.

CONCLUSIONS: Our findings support a crucial role of inverse agonist activity of ARB for the prevention of mechanical stress-induced AT1 receptor activation and aortic aneurysm progression in Marfan syndrome mice.