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

Abstract

AbstractBackgroundMarfan syndrome (MFS), an inherited disorder caused byFBN1gene mutations, causes fatal aortic aneurysm. Selective angiotensin II (Ang II) type 1 (AT1) receptor blockade is a preventive option for patients with MFS aortopathy, and recent clinical studies demonstrated that the inhibitory effect of an AT1receptor blocker (ARB) 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 MFS aortopathy remains poorly understood.MethodsCandesartan-7H is a candesartan derivative which lacks the carboxyl group critical for inverse agonist activity and works as a neutral antagonist for AT1receptor. Candesartan cilexetil (1 mg/kg/day), candesartan-7H (1 mg/kg/day or 20 mg/kg/day), or vehicle was administered toFbn1C1041G/+mice, and aortic aneurysm formation was analyzed using echocardiography, histological staining, andin situMMP assay. Activation of TGF-β signaling and mechanosensitive signaling was studied using western blot and immunohistochemical analysis.ResultsCandesartan cilexetil (1 mg/kg/day) and candesartan-7H (20 mg/kg/day) lowered blood pressures equally inFbn1C1041G/+mice, but that candesartan-7H (1 mg/kg/day) did not. Aortic aneurysmal progression in association with aortic wall thickening, degeneration of elastic fibers, deposition of collagen, MMP activation, and TGF-β signaling activation inFbn1C1041G/+mice was significantly suppressed by treatment with candesartan cilexetil (1 mg/kg/day), but not by candesartan-7H even at 20 mg/kg/day. In addition, candesartan cilexetil, but not candesartan-7H, inhibited up-regulation of mechanical stress–responsive transcriptional factor Egr-1 in ascending aorta ofFbn1C1041G/+mice.ConclusionsOur findings support a crucial role of inverse agonist activity of ARB for prevention of mechanical stress-induced AT1receptor activation and aortic aneurysm formation in MFS mice.