RESUMEN
Cardiovascular outcome in Marfan syndrome (MFS) patients most prominently depends on aortic aneurysm progression with subsequent aortic dissection. Angiotensin II receptor blockers (ARBs) prevent aneurysm formation in MFS mouse models. In patients, ARBs only slow down aortic dilation. Downstream signalling from the angiotensin II type 1 receptor (AT1R) is mediated by G proteins and ß-arrestin recruitment. AT1R also interacts with the monocyte chemoattractant protein-1 (MCP-1) receptor, resulting in inflammation. In this study, we explore the targeting of ß-arrestin signalling in MFS mice by administering TRV027. Furthermore, because high doses of the ARB losartan, which has been proven beneficial in MFS, cannot be achieved in humans, we investigate a potential additive effect by combining lower concentrations of losartan (25 mg/kg/day and 5 mg/kg/day) with barbadin, a ß-arrestin blocker, and DMX20, a C-C chemokine receptor type 2 (CCR2) blocker. A high dose of losartan (50 mg/kg/day) slowed down aneurysm progression compared to untreated MFS mice (1.73 ± 0.12 vs. 1.96 ± 0.08 mm, p = 0.0033). TRV027, the combination of barbadin with losartan (25 mg/kg/day), and DMX-200 (90 mg/kg/day) with a low dose of losartan (5 mg/kg/day) did not show a significant beneficial effect. Our results confirm that while losartan effectively halts aneurysm formation in Fbn1C1041G/+ MFS mice, neither TRV027 alone nor any of the other compounds combined with lower doses of losartan demonstrate a notable impact on aneurysm advancement. It appears that complete blockade of AT1R function, achieved by administrating a high dosage of losartan, may be necessary for inhibiting aneurysm progression in MFS.
Asunto(s)
Bloqueadores del Receptor Tipo 1 de Angiotensina II , Aneurisma de la Aorta , Losartán , Síndrome de Marfan , Transducción de Señal , Ratones , Síndrome de Marfan/tratamiento farmacológico , Síndrome de Marfan/patología , Modelos Animales de Enfermedad , Aneurisma de la Aorta/tratamiento farmacológico , Aneurisma de la Aorta/prevención & control , Oligopéptidos/administración & dosificación , Aorta Torácica/efectos de los fármacos , Aorta Torácica/patología , Pirimidinas/administración & dosificación , Combinación de Medicamentos , Losartán/administración & dosificación , Antagonistas de Receptores de Angiotensina/administración & dosificación , Transducción de Señal/efectos de los fármacos , Humanos , Bloqueadores del Receptor Tipo 1 de Angiotensina II/administración & dosificaciónRESUMEN
Marfan syndrome is a rare connective tissue disorder that causes aortic dissection-related sudden death. Current conventional treatments, beta-blockers, and type 1 angiotensin II receptor blockers are prescribed to slow down aortic aneurysm progression and delay (prophylactic) aortic surgery. However, neither of these treatments ceases aortic growth completely. This review focuses on potential alternative therapeutic leads in the field, ranging from widely used medication with beneficial effects on the aorta to experimental inhibitors with the potential to stop aortic growth in Marfan syndrome. Clinical trials are warranted to uncover their full potential.