Sheppard, M. B. | bioRxiv Science

bioRxiv2021

Losartan Increases Survival of the Fbn1mgR/mgR Mouse Model of Marfan Syndrome in and Age-Dependent Manner

Clinical trials investigating angiotensin receptor blockers (ARB) for attenuation of thoracic aortic aneurysm in people with Marfan syndrome have demonstrated variable efficacy. The primary objective of this study was to determine whether the age of mice at the time of losartan initiation affected mortality in fibrillin-1 hypomorphic (Fbn1mgR/mgR) mice. Male (n=40) and female (n=28) Fbn1mgR/mgR mice were randomized to receive losartan in drinking water (0.6 g/L) starting at either 24 or 50 days of age. Controls included Fbn1mgR/mgR mice (20M, 14F) and wild type (15M, 15F) littermates who were not administered the drug. Mortality of Fbn1mgR/mgR males receiving losartan at postnatal day 24 (P24) was not different from wild type controls (p=0.138). Survival of Fbn1mgR/mgR males administered losartan at P50 was not different compared to Fbn1mgR/mgR males receiving no drug (p=0.194) and decreased compared to wild type mice (p=0.002). Survival analysis after P50 demonstrated increased survival of Fbn1mgR/mgR males administered losartan at P50 compared to Fbn1mgR/mgR mice receiving no drug (p=0.017). Age is a critical variable that affects the therapeutic efficacy of losartan in male Fbn1mgR/mgR mice. Since overall mortality in female Fbn1mgR/mgR mice was lower than in male Fbn1mgR/mgR mice, a survival benefit with losartan was not detected in females.

physiology↗

bioRxiv2020

Inhibition of Angiotensin II Dependent AT1a Receptor Stimulation Attenuates Thoracic Aortic Pathology in Fibrillin-1C1041G/+ Mice

Graphic Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=157 SRC="FIGDIR/small/127670v1_ufig1.gif" ALT="Figure 1"> View larger version (36K): org.highwire.dtl.DTLVardef@8e7c32org.highwire.dtl.DTLVardef@7bf57aorg.highwire.dtl.DTLVardef@312d3forg.highwire.dtl.DTLVardef@9198bd_HPS_FORMAT_FIGEXP M_FIG C_FIG ObjectiveA cardinal feature of Marfan syndrome is thoracic aortic aneurysm (TAA). The contribution of ligand-dependent stimulation of angiotensin II receptor type 1a (AT1aR) to TAA progression remains controversial because the beneficial effects of angiotensin receptor blockers have been ascribed to off-target effects. This study used genetic and pharmacologic modes of attenuating angiotensin receptor and ligand, respectively, to determine their roles on TAA in mice with fibrillin-1 haploinsufficiency (Fbn1C1041G/+). Approach and ResultsTAA in Fbn1C1041G/+ mice were determined in both sexes and found to be strikingly sexual dimorphic. Males displayed progressive dilation over 12 months while ascending aortic dilation in Fbn1C1041G/+ females did not differ significantly from wild type mice. To determine the role of AT1aR, Fbn1C1041G/+ mice that were either +/+ or -/- for AT1aR were generated. AT1aR deletion reduced progressive expansion of ascending aorta and aortic root diameter from 1 to 12 months of age in males. Medial thickening and elastin fragmentation were attenuated. An antisense oligonucleotide against angiotensinogen (AGT-ASO) was administered to male Fbn1C1041G/+ mice to determine the effects of angiotensin II depletion. AGT-ASO administration, at doses that markedly reduced plasma AGT concentrations, attenuated progressive dilation of the ascending aorta and aortic root. AGT-ASO also reduced medial thickening and elastin fragmentation. ConclusionsGenetic approaches to delete AT1aR and deplete AngII production exerted similar effects in attenuating pathology in the proximal thoracic aorta of male Fbn1C1041G/+ mice. These data are consistent with ligand (AngII) dependent stimulation of AT1aR being responsible for aortic disease progression. HighlightsO_LIProfound sexual dimorphism of aortic disease occurs in Fbn1C1041G/+ mice, with female mice being more resistant and male mice being more susceptible. C_LIO_LIInhibition of the AngII-AT1aR axis attenuates aortic pathology in male Fbn1C1041G/+ mice. C_LIO_LIAntisense oligonucleotides targeting angiotensinogen deplete plasma angiotensinogen and attenuate thoracic aortic aneurysms. C_LI

physiology↗