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

Chen, J. Z.; Sawada, H.; Moorleghen, J. J.; Franklin, M. K.; Howatt, D. A.; Sheppard, M. B.; Mullick, A. E.; Lu, H. S.; Daugherty, A.

doi:10.1101/2020.06.01.127670

bioRxiv · 10.1101/2020.06.01.127670

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

Chen, J. Z.·Sawada, H.·Moorleghen, J. J.·Franklin, M. K.·Howatt, D. A.·Sheppard, M. B.·Mullick, A. E.·Lu, H. S.·Daugherty, A.

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Abstract

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

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Chen, J. Z., Sawada, H., Moorleghen, J. J., Franklin, M. K., Howatt, D. A., Sheppard, M. B., Mullick, A. E., Lu, H. S., Daugherty, A.. 2020-06-02. Inhibition of Angiotensin II Dependent AT1a Receptor Stimulation Attenuates Thoracic Aortic Pathology in Fibrillin-1C1041G/+ Mice. https://doi.org/10.1101/2020.06.01.127670

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