Angiotensin II Promotes Mitral Valve and Left Atrial Pathology in Fibrillin-1C1041G/+ Mice
- 1University of Kentucky
Abstract
Background: Activation of the renin-angiotensin system (RAS) contributes to aortic diseases caused by fibrillin-1 haploinsufficiency (Fbn1C1041G/+). However, whether RAS activation influences mitral valve disease associated with FBN1 variants remains undefined. This study determined whether inhibition or augmentation of the RAS affects mitral valve pathology in Fbn1C1041G/+ mice. Methods: Angiotensinogen (AGT) antisense oligonucleotides (ASOs) were administered for 12 weeks to inhibit the RAS in male and female Fbn1C1041G/+ mice. To augment the RAS, mice were infused with angiotensin II (AngII; 1,000 ng/kg/min) for 28 days. Mitral valve and heart function were monitored by ultrasound. At termination, hearts were dissected free and tissue sectioned to assess mitral valve leaflet thickness and pathology. Results: Mitral valve leaflet thickness was significantly increased in Fbn1C1041G/+ mice compared to Fbn1+/+ littermates of both sexes. ASO-mediated AGT inhibition did not alter this phenotype despite markedly reduced plasma AGT concentrations. AngII infusion increased mitral valve leaflet thickness in Fbn1C1041G/+ mice with increased proteoglycan and collagen content, while exerting minimal effects in Fbn1+/+ mice. Twenty-five percent of AngII-infused Fbn1C1041G/+ mice died of non-vascular causes. Ultrasound showed mitral valve dysfunction in AngII-infused Fbn1C1041G/+ mice. Grossly expanded left atria were common in AngII-infused Fbn1C1041G/+ mice. These markedly enlarged left atria contained increased fibrosis, macrophage accumulation, and platelet-rich masses. Conclusions: Mitral valves of Fbn1C1041G/+ mice did not respond to AGT inhibition but were markedly more susceptible to AngII infusion, with greater increases in thickness and compositional changes than mitral valves of Fbn1+/+ mice. In addition, AngII promoted mitral valve dysfunction that were associated with pronounced left atrial pathology.
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BibTeX
@misc{franklin2026angiotensin,
title = {{Angiotensin II Promotes Mitral Valve and Left Atrial Pathology in Fibrillin-1C1041G/+ Mice}},
author = {M. K. Franklin and D. A. Howatt and A. C. Pettey and J. J. Moorleghen and B. M. Levitan and A. E. Mullick and J. Saffitz and H. S. Lu and A. Daugherty},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.02.755732},
url = {https://www.biorxiv.org/content/10.64898/2026.10.02.755732v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Angiotensin II Promotes Mitral Valve and Left Atrial Pathology in Fibrillin-1C1041G/+ Mice
AU - M. K. Franklin
AU - D. A. Howatt
AU - A. C. Pettey
AU - J. J. Moorleghen
AU - B. M. Levitan
AU - A. E. Mullick
AU - J. Saffitz
AU - H. S. Lu
AU - A. Daugherty
PY - 2026
DA - 2026/10/02
PB - bioRxiv
DO - 10.64898/2026.10.02.755732
UR - https://www.biorxiv.org/content/10.64898/2026.10.02.755732v1
AB - Background: Activation of the renin-angiotensin system (RAS) contributes to aortic diseases caused by fibrillin-1 haploinsufficiency (Fbn1C1041G/+). However, whether RAS activation influences mitral valve disease associated with FBN1 variants remains undefined. This study determined whether inhibition or augmentation of the RAS affects mitral valve pathology in Fbn1C1041G/+ mice. Methods: Angiotensinogen (AGT) antisense oligonucleotides (ASOs) were administered for 12 weeks to inhibit the RAS in male and female Fbn1C1041G/+ mice. To augment the RAS, mice were infused with angiotensin II (AngII; 1,000 ng/kg/min) for 28 days. Mitral valve and heart function were monitored by ultrasound. At termination, hearts were dissected free and tissue sectioned to assess mitral valve leaflet thickness and pathology. Results: Mitral valve leaflet thickness was significantly increased in Fbn1C1041G/+ mice compared to Fbn1+/+ littermates of both sexes. ASO-mediated AGT inhibition did not alter this phenotype despite markedly reduced plasma AGT concentrations. AngII infusion increased mitral valve leaflet thickness in Fbn1C1041G/+ mice with increased proteoglycan and collagen content, while exerting minimal effects in Fbn1+/+ mice. Twenty-five percent of AngII-infused Fbn1C1041G/+ mice died of non-vascular causes. Ultrasound showed mitral valve dysfunction in AngII-infused Fbn1C1041G/+ mice. Grossly expanded left atria were common in AngII-infused Fbn1C1041G/+ mice. These markedly enlarged left atria contained increased fibrosis, macrophage accumulation, and platelet-rich masses. Conclusions: Mitral valves of Fbn1C1041G/+ mice did not respond to AGT inhibition but were markedly more susceptible to AngII infusion, with greater increases in thickness and compositional changes than mitral valves of Fbn1+/+ mice. In addition, AngII promoted mitral valve dysfunction that were associated with pronounced left atrial pathology.
ER -