CAROL Act Administrative Supplement: Determinants of Aorta Heterogeneity

ABSTRACT The primary goal of the parent award (R35HL155649: 06/01/2021-05/31/2028) is to explore cellular and molecular mechanisms of aortopathies. A key element of the proposed research in the parent award involves a Marfan mouse model with a fibrillin-1 missense mutation C1041G (FBN1C1041G/+) mimicking the C1039Y mutation in humans. Mitral valve insufficiency including mitral valve prolapse (MVP) is a prevalent disorder in patients with Marfan syndrome and a common cause of ventricular dysfunction, heart failure, arrhythmia, and sudden cardiac arrest/death. Mitral valve insufficiency in FBN1C1041G/+ Marfan mouse model recapitulates many pathological features of the human disease. Molecular mechanisms by which FBN1 disruption leads to mitral valve insufficiency have not been defined. Also, the factors that promote the progression of MVP are poorly understood. Although the literature implicates that the renin-angiotensin activation via induction of the TGF-β pathway contributes to mitral valve disorders using in vitro systems or in neonates of FBN1C1041G/+ mice, there is no evidence of whether inhibiting the renin-angiotensin system alleviates mitral valve insufficiency per se, thereby preventing its severe consequences such as heart failure, arrhythmia, and sudden cardiac arrest/death. On the basis of our research work and the literature evidence on vascular pathophysiology, this Administrative Supplement challenges the current knowledge of mitral valve disorders by testing a novel central hypothesis: Inhibition of the renin-angiotensin system improves Marfan syndrome-related mitral valve disorders independent of suppressing TGF-β. We will use pharmacological approaches targeting either the ligand (angiotensinogen = AGT) to produce angiotensin II (AngII) or the AngII acting receptor (AT1) of the renin-angiotensin system, neutralize TGF-β using a monoclonal antibody, or infuse AngII to test the central hypothesis with two specific aims. Aim 1 will determine whether inhibition of the renin-angiotensin system improves mitral valve disorders, but inhibition of TGF-β will augment the mitral valve insufficiency in FBN1C1041G/+ Marfan mouse model. Aim 2 will determine whether AngII infusion augments mitral valve disorders in FBN1C1041G/+ Marfan mouse model. The proposed project will benefit from (1) our extensive expertise in pharmacological approaches and unique tools to study both the ligand and the acting receptor of AngII as well as TGF-β, (2) advanced core facilities including ultrasonography and microscopy cores on campus that permit detailed quantification and characterization of mitral valve dysfunction and pathological progress, and (3) collaboration with Dr. Katherine Yutzey, a distinguished heart valve researcher. We are confident that the experiments proposed in this Administrative Supplement will assimilate preliminary data to enable the development of an R01, advancing the understanding of mechanisms of mitral valve disorders. Ultimately, this Administrative Supplement mechanism will not only strengthen the investigators’ capabilities in basic science research but also foster interaction with translational research in the clinical arena.