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Fibrotic Aortic Valve Stenosis in Hypercholesterolemic/Hypertensive Mice
Yi Chu1, Donald D Lund1, Hardik Doshi1
1From the Departments of Internal Medicine (Y.C., D.D.L., H.D., N.D.F., J.C., G.P.H., K.A.Z., M.K.D., R.M.B., M.W.C., R.M.W., D.D.H.), Pharmacology (H.L.K., C.D.S., D.D.H.), Molecular Physiology and Biophysics (M.W.C.), Central Microscopy Research Facility (J.Q.S.), Iowa Institute of Human Genetics Genomics Division (K.L.K.), University of Iowa Carver College of Medicine, Iowa City; Veterans Administration Medical Center, Iowa City (M.W.C.); and Department of Molecular, Cellular, and Developmental Biology, University of Colorado, Boulder (D.D.H.).
Hypercholesterolemic and hypertensive mice developed severe aortic valve stenosis (AVS) without significant calcification. This new fibrotic AVS model reveals structural changes and gene expression patterns contributing to the disease.
Area of Science:
- Cardiovascular Biology
- Translational Medicine
- Pathology
Background:
- Human aortic valve stenosis (AVS) is associated with hypercholesterolemia and hypertension.
- Existing animal models do not fully recapitulate the fibrotic nature of human AVS.
Purpose of the Study:
- To investigate aortic valve function, structure, and gene expression in a mouse model of combined hypercholesterolemia and hypertension.
- To establish a novel animal model for studying fibrotic aortic valve stenosis.
Main Methods:
- Utilized a mouse model combining hypercholesterolemia (Apoe(-/-)) and hypertension.
- Assessed aortic valve structure and function using echocardiography.
- Performed RNA sequencing to identify differentially expressed genes during stenosis development.
Main Results:
- Severe aortic stenosis developed exclusively in hypercholesterolemic/hypertensive mice, characterized by minimal calcification.
- Structural alterations included a longer intercusp raphe, collagen reorientation, and leaflet asymmetry.
- Increased expression of the profibrotic molecule plasminogen activator inhibitor 1 (PAI-1) at both RNA and protein levels was observed.
Conclusions:
- Hypercholesterolemic/hypertensive mice represent the first model of fibrotic aortic valve stenosis.
- This model mimics human AVS, particularly in children and some adults, by developing stenosis without significant calcification.
- Identified key structural changes and gene expression profiles that may drive the development of fibrotic AVS.
