ThiolReactive Compounds Attenuate Aortic Stenosis Background Aortic stenosis

Thiol-Reactive Compounds Attenuate Aortic Stenosis

Background • Aortic stenosis is a degenerative disease characterized by increased fibrosis and narrowing of aortic valves • Aortic stenosis leads to increased valve-wall shear stress • Platelets are a rich source of latent TGF-β 1, which can be activated by increased wall shear stress

Aortic Stenosis Problem OMRF’s Solution Aortic stenosis primarily affects people over 65 years of age, and the only treatment available is valve replacement Inhibiting platelet-derived TGF-β 1 activation with Thiol-Reactive Compounds such as, N-Acetyl Cysteine (NAC) and galunisertive (LY 2157299), represents a potential non-invasive therapeutic intervention for aortic stenosis

Data - One of the compounds used in proof-of-concept studies was N-Acetyl Cysteine (NAC) Echocardiographic quantification of stenosis in NACtreated and NAC-untreated atherosclerotic prone mice at 3 -5 and 5 -6 months on a high fat diet

Summary • Dr. Ahamed has shown that platelet-derived TGF-β 1 directly contributes to aortic stenosis progression • Atherosclerotic prone mice LDLR mice lacking platelet- derived TGF-β 1 were protected from developing aortic stenosis • Thiol-Reactive compounds, including NAC and galunisertive (LY 2157299), significantly attenuated aortic stenosis progression in LDLR mice by blocking plateletderived TGF-β 1 activation

Jasimuddin Ahamed, Ph. D. Assistant Member Cardiovascular Biology Research Program