Abstract 14741: Adipose Arteriole Endothelial Dysfunction Induced by Amyloid Proteins: A Novel Human Model to Study Protein Misfolding Diseases
Protein misfolding diseases such as Alzheimer’s disease (AD) and light chain amyloidosis (AL) remain intractable and share significant morbidity arising from vascular dysfunction. Previous cell culture studies show that despite differences in amino acid composition, amyloid proteins such as beta amyloid (Aβ in AD) and light chain proteins (LC in AL) induce cell injury via similar mechanisms. A human model to test tissue toxicity of amyloid proteins will be helpful to test mechanisms of amyloid injury. Our aim is to test the hypothesis that acute exposure to Aβ and LC proteins induces similar endothelial dysfunction in human arterioles.
Methods: Ex-vivo subcutaneous adipose arterioles from 10 subjects (56.5±2.5 years, all males) without known vascular disease, AD or AL were cannulated, pressurized and preconstricted with endothelin-1. Baseline control dilator response to acetylcholine (10-9-10-4M) and papaverine (10-4M) were measured and after washing, a second dilator response was performed following 1-hour exposure to the following proteins: 1. Aβ42 (2 µM), 2. full length LC (AL-09, 20 µg/mL) or 3. LC with variable region portion only (AL-09var, 20 µg/mL). AL-09 is a recombinant LC derived from a patient with cardiac amyloidosis.
Results: AL-09 and Aβ42, but not AL-09var reduced dilation to acetylcholine compared to control (see Figure).
Conclusions: Amyloidogenic proteins associated with AD and AL induced similar endothelial dysfunction in human adipose arterioles. Partial protein structure modulates vascular effects. The ex-vivo human adipose arteriole model is a viable model to test the pathophysiologic effects of amyloid proteins that may have mechanistic translational advantage over existing animal models.
- © 2012 by American Heart Association, Inc.