Abstract 16538: Oxidative Stress and Apoptotic Injury Induced by Amyloidogenic Light Chain Proteins in Human Coronary Artery Endothelial Cells
Background: Light chain amyloidosis (AL) is a disease associated with high mortality especially in patients with heart failure. The mechanisms underlying tissue toxicity remain poorly understood. Cardiac biopsy demonstrates perivascular arteriolar deposition of amyloidogenic light chain proteins (LC) associated with ischemic injury despite absence of significant conduit stenosis. We previously showed that acute exposure to LC caused endothelial dysfunction in human coronary arterioles associated with increased superoxide production. We aim to test the hypothesis that acute exposure to LC cause oxidative stress, reduce nitric oxide (NO) production and induce apoptotic/necrotic injury in human coronary artery endothelial cells (HCAEC).
Methods: LC from 4 biopsy-proven AL subjects with cardiac involvement (59±6 years old, all males, 3 lambda, 1 kappa type LC) were purified from urine using dialysis, lyophilization and size-exclusion filtration. Confluent HCAEC were exposed to 1 hour of LC (20 μg/mL) and superoxide was measured using hydroethidine (5 μM) fluorescence. Separately, HCAEC were exposed to 24 hour of LC (0, 10, 20 μg/mL) and NO gas production (NO analyzer) and apoptotic/necrotic injury (flow cytometry probing for annexin-V and propidium iodide fluorescent cells) were measured.
Results: See figure.
Conclusions: Acute exposure to amyloidogenic light chain proteins induces enhanced superoxide production, reduces NO and causes apoptotic/necrotic injury in human coronary artery endothelial cells. Oxidative stress leading to reduced NO bioavailability may underlie LC microvascular toxicity and this mechanistic pathway is a novel potential and early disease stage therapeutic target.
- © 2010 by American Heart Association, Inc.