Abstract 19567: LAMP2 Cardiomyopathy: The Consequences of Impaired Autophagy
Human mutations in the gene encoding lysosome-associated membrane protein-2 (LAMP2) cause Danon disease with profound cardiac manifestations: massive hypertrophy, conduction system abnormalities, and malignant ventricular arrhythmias. To understand the mechanisms accounting for LAMP2 cardiomyopathy we engineered a hypomorphic mutation (in-frame exon 6 deletion, designated L2Δ6) into the endogenous mouse Lamp2 gene. Although 25% of neonatal L2Δ6 mice died, surviving male L2Δ6 mice had near normal life expectancy. L2Δ6 hearts showed abnormal lysosome biogenesis and function: enzymes were mislocalized, lysosomes were abnormally distributed throughout the cytosol, and autophagosomes accumulated in myocytes with reduced total autophagic flux and over-expression of LC3-II. Cardiac studies showed preserved contractile function but abnormal relaxation, significant ventricular hypertrophy and prominent myocardial fibrosis. Electrophysiologic analyses revealed conduction system abnormalities and pacing-induced ventricular tachycardia. L2Δ6 myocytes had strikingly elevated Ca2+ transient amplitudes, increased phosphorylation of cardiac ryanodine receptors and decreased calstabin levels that results in cardiac arrhythmias. Together these data define failed autophagy, massive accumulation of autophagosomes, myocardial necrosis and aberrant calcium signaling as the cause of LAMP2 cardiomyopathy.
- © 2010 by American Heart Association, Inc.