LAMP2 Cardiomyopathy: Consequences of Impaired Autophagy in the Heart.
Ronny AlcalaiMichael AradHiroko WakimotoDor YadinJoshua M GorhamLibin WangElia BurnsBarry J MaronWilliam C RobertsTetsuo KonnoDavid A ConnerAntonio R Perez-AtaydeJon G SeidmanChristine E SeidmanPublished in: Journal of the American Heart Association (2021)
Background Human mutations in the X-linked lysosome-associated membrane protein-2 (LAMP2) gene can cause a multisystem Danon disease or a primary cardiomyopathy characterized by massive hypertrophy, conduction system abnormalities, and malignant ventricular arrhythmias. We introduced an in-frame LAMP2 gene exon 6 deletion mutation (denoted L2Δ6) causing human cardiomyopathy, into mouse LAMP2 gene, to elucidate its consequences on cardiomyocyte biology. This mutation results in in-frame deletion of 41 amino acids, compatible with presence of some defective LAMP2 protein. Methods and Results Left ventricular tissues from L2Δ6 and wild-type mice had equivalent amounts of LAMP2 RNA, but a significantly lower level of LAMP2 protein. By 20 weeks of age male mutant mice developed left ventricular hypertrophy which was followed by left ventricular dilatation and reduced systolic function. Cardiac electrophysiology and isolated cardiomyocyte studies demonstrated ventricular arrhythmia, conduction disturbances, abnormal calcium transients and increased sensitivity to catecholamines. Myocardial fibrosis was strikingly increased in 40-week-old L2Δ6 mice, recapitulating findings of human LAMP2 cardiomyopathy. Immunofluorescence and transmission electron microscopy identified mislocalization of lysosomes and accumulation of autophagosomes between sarcomeres, causing profound morphological changes disrupting the cellular ultrastructure. Transcription profile and protein expression analyses of L2Δ6 hearts showed significantly increased expression of genes encoding activators and protein components of autophagy, hypertrophy, and apoptosis. Conclusions We suggest that impaired autophagy results in cardiac hypertrophy and profound transcriptional reactions that impacted metabolism, calcium homeostasis, and cell survival. These responses define the molecular pathways that underlie the pathology and aberrant electrophysiology in cardiomyopathy of Danon disease.
Keyphrases
- left ventricular
- loop mediated isothermal amplification
- heart failure
- wild type
- endothelial cells
- cardiac resynchronization therapy
- hypertrophic cardiomyopathy
- cell death
- acute myocardial infarction
- amino acid
- oxidative stress
- aortic stenosis
- endoplasmic reticulum stress
- genome wide
- mitral valve
- left atrial
- sensitive detection
- induced pluripotent stem cells
- genome wide identification
- signaling pathway
- binding protein
- gene expression
- electron microscopy
- pluripotent stem cells
- blood pressure
- poor prognosis
- high fat diet induced
- atrial fibrillation
- type diabetes
- skeletal muscle
- acute coronary syndrome
- copy number
- autism spectrum disorder
- percutaneous coronary intervention
- long non coding rna
- ejection fraction
- congenital heart disease
- quantum dots
- aortic valve