Small-Vessel Vasculopathy Due to Aberrant Autophagy in LAMP-2 Deficiency

Scientific Reports
Huan T NguyenHiroyasu Tsukaguchi

Abstract

Lysosomal associated membrane protein 2 (LAMP2) is physiologically implicated in autophagy. A genetic LAMP2 defect causes Danon disease, which consists of two major phenotypes of myopathy and cardiomyopathy. In addition, arteriopathy may manifest on rare occasions but the pathological basis remains unknown. We encountered two Danon families that developed small-vessel vasculopathy in the coronary or cerebral arteries. To investigate the underlying mechanisms, we characterized the biological features of LAMP-2-deficient mice and cultured cells. LAMP-2-deficient mice at 9-24 months of age showed medial thickening with luminal stenosis due to proliferation of vascular smooth muscle cells (VSMC) in muscular arteries. Ultrastructural analysis of VSMC revealed various autophagic vacuoles scattered throughout the cytoplasm, suggesting impaired autophagy of long-lived metabolites and degraded organelles (i.e., mitochondria). The VSMC in Lamp2 null mice expressed more vimentin but less α-smooth muscle actin (α-SMA), indicating a switch from contractile to synthetic phenotype. Silencing of LAMP2 in cultured human brain VSMC showed the same phenotypic transition with mitochondrial fragmentation, enhanced mitochondrial respiration, and ove...Continue Reading

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Citations

Nov 8, 2019·Neuropathology and Applied Neurobiology·G CenacchiC Angelini
Jan 28, 2020·Expert Opinion on Therapeutic Targets·Dorien G De MunckWim Martinet
Sep 11, 2020·Cardiovascular Diabetology·Karima Ait-AissaModar Kassan
Nov 11, 2018·International Journal of Molecular Sciences·Kazuma SugieIchizo Nishino

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Datasets Mentioned

BETA
GTX54379

Methods Mentioned

BETA
environmental stress
biopsy
Light microscopy
electron microscopy
flow cytometery
GTPase
flow cytometry
electrophoresis
transmission electron microscopy
transfection

Software Mentioned

Image J
ImageJ
Wave
SPSS Statistics
ZEISS LSM
ZEISS LSM 510 META
FlowJo

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