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 overproduction of reactive oxygen species (ROS). These findings indicate that LAMP-2 deficiency leads to arterial medial hypertrophy with the phenotypic conversion of VSMC, resulting from age-dependent accumulation of cellular waste generated by aberrant autophagy.
Highlights
Recent studies showed that the lysosome/autophagic pathway is essential for the maintenance of vascular architecture and function[11]
The findings indicated that autophagy impairment and oxidative stress under LAMP-2 deficiency may accelerate the phenotypic switch of cells as an adaptive response, and this may play a critical role in the pathogenesis of medial hypertrophy
Association of small-vessel vasculopathy with LAMP-2 deficiency has been suggested by two previous findings in the literature: medial thickening of coronary arteries was observed in individuals who had a truncating mutation in both the hemizygous (p.Tyr109ter)[9] and heterozygous (p.Phe[151] fs*32)[10] state
Summary
Recent studies showed that the lysosome/autophagic pathway is essential for the maintenance of vascular architecture and function[11]. Pathological studies in Fabry patients showed that VSMC proliferation is induced in cerebral arteries[14]. We first present the case of a female carrier who is heterozygous for the truncating LAMP2 mutation and had young-onset stroke due to diffuse narrowing of the cerebral arteries without atherosclerosis. In another Danon family reported elsewhere[4,16,17], we re-examined the pathology of small arteries from a heterozygous mother and her hemizygous son with an exon-6 skipping mutation. The findings indicated that autophagy impairment and oxidative stress under LAMP-2 deficiency may accelerate the phenotypic switch of cells as an adaptive response, and this may play a critical role in the pathogenesis of medial hypertrophy
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