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

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.

A Nationwide Survey on Danon Disease in Japan

“…The detailed clinical records that were returned to us were carefully reviewed. In addition, a systematic literature review was conducted and yielded 15 articles or society reports [ 2 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 ].…”

Review: Danon disease: Review of natural history and recent advances

“…Several patients developed small‐vessel vasculopathy in various arteries. Pathological examination of the autoptic hearts of two relatives and of another patient , and the explanted heart of one female patient showed abnormal intramural coronary arteries, with medial wall thickening due to smooth muscle cells hypertrophy, leading to severe lumen narrowing. The molecular basis for vasculopathy is suggested to be an autophagic block, as LAMP‐2‐deficient mice showed smooth muscle cells with medial hypertrophy, vacuoles, increased LC3 puncta and a reduced number of autolysosomes .…”

“…Complete LAMP‐2 deficiency was demonstrated in explanted heart and in endomyocardial biopsies either by immunoblot or immunohistochemistry , suggesting that the latter should be performed on every endomyocardial biopsy. Muscle immunoblot analysis showed either trace amounts of normal‐sized LAMP‐2 in patients with null, splicing or exon 9b mutations or no significant protein reduction .…”

“…Many patients had hepatomegaly (36% of cases) , overt hepatopathy or increased liver enzyme levels from childhood .…”

“…Ischaemic thromboembolic strokes were reported in many female patients : one female with HCM and WPW syndrome presented recurrent hemiplegic migraines that progressed to an ischaemic attack with a thrombus in the LV apex , one with HCM died from a massive cerebrovascular stroke and one had a hemiparesis due to diffuse stenosis of the carotid arteries .…”