The Small LeucineRich Proteoglycan BGN Accumulate

Authors: Xiaojie Zhang Soo Jung Lee Marian F Young Michael M Wang

Publish Date: 2015/01/13

Volume: 6, Issue: 2, Pages: 148-155

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Abstract

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy CADASIL is an inherited form of cerebral small vessel disease caused by mutations in conserved residues of NOTCH3 Affected arteries of CADASIL feature fibrosis and accumulation of NOTCH3 A variety of collagen subtypes types I III IV and VI have been identified in fibrotic CADASIL vessels Biglycan BGN and decorin DCN are class I members of the small leucinerich proteoglycan SLRP family that regulate collagen fibril size Because DCN has been shown to deposit in arteries in cerebral small vessel disease we tested whether BGN accumulates in arteries of CADASIL brains BGN was strongly expressed in both small penetrating and leptomeningeal arteries of CADASIL brain BGN protein was localized to all three layers of arteries intima media and adventitia Substantially more immunoreactivity was observed in CADASIL brains compared to controls Immunoblotting of brain lysates showed a fourfold increase in CADASIL brains compared to controls Messenger RNA encoding BGN was also increased in CADASIL and was localized by in situ hybridization to all three vascular layers in CADASIL Human cerebrovascular smooth muscle cells exposed to purified NOTCH3 ectodomain upregulated BGN DCN and COL4A1 through mechanisms that are sensitive to rapamycin a potent mTOR inhibitor In addition BGN protein interacted directly with NOTCH3 protein in cell culture and in direct protein interaction assays In conclusion BGN is a CADASILenriched protein that potentially accumulates in vessels by mTORmediated transcriptional activation and/or posttranslational accumulation via protein interactions with NOTCH3 and collagen

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