Abstract
ABSTRACTCellular communication network factor 2 (CCN2/CTGF) is a matricellular protein with an established role in fibrotic diseases and cancers, and therapies targeting CCN2 is currently in Phase II and III clinical trials for idiopathic pulmonary fibrosis, pancreatic cancer and Duchenne Muscular Dystrophy. Recent studies have highlighed a protective role of CCN2 in aortic aneurysm disease, but its role in atherosclerosis remains to be investigated.We identified arteries as having the highest relative expression ofCCN2across 54 human tissues. In aortas,CCN2was among the highest expressed genes, andin situhybridization of human internal thoracic arteries revealed vascular smooth muscle cells (SMCs) as its principal source.Hypothesizing a role for CCN2 in SMC phenotype maintenance and athero-protection, we investigated inducible Ccn2 knockout (Ccn2Δ/Δ) mice in normo- and hyper-lipidemic settings. Induction of hyperlipidemia by single intravenous injection of 1·1011viral genomes of rAAV8-D377Y-mPcsk9 combined with 24 weeks of western type diet resulted in severe enlargement (3-5-fold increase of relative aorta mass compared to wildtype littermates,p< 0.0001) and whitening ofCcn2Δ/Δaortas. Oil Red O-staining ofen faceprepared thoracic aortas showed a marked increase in atherosclerosis inCcn2Δ/Δmice as compared to wildtype littermates (75% vs. 10% Oil Red O-positive aortic area,p< 0.0001). Transcriptomic profiling of cultivated SMCs derived from aortas of normolipidemic mice showed signatures of dedifferentiation (reduced expression ofe.g. Myocd, Acta2andMyh11) and modulation toward a synthetic, pro-inflammatory phenotype ofCcn2Δ/ΔSMCs. These effects were verifiedin vivoand inCCN2-silenced human aortic SMCs. Taken together, we find that CCN2 plays a critical athero-protective role in artery tissues, likely through maintaining SMCs in a differentiated, contractile phenotype.
Publisher
Cold Spring Harbor Laboratory
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