NG2 Proteoglycan Ablation Reduces Foam Cell Formation and Atherogenesis via Decreased Low-Density Lipoprotein Retention by Synthetic Smooth Muscle Cells

Abstract

Objectives Obesity and hyperlipidemia are critical risk factors for atherosclerosis. Since ablation of NG2 proteoglycan in mice leads to hyperlipidemia and obesity, we investigated the impact of NG2 ablation on atherosclerosis in ApoE null mice. Approach and Results Immunostaining indicates that NG2 expression in plaque, primarily by synthetic smooth muscle cells, increases during atherogenesis. NG2 ablation unexpectedly results in decreased (30%) plaque development, despite aggravated obesity and hyperlipidemia. Mechanistic studies reveal that NG2-positive plaque synthetic smooth muscle cells in culture can sequester low density lipoprotein to enhance foam-cell formation, processes in which NG2 itself plays direct roles. In agreement with these observations, low density lipoprotein retention and lipid accumulation in the NG2/ApoE knockout aorta is 30% less than that seen in the control aorta. Conclusion These results indicate that synthetic smooth muscle cell-dependent low density lipoprotein retention and foam cell formation outweigh obesity and hyperlipidemia in promoting mouse atherogenesis. Our study sheds new light on the role of synthetic smooth muscle cells during atherogenesis. Blocking plaque NG2 or altering synthetic smooth muscle cells function may be promising therapeutic strategies for atherosclerosis.

NG2 targets tumorigenic Rb inactivation in Pit1-lineage pituitary cells

“…Abnormalities of the pituitary gland have not been described in global NG2 knockout mice (Chang et al 2012, She et al 2015. In marked contrast, here we show that targeted pRb inactivation in NG2-expressing cells results in striking pituitary tumor development in the anterior pituitary gland.…”

A role for proteoglycans in vascular disease

“…With the advent of extraction techniques, which preserved the protein moieties of the PGs and provided a means to recover intact PGs from vascular lesions [64-67], together with the use of antibodies, which recognized different core proteins, it became clear that the different GAGs within the lesions were attached to specific core proteins. Thus, it is now recognized that the bulk of the CS chains present in atherosclerotic lesions are present as the PG versican, although other CS-containing PGs such as aggrecan [68, 69] and NG2 [70] have been found as well! The DS chains within blood vessels and atherosclerotic lesions are distributed between two highly homologous core proteins of the small leucine rich repeat (SLRP) family and form the PGs decorin and biglycan while KS is also present in the SLRP family as fibromodulin and lumican [6, 7].…”

Vascular Smooth Muscle Cells

“…16 She et al reported that the conversion of SMCs to foam cells may be accelerated by expression of neural/glial antigen-2 (NG2) proteoglycan on the surface of synthetic SMCs. 66 Despite the fact that ablation of NG2 proteoglycan in mice leads to hyperlipidemia and obesity, both risk factors for the progression of atherosclerosis, when tested on an ApoE-null background loss of NG2 expression unexpectedly results in reduced plaque development. 66 These results suggest that local acquisition of a macrophage like proinflammatory phenotype by plaque SMCs plays a more predominant role in plaque progression than systemic hyperlipidemia or obesity.…”

“…66 Despite the fact that ablation of NG2 proteoglycan in mice leads to hyperlipidemia and obesity, both risk factors for the progression of atherosclerosis, when tested on an ApoE-null background loss of NG2 expression unexpectedly results in reduced plaque development. 66 These results suggest that local acquisition of a macrophage like proinflammatory phenotype by plaque SMCs plays a more predominant role in plaque progression than systemic hyperlipidemia or obesity. Finally, an emphasis on the role of local factors in the control of macrophage-like phenotype transition of plaque SMCs emphasizes the role of SMC-derived ECM proteins in plaque progression.…”