Leucine-Rich Alpha-2 Glycoprotein 1 Accumulates in Complicated Atherosclerosis and Promotes Calcification

Author:

Grzesiak Lucile12ORCID,Amaya-Garrido Ana12ORCID,Feuillet Guylène12,Malet Nicole12,Swiader Audrey12,Sarthou Marie-Kerguelen12ORCID,Wahart Amandine12ORCID,Ramel Damien12ORCID,Gayral Stéphanie12,Schanstra Joost Peter12,Klein Julie12ORCID,Laffargue Muriel12ORCID

Affiliation:

1. Institut National de la Santé et de la Recherche Médicale (INSERM), U1297, Institute of Cardiovascular and Metabolic Disease, 31432 Toulouse, France

2. Department of Biology, Université Toulouse III Paul-Sabatier, 31062 Toulouse, France

Abstract

Atherosclerosis is the primary cause of cardiovascular disease. The development of plaque complications, such as calcification and neo-angiogenesis, strongly impacts plaque stability and is a good predictor of mortality in patients with atherosclerosis. Despite well-known risk factors of plaque complications, such as diabetes mellitus and chronic kidney disease, the mechanisms involved are not fully understood. We and others have identified that the concentration of circulating leucine-rich α-2 glycoprotein 1 (LRG1) was increased in diabetic and chronic kidney disease patients. Using apolipoprotein E knockout mice (ApoE−/−) (fed with Western diet) that developed advanced atherosclerosis and using human carotid endarterectomy, we showed that LRG1 accumulated into an atherosclerotic plaque, preferentially in calcified areas. We then investigated the possible origin of LRG1 and its functions on vascular cells and found that LRG1 expression was specifically enhanced in endothelial cells via inflammatory mediators and not in vascular smooth muscle cells (VSMC). Moreover, we identified that LRG1 was able to induce calcification and SMAD1/5-signaling pathways in VSMC. In conclusion, our results identified for the first time that LRG1 is a direct contributor to vascular calcification and suggest a role of this molecule in the development of plaque complications in patients with atherosclerosis.

Funder

Inserm, the European Union ERA CVD JTC2017

European Union’s Horizon 2020 Research and Innovation programme under the Marie Skłodowska-Curie

National Research Agency

FEDER-région Occitanie program

University of Toulouse

Publisher

MDPI AG

Subject

Inorganic Chemistry,Organic Chemistry,Physical and Theoretical Chemistry,Computer Science Applications,Spectroscopy,Molecular Biology,General Medicine,Catalysis

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