Role of the Scavenger Receptor CD36 in Accelerated Diabetic Atherosclerosis.

Miquel Navas-Madroñal,Maria Rosa Sarrias,María Galán,Esmeralda Castelblanco,Marta Consegal,Anna Ramirez-Morros,Nuria Alonso,Mercedes Camacho,Dídac Mauricio,Paulina Perez

doi:10.3390/ijms21197360

Miquel Navas-Madroñal, Maria Rosa Sarrias + Show 8 more

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https://doi.org/10.3390/ijms21197360

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Abstract

Diabetes mellitus entails increased atherosclerotic burden and medial arterial calcification, but the precise mechanisms are not fully elucidated. We aimed to investigate the implication of CD36 in inflammation and calcification processes orchestrated by vascular smooth muscle cells (VSMCs) under hyperglycemic and atherogenic conditions. We examined the expression of CD36, pro-inflammatory cytokines, endoplasmic reticulum (ER) stress markers, and mineralization-regulating enzymes by RT-PCR in human VSMCs, cultured in a medium containing normal (5 mM) or high glucose (22 mM) for 72 h with or without oxidized low-density lipoprotein (oxLDL) (24 h). The uptake of 1,1′-dioctadecyl-3,3,3′,3-tetramethylindocarbocyanine perchlorate-fluorescently (DiI) labeled oxLDL was quantified by flow cytometry and fluorimetry and calcification assays were performed in VSMC cultured in osteogenic medium and stained by alizarin red. We observed induction in the expression of CD36, cytokines, calcification markers, and ER stress markers under high glucose that was exacerbated by oxLDL. These results were confirmed in carotid plaques from subjects with diabetes versus non-diabetic subjects. Accordingly, the uptake of DiI-labeled oxLDL was increased after exposure to high glucose. The silencing of CD36 reduced the induction of CD36 and the expression of calcification enzymes and mineralization of VSMC. Our results indicate that CD36 signaling is partially involved in hyperglycemia and oxLDL-induced vascular calcification in diabetes.

Highlights

Pathologic calcification of cardiovascular structures very frequently occurs in the elderly and people suffering from diabetes and atherosclerosis and is considered an important marker of cardiovascular morbidity and mortality [1]
To determine whether exposure to high glucose (HG) in combination with oxidized low-density lipoprotein (oxLDL) could induce a synergistic effect on CD36 expression, primary human vascular smooth muscle cells (VSMCs) were incubated with medium supplemented with 5 mM or with 22 mM for 72 h and with oxLDL for the last 24 h
We studied the effect of the exposure to HG (22 mM) with or without oxLDL in the expression of pro-calcification markers, such as alkaline phosphatase (ALPL), secreted phosphoprotein 1 (SPP1, known as osteopontin), and bone morphogenetic protein 2 (BMP2) in VSMC

Summary

Introduction

Pathologic calcification of cardiovascular structures very frequently occurs in the elderly and people suffering from diabetes and atherosclerosis and is considered an important marker of cardiovascular morbidity and mortality [1]. VSMC possess remarkable plasticity with the ability to reprogram their expression pattern as contractile, synthetic, osteochondrogenic, and macrophage-like phenotypes This is relevant in human arteries, which are enriched in VSMC. Vascular smooth muscle cells express scavenger receptors for oxLDL uptake [13,14] and acquire macrophage-like phenotypes upon lipid loading by expressing macrophage markers and suppressing VSMC markers [15,16]. Because they cannot egress from the plaque, uptake of excess lipid by medial and intimal VSMC leads to plaque progression, apoptosis, and eventual plaque instability [17]

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