Ziad Mallat

CLA-1/SR-BI Is Expressed in Atherosclerotic Lesion Macrophages and Regulated by Activators of Peroxisome Proliferator-Activated Receptors

BACKGROUNDnThe scavenger receptors are cell-surface receptors for native and modified lipoproteins that play a critical role in the accumulation of lipids by macrophages. CLA-1/SR-BI binds HDL with high affinity and is involved in the cholesterol reverse-transport pathway. Peroxisome proliferator-activated receptors (PPARs) are transcription factors regulating the expression of genes implicated in lipid metabolism, cellular differentiation, and inflammation. Here, we investigated the expression of CLA-1/SR-BI in macrophages and its regulation by PPARs.nnnMETHODS AND RESULTSnCLA-1 is undetectable in human monocytes and is induced upon differentiation into macrophages. Immunohistological analysis on human atherosclerotic lesions showed high expression of CLA-1 in macrophages of the lipid core colocalizing with PPARalpha and PPARgamma staining. Activation of PPARalpha and PPARgamma resulted in the induction of CLA-1 protein expression in monocytes and in differentiated macrophages. Finally, SR-BI expression is increased in atherosclerotic lesions of apoE-null mice treated with either PPARgamma or PPARalpha ligands.nnnCONCLUSIONSnOur data demonstrate that CLA-1/SR-BI is expressed in atherosclerotic lesion macrophages and induced by PPAR activation, identifying a potential role for PPARs in cholesterol homeostasis in atherosclerotic lesion macrophages.

Reduction of atherosclerosis by the peroxisome proliferator-activated receptor alpha agonist fenofibrate in mice.

Several clinical and angiographic intervention trials have shown that fibrate treatment leads to a reduction of the coronary events associated to atherosclerosis. Fibrates are ligands for peroxisome proliferator-activated receptor α (PPARα) that modulate risk factors related to atherosclerosis by acting at both systemic and vascular levels. Here, we investigated the effect of treatment with the PPARα agonist fenofibrate (FF) on the development of atherosclerotic lesions in apolipoprotein (apo) E-deficient mice and human apoA-I transgenic apoE-deficient (hapoA-I Tg × apoE-deficient) mice fed a Western diet. In apoE-deficient mice, plasma lipid levels were increased by FF treatment with no alteration in the cholesterol distribution profile. FF treatment did not reduce atherosclerotic lesion surface area in the aortic sinus of 5-month-old apoE-deficient mice. By contrast, FF treatment decreased total cholesterol and esterified cholesterol contents in descending aortas of these mice, an effect that was more pronounced in older mice exhibiting more advanced lesions. Furthermore, FF treatment reduced MCP-1 mRNA levels in the descending aortas of apoE-deficient mice, whereas ABCA-1 expression levels were maintained despite a significant reduction of aortic cholesterol content. In apoE-deficient mice expressing a human apoA-I transgene, FF increased human apoA-I plasma and hepatic mRNA levels without affecting plasma lipid levels. This increase in human apoA-I expression was accompanied by a significant reduction in the lesion surface area in the aortic sinus. These data indicate that the PPARα agonist fenofibrate reduces atherosclerosis in these animal models of atherosclerosis.

Immune regulation in atherosclerosis and the hygiene hypothesis

Atherosclerosis is a chronic inflammatory disease of the arterial wall where both innate and adaptive immune responses contribute to disease initiation and progression. The hygiene hypothesis implies that dysregulation of the immune response has led to increased susceptibility to immuno-inflammatory diseases. Recent studies established that subtypes of T cells, regulatory T cells, actively involved in the maintenance of immunological tolerance, inhibit the development and progression of atherosclerosis. Here, we review the immune regulatory pathways of atherosclerosis and discuss the potential implication of pathogens and their associated molecular patterns in the regulation of the immuno-inflammatory response of atherosclerosis.