These findings – published by the journal Circulation - come from a collaborative research carried out by EVGN laboratories in Paris and Maastricht (The Netherlands), together with colleagues from Lille University (France) and the Hôpital Bichat in Paris.

Lactadherin is a protein initially described in the milk fat globule membrane of human milk, where it is quite abundant. Its activity has been characterized by many groups - including Professor Alain Tedgui’s, EVGN scientist from INSERM Paris (Unit 689), who found that this substance plays a critical role in the modulation of neovascularization (blood vessels growth that follows an ischemic event). 

In the present study, the scientists asked what if lactadherin is missing? and set out to shed light on the consequences of its deficiency on atherosclerosis progression, whose hallmark is represented by the weakening of atherosclerotic plaques and subsequent higher risk of thrombosis. “Using an experimental animal model – explains first author of the paper Hafid Ait-Oufella from Tedgui’s laboratory, who received the “Young Investigator Award” during the Fourth EVGN Meeting in Bristol (September 17-20) – we first observed that lactadherin is expressed both in normal and in atherosclerotic human arteries, although at different levels, being less abundant in the latter condition. Then, we found that animals totally lacking lactadherin expression were unable to get rid of cellular debris resulting from apoptosis, or cellular suicide, a quite common event in advanced atherosclerotic plaques”. In a healthy organism, in fact, apoptosis plays a beneficial role in that it eliminates damaged cells, that, when left in place, could stimulate and sustain inflammatory reactions. This elimination (or phagocytosis) is carried out by specialized cells called macrophages, that eat up the debris and maintain the local environment in healthy conditions. The presence of lactadherin guarantees an optimal clearance of dying cells and cellular waste by these phagocytic cells. This, in turn, limits the onset of inflammation that, as many laboratories proved, fuels atherosclerotic lesions. 

“Without this substance – points out the researcher – macrophages gathering around the lesions fail to accomplish their job, triggering a number of collateral biochemical alterations that promote inflammation and speed up the atherosclerotic progression”. 

Altered or missing expression of lactadherin, as Ait-Oufella and colleagues noticed, is also associated with decreased production of interleukin-10 and increased amounts of interferon, two events known to boost atherosclerosis. 

“Without lactadherin – comments EVGN scientist Ziad Mallat from INSERM, who coordinated the research – it is as if the immune responses of the organism switched towards the so-called Th1 patwhay, the immune arm of our organism that promotes inflammation. But there is another striking observation: without this protein a subset of lymphocytes called Treg shows altered behaviours, failing to exert their usual protective effect against atherosclerosis”. 

These data suggest that the lactadherin-mediated phagocytosis is critical for maintaining an anti-inflammatory mileu, making this molecule a potential therapeutic tool to modulate atherosclerosis progression. 

Full paper is available in Circulation. 2007;115:2168-2177 - “Lactadherin Deficiency Leads to Apoptotic Cell Accumulation and Accelerated Atherosclerosis in Mice”