High density lipoproteins (HDL), these cholesterol transporters made up of lipids and proteins offer unexpected benefits. Not only do they protect against the risk of ischemia but, in the event of a heart attack, this effect is intensified by a remodeling of their structure. A discovery which opens up new therapeutic avenues.
HDL-cholesterol (HDL-c) is commonly referred to as good cholesterol, in opposition to LDL-cholesterol. These are particles made up of lipids and proteins which transport cholesterol to the liver, where it is eliminated. In addition, HDL-c plays an anti-thrombotic role, meaning that it reduces the risk of platelet aggregation which can lead to the formation of blood clots and, potentially, blocked arteries. HDL-c is also of interest for its anti-apoptotic effects, in which vessel wall cells (endothelial cells) are protected, as well as for its anti-inflammatory effects. In short, it would seem obvious that increasing blood levels of HDL-c can ward off ischemic events and improve vascular health. Except that while statins have been shown to be effective in reducing LDL-c, the use of compounds to increase HDL-c systematically fails to improve the health of subjects at risk.
“None of the trials intended to increase total HDL-c levels has succeeded in reducing thrombosis risk, notes Cécile Vindis*. That being said, I don’t think we need to take issue with the approach but rather keep working on it and refining it. Different fractions of HLD-c exist with different structures and probably different functions. We need to take things from there and understand how they each work in order to target them more effectively.” Indeed, HDL-c forms a heterogeneous population of HDL2 particles (richer in lipids) and HDL3 particles (richer in proteins), which in turn are divided into several sub-groups. For a better understanding of the anti-thrombotic properties of these various particles, Cécile Vindis and her colleagues studied the HDL2 and HDL3 fractions of patients having experienced a heart attack and of subjects at cardiovascular risk (with hypertension, diabetes, dyslipidemia or who smoke) having not experienced a heart attack.
Superior anti-thrombotic activity
In vitro, after having placed these fractions in contact with the platelets of healthy subjects, they were surprised to observe that the HDL2 fraction of post-heart attack individuals presented the strongest anti-thrombotic activity. It was greater than that of their own HDL3, itself greater than that of the two HDL populations taken from the cohort of subjects at cardiovascular risk but who had not had a heart attack.
The researchers then pursued their investigations, analyzing the signaling pathways implicated in clot formation and the composition of these various HDL fractions. They observed that HDL2s from post-heart attack patients were especially rich in oxidized polyunsaturated fatty acids compared with the other HDL fractions. However, only the HDL2s possess an anti-thrombotic effect: when isolated and placed in contact with platelets, this category of lipids is sufficient to diminish aggregation.
“Our results suggest that HDL2s undergo actual remodeling during a thrombotic event, leading to an increase in their efficacy and a reduced risk of relapse. But the mechanisms associated with this remodeling remain to be elucidated”, states Cécile Vindis.
In the meantime, the researchers are already working on these various oxidized polyunsaturated fatty acids, in order to identify the most effective among them and to test their anti-inflammatory potential. For this the authors will create HDL particles enriched with some of these oxidized polyunsaturated fatty acids, by modifying the mixtures and concentrations. “Ultimately, the idea is to be able to administer to patients synthetic HDLs offering major anti-thrombotic efficacy, to limit the risk of relapse after an initial ischemic event”, concludes Cécile Vindis.
*unit 1048 Inserm/UT3 Paul Sabatier, the Lipids, Peroxidation, Signaling in Vascular Diseases team in collaboration with the Platelet production and function, signaling and phosphoinositides team, Institute of Cardiovascular and Metabolic Diseases, Toulouse
C Garcia et al, Acute Coronary Syndrome remodels the antiplatelet aggregation properties of high-density lipoprotein particle subclasses. J Thromb Haemost, online edition of March 15, 2018