sPLA2 and atherosclerosis

   Atherosclerosis: from a "plumbing" problem to an immune-inflammation perspective

Atherosclerosis is a process that begins as early as childhood, and develops over decades. It is often silent until it triggers in later life adverse cardiovascular events such as myocardial infarction and stroke. Previously, physicians thought of atherosclerosis as a plumbing problem, principally caused by high levels of blood cholesterol. The understanding of the physiopathology of this disease has now entered a new era based on understanding of the biology and a critical reappraisal of the pathobiology of atherothrombosis. Recent investigations of atherosclerosis have focused on inflammation, providing new insight into mechanisms of disease.

Animation

To better understand atherosclerosis, click on the picture above to open a short video detailing the mechanisms of this disease.

   sPLA2 plays a causal role in atherosclerosis

Phospholipases A2 (PLA2s) belongs to a superfamily of enzymes. PLA2 family comprises cytosolic enzymes and extracellular enzymes: Lp-PLA2 and secreted PLA2 (sPLA2). The sPLA2 family is involved in inflammation process. sPLA2 enzymes catalyse the hydrolysis of fatty acids. The products of this hydrolysis can trigger a variety of pro-inflammatory actions that lead to atherosclerotic plaque development. sPLA2 enhance lesion formation through the generation of atherogenic lipoproteins.

Human sPLA2 enzymes are a family of 9 structurally related enzymes responsible of:

• Modification of LDL and HDL particles. LDL and HDL are usually called "bad" and "good" cholesterol. The hydrolysis of LDL and HDL by sPLA2 enhances lesion formation. Hydrolysis by sPLA2 may also impact lipid accumulation in the vessel wall by reducing the anti-atherogenic functions of HDL36.
• Generation of bioactive lipid mediators, contributing to the pro-inflammatory process.

Modification of LDL by sPLA2 is a causal process of atherosclerosis. Modified LDL are taken up by macrophages. Macrophages turn into foam cells, leading to the formation of plaque. The pro-inflammatory process is enhanced by the production of bioactive lipid mediators and inflammatory mediators. The following figure shows how sPLA2 enzymes activity is at the origin of the process of plaque formation.

Role of sPLA2 in atherosclerosis development

   sPLA2 is a potent cardiovascular biomarker

The crucial role of sPLA2 in atherosclerosis plaque development has been demonstrated in multiple publications. Hence, a high level of sPLA2 activity signals an increased risk of atherosclerosis plaque development and, in turn, of adverse cardiovascular event. This hypothesis has been confirmed in many clinical studies on over 9,000 patients

sPLA2 activity is a powerful predictor of cardiovascular among patients that have already suffered from a cardiovascular accident. For them acute management and better stratification are critical unmet needs.

sPLA2 activity is an independent risk factor to allow a 2- to 4- fold CV risk increase prediction. It would allow physicians to anticipate more accurately cardiovascular events. Serum sPLA2 activity provides additive value to traditional risk factors (blood pressure, hsCRP, lipid profile) and traditional risk scores (Framingham, European SCORE). Moreover, there is an important need for biomarkers in theragnostic approaches to personalize the medication strategies. This is the area where the unmet needs are the most crucial. Indeed, Framingham scores and lipids profile do not reflect the new paradigm of the understanding of atherosclerosis. Up to 50% of patients with coronary heart disease do not have high cholesterol or other traditional risk factor and are thus not recognized of being at risk (Dzau V.J., Circulation, 2004). Moreover there is a large group considered at medium risk that could benefit from stratification tools. With the actual clinical validation and the genetic and biomolecular data, sPLA2 activity can be considered as a risk factor. Therefore, it could be included in the routine check-up for cardiovascular risk assessment.