Defense mechanisms neutralizing oxidized phospholipids

Human blood contains phospholipids, some of which are prone to oxidation. Oxidized phospholipids (OxPLs) are toxic and pro-inflammatory substances that are both markers and makers in several pathologies, including atherosclerosis. In order to prevent accumulation of OxPLs and development of their harmful effects, blood plasma contains natural defense mechanisms. These include enzymatic neutralization of OxPLs, binding of antibodies and other plasma proteins to OxPLs, and removal of OxPLs by endocytotic receptors. We hypothesize that the mechanisms that inactivate atherogenic OxPLs are not less important for atherogenesis than the processes that generate these bad lipids. The project will apply mass spectrometry of lipids and proteins in order to characterize enzymatic modifications of OxPLs and to identify OxPL-binding proteins that mask OxPLs and thus prevent damage of cellular targets. The project will provide new insights into the mechanisms detoxifying OxPLs in blood plasma and thus improve our understanding of the balance between the pro- and anti-atherogenic processes, which determines an individual risk of cardiovascular disease.

The main result of this project is that human blood plasma contains natural defense mechanisms that can break down harmful oxidized lipid molecules and neutralize them by binding to them. Until now, this protective function of the blood has received much less attention than the formation of the harmful molecules themselves. The findings show that the risk of vascular damage depends not only on how many oxidized fat molecules are formed, but also on how effectively the body can make them harmless. The project focused on oxidized phospholipids. These are altered fat components that arise when lipids in the blood and in cell membranes are chemically damaged. They can promote inflammation in blood vessels. Such processes contribute to atherosclerosis, the gradual damage of the vessel wall that increases the long-term risk of heart attack and stroke. The project showed that the body counters these harmful molecules through several natural defense mechanisms. One part of this protection is based on enzymes in blood plasma that break down oxidized phospholipids. Among the range of enzymes studied, some were found to contribute particularly strongly to the breakdown of these molecules. Highly oxidized molecules were especially susceptible to this degradation. These findings provided a clearer picture of how blood contributes to the detoxification of harmful lipid products. In addition, the project demonstrated that many plasma proteins bind to oxidized phospholipids. By binding to them, these proteins effectively shield the harmful molecules and prevent their interaction with cells and reduce their ability to trigger inflammatory effects. In a comprehensive analysis, numerous plasma proteins were identified that preferentially bind to oxidized lipids. For several of these proteins, the neutralizing effect was also confirmed experimentally. The findings further showed that this protective function is not limited to a few individual types of molecules, but is carried out by a variety of different protein classes. Further biochemical analyses narrowed down the group of potentially especially important protective proteins to fewer than 50. Another major advance was the development and standardization of a sensitive assay that can reliably measure the ability of blood plasma to neutralize oxidized phospholipids. Parameters for handling and storing samples were also defined to ensure reliable results. This insight is particularly important for future clinical studies. Overall, the project has substantially improved our understanding of how the body protects itself against harmful lipid damage in the blood. In the long term, these findings may help to develop new markers of cardiovascular risk and support new approaches for prevention, diagnosis, and therapy.