Cells of the innate immune system that play an essential role in development of atherosclerosis have a protein, an endogenous peptide, that reduces the levels of cholesterol in mice — and consequently helps to inhibit or mitigate the disease.
Atherosclerosis remains one of the causes of premature death in present day Western societies. The term itself refers to insoluble, fatty deposits that are formed on the inside wall of main blood vessels leading to a continual, localized inflammation. These so-called plaques obstruct blood flow and can ultimately lead to heart attacks and strokes.
The unresolved inflammatory reactions that lead to atherosclerosis are initiated through immune cells according to perturbations in lipid metabolism due to the presence of more cholesterol (hypercholesterolemia) in the circulation.
Researchers have now shown in mice that one of the cell types concerned produces a protein that inhibits atherosclerosis by regulating cholesterol metabolism. The new discovery, reported in the journal EBioMedicine, might open up new options for the cure of atherosclerosis.
Initiation and progression of atherosclerosis are intently linked to the activation of special classes of cells which can be part of the immune process. In prior experiments, the researchers had shown that white blood cells called neutrophils play a predominant position in the system. Probably the most plentiful protein observed in human neutrophils is human neutrophil peptide 1 (HNP1), which is famous to have anti-microbial and pro-inflammatory functions.
In contrast, mouse neutrophils mainly don’t express this protein at all. According to the authors, this provided them with a targeted possibility to study the function of this protein. To take action, they genetically developed a mouse strain that is not only inclined towards atherosclerosis, but in addition produces excessive stages of HNP1. The LMU group discovered that the atherosclerotic lesions that formed in these mice were a lot smaller than those found in the mice that lacked HNP1.
After they examined the HNP1-expressing mice more intently, the researchers found out that the animals had decreased stages of circulating cholesterol than control mice. Due to the fact that cholesterol is not soluble in water, it’s transported in the bloodstream in association with so-called lipoproteins. Lipoproteins are divided into good fats and unhealthy fats. The good fats, together with HDL, transport cholesterol from the tissues to the liver and therefore cut down the risk of atherosclerosis.
The dangerous fats, like LDL, carry cholesterol within the reverse path — from the liver to the tissues. High levels of circulating LDL for this reason enable more cholesterol to be delivered to endothelial cells which are specially prone to damage or are already damaged, and as a consequence tend to create atherosclerosis. The authors claimed they were able to show that HNP1 binds to LDL in the bloodstream and induces fast uptake of circulating LDL by the liver, thus lowering hypercholesterolemia. This will account for the lesser atherosclerotic lesions in HNP1-expressing mice.
The researchers consider that their findings may result in new procedures to the treatment of hyperlipidemia. Given that HNP1 is a normal constituent of the human body, therapeutic use of the protein would be expected to be free from side effects and must not compromise immune defenses.