PCSK9 Inhibition May Reduce Cardiovascular Disease Risk via Immune Mechanisms as well as via Lowered Cholesterol
A range of new approaches to lowered cholesterol aim to improve upon statins in reducing the incidence of cardiovascular disease. One of the most promising of these involves inhibition of PCSK9. How does lowered cholesterol help? Oxidized cholesterol in the bloodstream rises with age as a result of increased oxidative stress throughout the body, and these damaged molecules can irritate blood vessel walls. Cells react by generating inflammatory signals, calling in immune cells to help remove the cholesterol. Unfortunately, these cells may be overwhelmed by the damaged cholesterol. This gives rise to areas of damage that grow to become fatty atherosclerotic lesions, weakening and distorting blood vessels, and ultimately causing death or serious injury when they rupture. When there is less cholesterol, the progression of this condition is slowed. Does PCSK9 inhibition in fact produce all of its benefits through lowered cholesterol, however? The results here suggest that it also interferes with the inflammatory aspect of atherosclerosis.
T cells and dendritic cells are common in atherosclerotic plaques. Atherosclerosis is a chronic inflammatory process in which activation of these immune cells may play a major role in the development of cardiovascular disease. Researchers developed an experimental system to directly study how these immune cells from human atherosclerotic plaques are activated in order to discover mechanisms and potential therapies. Specifically, they examined proprotein convertase subtilisin kexin 9 (PCSK9), which is known to target the low-density lipoprotein (LDL) cholesterol receptor for degradation, resulting in increased LDL levels. Knowledge of this mechanism has led to the development of PCSK9 inhibitors, which lower LDL cholesterol.
Researchers investigated the immune effects of PCSK9 on the induction of dendritic cell maturation and T cell activation by oxidised LDL. T cells were isolated from patients with atherosclerotic plaques and from healthy individuals. Human peripheral blood monocytes were differentiated into dendritic cells. The dendritic cells were pretreated with oxidised LDL and then co-cultured with T cells from atherosclerotic plaques and from blood. The researchers found that oxidised LDL promoted the maturation of dendritic cells. These dendritic cells then mediated the activation of T cells into T helper cells. Oxidised LDL also induced PCSK9. PCSK9 inhibition reversed the effects of oxidised LDL on dendritic cells and T cells. Dendritic cell maturation was repressed, as was the activation of T cells.
"We demonstrated for the first time that PCSK9 inhibition reversed the effects of oxidised LDL on immune activation. This changed a pro-inflammatory profile into an anti-inflammatory state that is potentially anti-atherosclerotic. Our study suggests that the benefits of PCSK9 inhibition extend beyond lowering LDL cholesterol."
Link: https://www.eurekalert.org/pub_releases/2017-08/esoc-pca081817.php