Activated T-cells and dendritic cells (DCs) occur in atherosclerotic plaques. Proprotein convertase subtilisin kexin 9 (PCSK9) targets the LDL?receptor (LDLR) and results in increased LDL?levels. Effects of PCSK9 on T-cell activation was studied here.

T-cells were isolated from carotid specimens of patients undergoing carotid endarterectomy, or from peripheral blood of healthy individuals. Human peripheral blood monocytes were differentiated into DCs.

Naive T-cells were co?cultured with pretreated DCs. The effects of PCSK9 and its inhibition by silencing were studied. OxLDL induced PCSK9 in DCs and promoted DC maturation with increased expression of CD80, CD83, CD86 and HLA?DR and the scavenger receptors LOX?1, CD36 and SR?A.

T-cells exposed to OxLDL?treated DCs proliferated and produced IFN?γ and IL?17, thus with polarization to Th1 and Th17 subsets. PCSK9 inhibition is a new therapeutic strategy for atherosclerosis which is known to lower LDL cholesterol.

Research from Karolinska Institutet, presented at the ESC Congress last year and now published in the Journal of Internal Medicine, showed that PCSK9 inhibitors could ameliorate cardiovascular disease by immune mechanisms that are independent of LDL lowering.

Atherosclerosis has been a chronic inflammatory process involving cells of the immune system such as T-cells and dendritic cells. Lipid-lowering statins are commonly used to treat the condition.

In recent years a new class of atherosclerosis drugs which inhibit the enzyme PCSK9 (proprotein convertase subtilisin kexin 9) has reached the marked. PCSK9 is known to target the LDL receptor, resulting in increased levels of low-density lipoprotein (LDL).

Researchers at Karolinska Institutet have examined how immune cells from human atherosclerotic plaques are affected by PCSK9. Using a new experimental system, they found that oxidized LDL, a central player in atherosclerosis, induced PCSK9 and promoted the maturation of dendritic cells. These dendritic cells then mediated the activation of T cells into a pro-inflammatory phenotype. PCSK9 inhibition reversed the effects of oxidized LDL on immune activation.

Could be anti-atherosclerotic

The researcher demonstrated immunological effects of PCSK9 concerning activation and maturation of DCs and plaque T-cells by OxLDL, a central player in atherosclerosis. This might directly influence atherosclerosis and cardiovascular disease, independent of LDL?lowering.???????

???????"This anti-inflammatory effect was unexpected and could potentially be anti-atherosclerotic, suggesting that the benefits of PCSK9 inhibition extend beyond lowering LDL cholesterol," said lead author Johan Frostegård, Professor at the Institute of Environmental Medicine, Karolinska Institutet.