Proprotein convertase subtilisin/kexin type 9 (PCSK9) promotes
atherosclerosis by increasing
low-density lipoprotein (
LDL) cholesterol levels through degradation of hepatic
LDL receptor (LDLR). Studies have described the systemic effects of PCSK9 on
atherosclerosis, but whether PCSK9 has local and direct effects on the plaque is unknown. To study the local effect of human PCSK9 (hPCSK9) on atherosclerotic lesion composition, independently of changes in serum
cholesterol levels, we generated chimeric mice expressing hPCSK9 exclusively from macrophages, using marrow from hPCSK9 transgenic (hPCSK9tg) mice transplanted into
apoE(-/-) and LDLR(-/-) mice, which were then placed on a high-fat diet (HFD) for 8 weeks. We further characterized the effect of hPCSK9 expression on the inflammatory responses in the spleen and by mouse peritoneal macrophages (MPM) in vitro. We found that
MPMs from transgenic mice express both murine (m) Pcsk9 and hPCSK9 and that the latter reduces macrophage LDLR and LRP1 surface levels. We detected hPCSK9 in the serum of mice transplanted with hPCSK9tg marrow, but did not influence
lipid levels or atherosclerotic lesion size. However, marrow-derived PCSK9 progressively accumulated in lesions of
apoE(-/-) recipient mice, while increasing the infiltration of Ly6C(hi) inflammatory monocytes by 32% compared with controls. Expression of hPCSK9 also increased CD11b- and Ly6C(hi) -positive cell numbers in spleens of
apoE(-/-) mice. In vitro, expression of hPCSK9 in LPS-stimulated macrophages increased
mRNA levels of the pro-inflammatory markers Tnf and Il1b (40% and 45%, respectively) and suppressed those of the anti-inflammatory markers
Il10 and Arg1 (30% and 44%, respectively). All PCSK9 effects were LDLR-dependent, as PCSK9
protein was not detected in lesions of LDLR(-/-) recipient mice and did not affect macrophage or splenocyte
inflammation. In conclusion, PCSK9 directly increases atherosclerotic lesion
inflammation in an LDLR-dependent but
cholesterol-independent mechanism, suggesting that therapeutic PCSK9 inhibition may have vascular benefits secondary to
LDL reduction.