Abstract
Background: Accumulation of oxidized lipids in monocyte-derived macrophages results in foam cell formation and induces chronic inflammation in the vascular wall, thus contributing to the onset and progression of atherosclerosis. Scavenger receptor CD36 is the most important clearance receptor for ox-LDL, and has been implicated in triggering inflammatory responses in macrophages by ox-LDL. Genetically deleting CD36 reduced foam cell formation and lesion size in ApoE -/- mice. Additionally, circulating macrophages isolated from patients that are deficient of CD36 show much less ox-LDL uptake and accumulation than those from normal subjects. Recently, proprotein convertase subtilisin/kexin type 9 (PCSK9) has been identified as a regulator of CD36 protein degradation. Interestingly, we found that inhibiting the hepatic (pro)renin receptor [(P)RR] dramatically increased plasma PCSK9 levels in C57BL/6J mice. Thus, we wondered if the (P)RR could regulate CD36 protein degradation and functions by increasing PCSK9 levels. Methods and Results: We inhibited hepatic (P)RR expression in PCSK9 -/- mice and wildtype mice, using GalNAc-modified anti-sense oligos targeting the (P)RR. Hepatic (P)RR inhibition reduced hepatic CD36 protein abundance by ~40% in WT mice, without affecting CD36 transcriptional levels. Unexpectedly, inhibiting hepatic (P)RR in PCSK9 -/- mice showed a similar reduction in hepatic CD36 protein abundance, suggesting that such reduction in CD36 is unlikely to be mediated by increased plasma PCSK9 levels. To clarify this, we exogenously expressed CD36 in HEK293T cells and studied whether silencing the (P)RR could directly affect CD36 protein abundance. Indeed, silencing the (P)RR reduced exogenously expressed CD36 by almost 50%, confirming that the (P)RR directly controls CD36 degradation. Functional studies revealed that inhibiting/deleting the (P)RR attenuated fatty acid uptake in differentiated 3T3-L1 adipocytes, and ox-LDL uptake in circulating mouse macrophages in a CD36-dependent manner. Conclusion: The (P)RR acts as a post-transcriptional regulator of CD36, and this occurs in a PCSK9-independent manner. Macrophagic (P)RR may play a role in the development of atherosclerosis by interacting with CD36.
Published Version
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