Abstract
Objective: Elevated plasma cholesterol concentrations contributes to ischemic cardiovascular diseases. Recently, we showed that inhibiting hepatic (pro)renin receptor [(P)RR] attenuated diet-induced hypercholesterolemia and hypertriglyceridemia in low-density lipoprotein receptor (LDLR) deficient mice. The purpose of this study was to determine whether inhibiting hepatic (P)RR could attenuate atherosclerosis. Approach and Results: Eight-week-old male LDLR -/- mice were injected with either saline or N-acetylgalactosamine-modified antisense oligonucleotides (G-ASOs) primarily targeting hepatic (P)RR and were fed a western-type diet (WTD) for 16 weeks. (P)RR G-ASOs markedly reduced plasma cholesterol concentrations from 2,211 ± 146 to 1,128 ± 121 mg/dL. Fast protein liquid chromatography (FPLC) analyses revealed that cholesterol in very low-density lipoprotein (VLDL) and intermediate density lipoprotein (IDL)/LDL fraction were potently reduced by (P)RR G-ASOs. Moreover, (P)RR G-ASOs reduced plasma triglyceride concentrations by more than 80%. Strikingly, despite marked reduction in plasma lipid concentrations, atherosclerosis was not reduced but rather increased in these mice. Further testing in ApoE -/- mice confirmed that (P)RR G-ASOs reduced plasma lipid concentrations but not atherosclerosis. Transcriptomic analysis of the aortas revealed that (P)RR G-ASOs induced the expression of the genes involved in immune responses and inflammation. Further investigation revealed that (P)RR G-ASOs also inhibited (P)RR in macrophages and in enhanced inflammatory responses to exogenous stimuli. Moreover, deleting the (P)RR in macrophages resulted in accelerated atherosclerosis in WTD fed ApoE -/- mice. Conclusion: (P)RR G-ASOs reduced the plasma lipids in atherosclerotic mice due to hepatic (P)RR deficiency. However, augmented pro-inflammatory responses in macrophages due to (P)RR downregulation counteracted the beneficial effects of lowered plasma lipid concentrations on atherosclerosis. Our study demonstrated that hepatic (P)RR and macrophage (P)RR played a counteracting role in atherosclerosis.
Original language | English |
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Article number | 725203 |
Journal | Frontiers in Cardiovascular Medicine |
Volume | 8 |
DOIs | |
Publication status | Published - Dec 2021 |
Bibliographical note
FUNDING:The author XL is supported by National Natural Science
Foundation of China (81870605), Shenzhen Municipal Science
and Technology Innovation Council (JCYJ20190808170401660),
and Shenzhen Key Laboratory of Metabolism and Cardiovascular
Homeostasis (ZDSYS20190902092903237). YuS is supported by
National Natural Science Foundation of China (81800383).
FL is supported by National Natural Science Foundation
of China (81670702), and Shenzhen Municipal Science and
Technology Innovation Council (GJHZ20170310090257380).
AHJD is supported by the Top Institute Pharma (T2-301). YiS
is supported by Guangdong Basic and Applied Basic Research
Foundation (2019A1515110993). YJ is supported by Shenzhen
Municipal Science and Technology Innovation Council (Grant
No. JCYJ20180305124812444).
Copyright © 2021 Ye, Yang, Ren, Lu, Sun, Lin, Tan, Wang, Nguyen, Bader, Mullick, Danser, Daugherty, Jiang, Sun, Li and Lu.