(Pro)renin Receptor Inhibition Reduces Plasma Cholesterol and Triglycerides but Does Not Attenuate Atherosclerosis in Atherosclerotic Mice

Dien Ye, Xiaofei Yang, Liwei Ren, Hong S. Lu, Yuan Sun, Hui Lin, Lunbo Tan, Na Wang, Genevieve Nguyen, Michael Bader, Adam E. Mullick, A. H.Jan Danser, Alan Daugherty, Yizhou Jiang, Yidan Sun, Furong Li, Xifeng Lu

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

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 languageEnglish
Article number725203
JournalFrontiers in Cardiovascular Medicine
Volume8
DOIs
StatePublished - 2021

Bibliographical note

Publisher Copyright:
Copyright © 2021 Ye, Yang, Ren, Lu, Sun, Lin, Tan, Wang, Nguyen, Bader, Mullick, Danser, Daugherty, Jiang, Sun, Li and Lu.

Keywords

  • (Pro)renin receptor (PRR)
  • V-ATPase = vacuolar H+-adenosine triphosphatase
  • cholesterol
  • macrophage
  • renin- angiotensin system

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Fingerprint

Dive into the research topics of '(Pro)renin Receptor Inhibition Reduces Plasma Cholesterol and Triglycerides but Does Not Attenuate Atherosclerosis in Atherosclerotic Mice'. Together they form a unique fingerprint.

Cite this