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(Pro)renin receptor inhibition reduces plasma cholesterol and triglycerides but does not attenuate atherosclerosis in atherosclerotic mice

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Item Type:Article
Title:(Pro)renin receptor inhibition reduces plasma cholesterol and triglycerides but does not attenuate atherosclerosis in atherosclerotic mice
Creators Name:Ye, D. and Yang, X. and Ren, L. and Lu, H.S. and Sun, Y. and Lin, H. and Tan, L. and Wang, N. and Nguyen, G. and Bader, M. and Mullick, A.E. and Danser, A.H.J. and Daugherty, A. and Jiang, Y. and Sun, Y. and Li, F. and Lu, X.
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.
Keywords:Macrophage, Cholesterol, V-ATPase = Vacuolar H+-Adenosine Triphosphatase, Renin-Angiotensin System, (Pro)Renin Receptor (PRR), Animals, Mice
Source:Frontiers in Cardiovascular Medicine
Publisher:Frontiers Media SA
Page Range:725203
Date:24 December 2021
Official Publication:https://doi.org/10.3389/fcvm.2021.725203
PubMed:View item in PubMed

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