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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., Yang, X., Ren, L., Lu, H.S., Sun, Y., Lin, H., Tan, L., Wang, N., Nguyen, G., Bader, M., Mullick, A.E., Danser, A.H.J., Daugherty, A., Jiang, Y., Sun, Y., 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 |
| ISSN: | 2297-055X |
| Publisher: | Frontiers Media SA |
| Volume: | 8 |
| 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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