(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

doi:10.3389/fcvm.2021.725203

(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^*

^*Corresponding author for this work

Internal Medicine

Research output: Contribution to journal › Article › Academic › peer-review

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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
Article number	725203
Journal	Frontiers in Cardiovascular Medicine
Volume	8
DOIs	https://doi.org/10.3389/fcvm.2021.725203
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.

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(Pro)renin Receptor Inhibition Reduces Plasma Cholesterol and Triglycerides but Does Not Attenuate Atherosclerosis in Atherosclerotic MicFinal published version, 2.02 MB

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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., & Lu, X. (2021). (Pro)renin Receptor Inhibition Reduces Plasma Cholesterol and Triglycerides but Does Not Attenuate Atherosclerosis in Atherosclerotic Mice. Frontiers in Cardiovascular Medicine, 8, Article 725203. https://doi.org/10.3389/fcvm.2021.725203

@article{6663682a949a4aaf978ee43711d0e92e,

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

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. ",

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

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 {\textcopyright} 2021 Ye, Yang, Ren, Lu, Sun, Lin, Tan, Wang, Nguyen, Bader, Mullick, Danser, Daugherty, Jiang, Sun, Li and Lu.",

year = "2021",

month = dec,

doi = "10.3389/fcvm.2021.725203",

language = "English",

volume = "8",

journal = "Frontiers in Cardiovascular Medicine",

issn = "2297-055X",

publisher = "Frontiers Media S.A.",

}

Ye, D, Yang, X, Ren, L, Lu, HS, Sun, Y, Lin, H , Tan, L , Wang, N, Nguyen, G, Bader, M, Mullick, AE, Danser, AHJ, Daugherty, A, Jiang, Y, Sun, Y, Li, F & Lu, X 2021, '(Pro)renin Receptor Inhibition Reduces Plasma Cholesterol and Triglycerides but Does Not Attenuate Atherosclerosis in Atherosclerotic Mice', Frontiers in Cardiovascular Medicine, vol. 8, 725203. https://doi.org/10.3389/fcvm.2021.725203

TY - JOUR

T1 - (Pro)renin Receptor Inhibition Reduces Plasma Cholesterol and Triglycerides but Does Not Attenuate Atherosclerosis in Atherosclerotic Mice

AU - Ye, Dien

AU - Yang, Xiaofei

AU - Ren, Liwei

AU - Lu, Hong S

AU - Sun, Yuan

AU - Lin, Hui

AU - Tan, Lunbo

AU - Wang, Na

AU - Nguyen, Genevieve

AU - Bader, Michael

AU - Mullick, Adam E

AU - Danser, A H Jan

AU - Daugherty, Alan

AU - Jiang, Yizhou

AU - Sun, Yidan

AU - Li, Furong

AU - Lu, Xifeng

N1 - 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.

PY - 2021/12

Y1 - 2021/12

N2 - 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.

AB - 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.

U2 - 10.3389/fcvm.2021.725203

DO - 10.3389/fcvm.2021.725203

M3 - Article

C2 - 35004870

SN - 2297-055X

VL - 8

JO - Frontiers in Cardiovascular Medicine

JF - Frontiers in Cardiovascular Medicine

M1 - 725203

ER -

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

Abstract

Bibliographical note

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