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

Dien Ye1,2,3, Xiaofei Yang4, Liwei Ren1,3

  • 1Department of Pharmacology, College of Pharmacy, Shenzhen Technology University, Shenzhen, China.

Frontiers in Cardiovascular Medicine
|January 10, 2022
PubMed

Insights

Inhibiting hepatic (pro)renin receptor [(P)RR] lowered lipids but worsened atherosclerosis by increasing inflammation in macrophages. Hepatic and macrophage (P)RR have counteracting roles in atherosclerosis development.

Area of Science:

  • Cardiovascular Research
  • Molecular Biology
  • Immunology

Background:

  • Elevated plasma cholesterol contributes to ischemic cardiovascular diseases.
  • Hepatic (pro)renin receptor [(P)RR] inhibition previously attenuated hyperlipidemia in LDLR deficient mice.
  • The role of hepatic (P)RR in atherosclerosis requires further investigation.

Purpose of the Study:

  • To determine if inhibiting hepatic (pro)renin receptor [(P)RR] could attenuate atherosclerosis.
  • To investigate the impact of (P)RR inhibition on lipid profiles and atherosclerotic lesion development.
  • To elucidate the counteracting roles of hepatic and macrophage (P)RR in atherosclerosis.

Main Methods:

  • Low-density lipoprotein receptor (LDLR) deficient and apolipoprotein E (ApoE) deficient mice were treated with N-acetylgalactosamine-modified antisense oligonucleotides (G-ASOs) targeting hepatic (P)RR.
  • Mice were fed a western-type diet (WTD) for 16 weeks.
  • Plasma lipid concentrations, atherosclerosis, and aortic gene expression were analyzed. Macrophage (P)RR function was assessed through genetic deletion and inflammatory response assays.

Main Results:

  • (P)RR G-ASOs significantly reduced plasma cholesterol and triglyceride levels in LDLR-/- mice.
  • Despite lipid reduction, atherosclerosis was not attenuated but rather increased in (P)RR G-ASO treated mice.
  • Transcriptomic analysis revealed (P)RR G-ASOs induced pro-inflammatory gene expression in aortas and inhibited (P)RR in macrophages, exacerbating atherosclerosis upon deletion.

Conclusions:

  • Hepatic (P)RR inhibition effectively reduces plasma lipids but can promote atherosclerosis by enhancing macrophage inflammation.
  • (P)RR downregulation in macrophages counteracts the beneficial effects of lipid lowering on atherosclerosis.
  • Hepatic and macrophage (P)RR play counteracting roles in the development of atherosclerosis.

Keywords:
(Pro)renin receptor (PRR)V-ATPase = vacuolar H+-adenosine triphosphatasecholesterolmacrophagerenin- angiotensin system

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