Two Amino Acids Proximate to the Renin Cleavage Site of Human Angiotensinogen Do Not Affect Blood Pressure and Atherosclerosis in Mice—Brief Report

Chia Hua Wu, Congqing Wu, Deborah A. Howatt, Jessica J. Moorleghen, Lisa A. Cassis, Alan Daugherty, Hong S. Lu

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

Abstract

OBJECTIVE: Renin cleavage of angiotensinogen has species specificity. As the residues at positions 11 and 12 are different between human angiotensinogen and mouse angiotensinogen, we determined whether these 2 residues in angiotensinogen affect renin cleavage and angiotensin II-mediated blood pressure regulation and atherosclerosis using an adenoassociated viral approach for manipulating angiotensinogen in vivo. APPROACH AND RESULTS: Hepatocyte-specific angiotensinogen deficient (hepAGT−/−) mice in an LDL receptor–deficient background were infected with adenoassociated virals containing a null insert, human angiotensinogen, or mouse angiotensinogen expressing the same residues of the human protein at positions 11 and 12 (mouse angiotensinogen [L11V;Y12I]). Expression of human angiotensinogen in hepAGT−/− mice led to high plasma human angiotensinogen concentrations without changes in plasma endogenous mouse angiotensinogen, plasma renin concentrations, blood pressure, or atherosclerosis. This is consistent with human angiotensinogen not being cleaved by mouse renin. To determine whether the residues at positions 11 and 12 in human angiotensinogen lead to the inability of mouse renin to cleave human angiotensinogen, hepAGT−/− mice were injected with adenoassociated viral vector encoding mouse angiotensinogen (L11V;Y12I). Expression of mouse angiotensinogen (L11V;Y12I) in hepAGT−/− mice resulted in increased plasma mouse angiotensinogen concentrations, reduced renin concentrations, and increased renal AngII concentrations that were comparable to their concentrations in hepAGT+/+ mice. This mouse angiotensinogen variant increased blood pressure and atherosclerosis in hepAGT−/− mice to the magnitude of hepAGT+/+ mice. CONCLUSIONS: Replacement of L11 and Y12 to V11 and I12, respectively, in mouse angiotensinogen does not affect renin cleavage, blood pressure, and atherosclerosis in LDL receptor–deficient mice.

Original languageEnglish
Pages (from-to)2108-2113
Number of pages6
JournalArteriosclerosis, Thrombosis, and Vascular Biology
Volume40
Issue number9
DOIs
StatePublished - Sep 1 2020

Bibliographical note

Funding Information:
The authors’ research work was supported by the National Heart, Lung, and Blood Institute of the National Institutes of Health under award number R01HL139748. C. Wu is K99 awardee (K99HL145117) of the National Heart, Lung, and Blood Institute of the National Institutes of Health. The content in this manuscript is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Publisher Copyright:
© 2020 American Heart Association, Inc.

Keywords

  • angiotensin
  • atherosclerosis
  • blood pressure
  • hepatocyte
  • species specificity

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Fingerprint

Dive into the research topics of 'Two Amino Acids Proximate to the Renin Cleavage Site of Human Angiotensinogen Do Not Affect Blood Pressure and Atherosclerosis in Mice—Brief Report'. Together they form a unique fingerprint.

Cite this