title: ERp44 Exerts Redox-Dependent Control of Blood Pressure at the ER.
abstract: Blood pressure maintenance is vital for systemic homeostasis, and angiotensin II is a critical regulator. The upstream mechanisms that regulate angiotensin II are not completely understood. Here, we show that angiotensin II is regulated by ERp44, a factor involved in disulfide bond formation in the ER. In mice, genetic loss of ERp44 destabilizes angiotensin II and causes hypotension. We show that ERp44 forms a mixed disulfide bond with ERAP1, an aminopeptidase that cleaves angiotensin II. ERp44 controls the release of ERAP1 in a redox-dependent manner to control blood pressure. Additionally, we found that systemic inflammation triggers ERAP1 retention in the ER to inhibit hypotension. These findings suggest that the ER redox state calibrates serum angiotensin II levels via regulation of the ERp44-ERAP1 complex. Our results reveal a link between ER function and normotension and implicate the ER redox state as a potential risk factor in the development of cardiovascular disease.
authors.affiliation: RIKEN Brain Science Institute (BSI), Laboratory for Developmental Neurobiology, 2-1 Hirosawa, Wako City, Saitama 351-0198, Japan. Electronic address: chihiro@brain.riken.jp.
authors.forename: Chihiro
authors.initials: C
authors.lastname: Hisatsune
authors.affiliation: RIKEN Brain Science Institute (BSI), Laboratory for Developmental Neurobiology, 2-1 Hirosawa, Wako City, Saitama 351-0198, Japan.
authors.forename: Etsuko
authors.initials: E
authors.lastname: Ebisui
authors.affiliation: RIKEN Brain Science Institute (BSI), Research Resources Center, 2-1 Hirosawa, Wako City, Saitama 351-0198, Japan.
authors.forename: Masaya
authors.initials: M
authors.lastname: Usui
authors.affiliation: RIKEN Brain Science Institute (BSI), Laboratory for Developmental Neurobiology, 2-1 Hirosawa, Wako City, Saitama 351-0198, Japan.
authors.forename: Naoko
authors.initials: N
authors.lastname: Ogawa
authors.affiliation: RIKEN Brain Science Institute (BSI), Laboratory for Developmental Neurobiology, 2-1 Hirosawa, Wako City, Saitama 351-0198, Japan.
authors.forename: Akio
authors.initials: A
authors.lastname: Suzuki
authors.affiliation: RIKEN Brain Science Institute (BSI), Research Resources Center, 2-1 Hirosawa, Wako City, Saitama 351-0198, Japan.
authors.forename: Nobuko
authors.initials: N
authors.lastname: Mataga
authors.affiliation: Department of Anatomy, School of Medicine, Hokkaido University, Sapporo 060-8638, Japan.
authors.forename: Hiromi
authors.initials: H
authors.lastname: Takahashi-Iwanaga
authors.affiliation: RIKEN Brain Science Institute (BSI), Laboratory for Developmental Neurobiology, 2-1 Hirosawa, Wako City, Saitama 351-0198, Japan; Calcium Oscillation Project, ICORP-SORST, Japan Science and Technology Agency (JST), 4-1-8 Honcho, Kawaguchi, Saitama 332-0012, Japan. Electronic address: mikosiba@brain.riken.jp.
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Mikoshiba
mesh_terms: D000595:Amino Acid Sequence; D000626:Aminopeptidases / Q000235:genetics / Q000378:metabolism*; D000804:Angiotensin II / Q000097:blood / Q000378:metabolism; D000818:Animals; D001794:Blood Pressure; D015153:Blotting, Western; D002478:Cells, Cultured; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015778:Minor Histocompatibility Antigens; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D010084:Oxidation-Reduction; D011485:Protein Binding; D034622:RNA Interference; D017386:Sequence Homology, Amino Acid
chemical_list: C520556:ERp44 protein, mouse; D008565:Membrane Proteins; D015778:Minor Histocompatibility Antigens; D018832:Molecular Chaperones; D000804:Angiotensin II; D000626:Aminopeptidases; C509944:ERAP1 protein, mouse