ERp 44 Exerts Redox-Depe ndent Control of Blood Pressure at the ER Graphical Abstract Highlights

Graphical Abstract Highlights d Genetic loss of ERp44 destabilizes angiotensin II and causes hypotension in mice d ERp44 binds to ERAP1 in the ER in a redox-dependent manner d ERp44 suppresses the release of ERAP1, which cleaves angiotensin II in plasma d ERp44-ERAP1 complex inhibits hypotension during systemic inflammation In Brief Hisatsune et al. show that ERp44 inhibits hypotension during inflammation by regulating angiotensin II. ERp44 does this by sequestering the angiotensin II peptidase, ERAP1, via a redox-regulated disulfide bond with ERAP1. SUMMARY Blood pressure maintenance is vital for systemic ho-meostasis, 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 amino-peptidase 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 angio-tensin 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.