RIKEN Brain Science Institute (BSI), Laboratory for Developmental Neurobiology, 2-1 Hirosawa, Wako City, Saitama 351-0198, Japan.
RIKEN Brain Science Institute (BSI), Laboratory for Developmental Neurobiology, 2-1 Hirosawa, Wako City, Saitama 351-0198, Japan.
Mol Cell. 2015 Jun 18;58(6):1015-27. doi: 10.1016/j.molcel.2015.04.008. Epub 2015 May 7.
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.
血压的维持对全身内环境稳定至关重要，血管紧张素 II 是一种关键的调节因子。然而，调节血管紧张素 II 的上游机制尚不完全清楚。在这里，我们发现 ERp44 可调节血管紧张素 II，它是内质网中参与二硫键形成的一个因素。在小鼠中，ERp44 的遗传缺失会使血管紧张素 II 不稳定，导致低血压。我们发现 ERp44 与 ERAP1 形成混合二硫键，后者是一种切割血管紧张素 II 的氨肽酶。ERp44 以氧化还原依赖的方式控制 ERAP1 的释放，从而控制血压。此外，我们发现系统性炎症会触发 ERAP1 在 ER 中的滞留，从而抑制低血压。这些发现表明，内质网的氧化还原状态通过调节 ERp44-ERAP1 复合物来校准血清血管紧张素 II 水平。我们的研究结果揭示了 ER 功能与正常血压之间的联系，并暗示 ER 氧化还原状态可能是心血管疾病发展的一个潜在风险因素。
