Basic Biomedical Sciences, Sanford School of Medicine, University of South Dakota, Vermillion, South Dakota, United States of America.
PLoS One. 2013 Oct 30;8(10):e78564. doi: 10.1371/journal.pone.0078564. eCollection 2013.
Hypertension is a highly prevalent disorder and a major risk factor for cardiovascular diseases. Hypertensive vascular remodeling is the pathological mal-adaption of blood vessels to the hypertensive condition that contributes to further development of high blood pressure and end-organ damage. Hypertensive remodeling involves, at least in part, changes in protein turnover. The ubiquitin proteasome system (UPS) is a major protein quality and quantity control system. This study tested the hypothesis that the proteasome inhibitor, bortezomib, would attenuate AngII-induced hypertension and its sequelae such as aortic remodeling in rats.
METHODOLOGY/PRINCIPAL FINDINGS: Male Sprague Dawley rats were subjected to AngII infusion for two weeks in the absence or presence of bortezomib. Mean arterial pressure was measured in conscious rats. Aortic tissue was collected for estimation of wall area, collagen deposition and expression of tissue inhibitors of matrix metalloproteases (TIMP), Ki67 (a marker of proliferation), reactive oxygen species (ROS) and VCAM-1 (a marker of inflammation). AngII infusion increased arterial pressure significantly (160±4 mmHg vs. vehicle treatment 133±2 mmHg). This hypertensive response was attenuated by bortezomib (138±5 mmHg). AngII hypertension was associated with significant increases in aortic wall to lumen ratio (∼29%), collagen deposition (∼14%) and expression of TIMP1 and TIMP2. AngII also increased MMP2 activity, proteasomal chymotrypsin-like activity, Ki67 staining, ROS generation and VCAM-1 immunoreactivity. Co-treatment of AngII-infused rats with bortezomib attenuated these AngII-induced responses.
Collectively, these data support the idea that proteasome activity contributes to AngII-induced hypertension and hypertensive aortic vascular remodeling at least in part by modulating TIMP1/2 and MMP2 function. Preliminary observations are consistent with a role for ROS, inflammatory and proliferative mechanisms in this effect. Further understanding of the mechanisms by which the proteasome is involved in hypertension and vascular structural remodeling may reveal novel targets for pharmacological treatment of hypertension, hypertensive remodeling or both.
高血压是一种高发疾病，也是心血管疾病的主要危险因素。高血压血管重塑是血管对高血压状况的病理性适应不良，导致血压进一步升高和靶器官损伤。血管重塑至少部分涉及蛋白质周转的变化。泛素蛋白酶体系统（UPS）是一种主要的蛋白质质量和数量控制系统。本研究检验了这样一个假设，即蛋白酶体抑制剂硼替佐米（Bortezomib）可减轻血管紧张素 II（AngII）诱导的高血压及其在大鼠中的后果，如主动脉重塑。
方法/主要发现：雄性 Sprague Dawley 大鼠在无或有硼替佐米的情况下接受 AngII 输注两周。在清醒大鼠中测量平均动脉压。收集主动脉组织，用于估计壁面积、胶原沉积以及基质金属蛋白酶组织抑制剂（TIMP）、Ki67（增殖标志物）、活性氧（ROS）和 VCAM-1（炎症标志物）的表达。AngII 输注显著增加动脉压（160±4mmHg 与对照治疗 133±2mmHg）。硼替佐米减轻了这种高血压反应（138±5mmHg）。AngII 高血压与主动脉壁腔比（约 29%）、胶原沉积（约 14%）和 TIMP1 和 TIMP2 的表达显著增加有关。AngII 还增加了 MMP2 活性、蛋白酶体糜蛋白酶样活性、Ki67 染色、ROS 生成和 VCAM-1 免疫反应性。AngII 输注大鼠的硼替佐米联合治疗减轻了这些 AngII 诱导的反应。
总的来说，这些数据支持这样一种观点，即蛋白酶体活性至少部分通过调节 TIMP1/2 和 MMP2 功能，促进 AngII 诱导的高血压和高血压性主动脉血管重塑。初步观察结果与 ROS、炎症和增殖机制在这种效应中的作用一致。进一步了解蛋白酶体在高血压和血管结构重塑中的作用机制，可能为高血压、高血压性重塑或两者的药物治疗揭示新的靶点。
