高血压是致心脑血管疾病的元凶。随着人口老龄化老年性高血压发病率逐年增多，但其发病机理不明。其诸多发病原因的下游共同点是血管中氧自由基增多。Rac1是NOX的调节亚基。血管转Rac1持久活性突变体小鼠有高血压表型。Rac1无高活性突变体，但有一天然持久活性剪接变异体Rac1b。申请人在血管平滑肌中发现其转录量及活性占比达20%，但生理意义不明！在WT年轻大鼠，高血压能上调血管中Rac1b并加重血管Rac1b-TG鼠血管中膜厚度，-KO鼠中膜不增厚。中老年TG-high鼠有恶性高血压，-low鼠有类似老年性高血压，而-KO鼠BP随增龄不变。芯片筛选出VPO1为Rac1b下游靶基因。接下来要完善高血压记录及解明：动脉中Rac1b随增龄改变、与NOX结合及持续产生自由基、抗氧化剂降压效果、VPO1促细胞增生及调节胞外间质成份及其机制。证明Rac1b是通过VPO1致动脉硬化及老年性高血压的责任分子。

Hypertension (HT) is affecting about 30% of the adult population worldwide and the total number of patients with HT reaches 2 billion, including 270~440 million in China. HT is associated with significantly increased risk of cardiovascular diseases and stroke. Of the patients with HT, HT in the elderly (HTeld) accounts for a big percentage. Arterial stiffness and a thickened media (TM) have closely participated in the pathogenesis of HTeld and its complications. TM is associated with a narrowed inner lumen, and an increased ratio of medial to inner lumen, with changes in a series of dysfunction such as decreased compliance, increased stiffness, deteriorated endothelial function, and compromised vascular constriction/relaxation. TM is a result of abnormal hypertrophy, disarrangement, and proliferation of vascular smooth muscle cells (VSMCs), excessive secretion/deposition of extracellular matrix col-1, col-3, fibronectin, and reduced production of elastin...All HTeld-causing pathogens have a common downstream mechanical feature, i.e. a potentiated effect of reactive oxygen species (ROS) in the local vessels. Small G-protein Rac1 is the regulatory subunit of the ROS-producing NOX 1~3. Previous studies demonstrated that the transgenic mice of vascular-specific overexpression of constitutive Rac1-V12 artificial mutant has HT and TM features. Unlike several activating mutations reported in other members of Ras family members, there has been no any mutation discovered in the Rac1 gene...Instead, Rac1 gene has an alternatively-spliced form of Rac1b. Rac1b is characterized by the insertion of an additional 19 amino acids (exon-3b) behind the switch-II region. Rac1b exists in cells in a predominantly active GTP-bound form and triggers different downstream signaling cascades as compared to Rac1. We have already reported Rac1b-specific 505 DEGs and that Rac1b enhances cell spreading, potentiates cell proliferation through JNK2/c-JUN/Cyclin-D1 and inhibits apoptosis through AKT2/MCL1 pathways. Furthermore, we found and confirmed that PXDN/VPO1 is a significant DEG of Rac1b over Rac1...In our pilot studies, we found that Rac1b is mildly expressed in WT rat aorta and potentiated in the HT aorta induced by both Ang-II infusion and abdominal aortic coarctation (AAC). While Rac1b-KO rat demonstrated a remarkably-attenuated AAC-induced TM. We found that young Rac1b-TG-high rat has TM and deteriorated relaxation prior to HT as compared to WT and Rac1b-KO rats. As aging, TG-high rats developed a malignant HT while Rac1b-TG-low rat has a HT type similar to human HTeld. Both TG-high and –low rats has shorter life span, damaged vessel distensibility, and typical hypertensive TM in aorta, carotid artery, and small resistant arteries. Most importantly, Rac1b-KO rats have no rise in BP as growing older. These results strongly indicated that Rac1b’s up-regulation is involved in the process of the Ang-II- or AAC-induced TM. We thus hypothesize that Rac1b plays an important role in the pathogenesis of TM and HTeld through PXDN/VPO1...Next we schedule: to study whether Rac1b has age-dependent changes in expression and activity, to identify whether Rac1b bind to NOX1~3 and constitutively produce ROS, to test anti-HT effect of the antioxidant NAC, to study PXDN/VPO1’s effects on pro-proliferation and on changes of ECM secretion of col-1, col-3, fibronectin, elastin, and to identify Rac1b-PXDN/VPO1-HOCl-TM/HTeld pathway using a rat with global knock-out of Rac1b gene, a rat with global knock-out of PXDN/VPO1 gene (global KO is not lethal), and a cross-bred double knock-out of both Rac1b and PXDN/VPO1 genes. Our study aims to elucidate whether Rac1b and its downstream PXDN/VPO1 is a new drug-discovery target for effectively blocking or retardating the pathogenesis of HTeld and its complications.