Ischemic stroke is the third leading cause of death in the United States. There are limited avenues for reducing cerebral damage and promoting repair after ischemic stroke. The angiotensin (Ang) converting enzyme (ACE), Ang II and Ang AT1 receptor of the renin-angiotensin system (RAS) participate in the pathophysiology of various cardiovascular diseases including hypertension and stroke. With the discovery of the Ang converting enzyme 2 (ACE2), Ang (1-7) and Mas receptor, accumulating evidence suggest that the ACE2/Ang (1-7)/Mas axis counteracts the ACE/Ang II/AT1 axis in control of blood pressure and flow. However, the role of these counteracting axes in ischemic stroke is largely unknown. Reactive oxygen species (ROS) have been recognized as a major factor contributing to ischemic damage. Nitric oxide (NO) from endothelium nitric oxide synthase (eNOS) is important in maintaining normal cerebral blood flow. Activation of ACE/Ang II/AT1 axis has been shown to induce overproduction of NADPH oxidase (NOX) derived ROS and reduction of eNOS derived NO. A recent report shows that Ang (1-7)/Mas negatively modulates Ang II/AT1 activated NADPH oxidase in human endothelial cells. Evidence suggests that activation of ACE/Ang II/AT1 axis worsens ischemic stroke via both blood flow dependent and independent mechanisms. The bone marrow (BM) derived endothelial progenitor cells (EPCs) and ischemia-induced up-regulation of hypoxia induced factor-1 (HIF-1), stromal derived factor-1a (SDF-1a) and its receptor CXCR4 participate in the repair processes (angiogenesis and neurogenesis) after ischemic stroke. Taken together, we hypothesize that the ACE2/Ang (1-7)/Mas axis counteracts ACE/Ang II/AT1 in control of neural, cerebrovascular and EPCs function through modulating NOX/ROS, eNOS/NO and HIF-1/SDF-1a/CXCR4 signaling pathways, thereby playing an important role in cerebral ischemic damage and repair. To test this hypothesis, there transgenic mice models, R+A+ (renin and angiotensinogen over-expression), ACE2+ (ACE2 over-expressed in the brain) and R+A+ACE2+ (ACE2 over-expressed in the brain of R+A+) mice, and a lentiviral vector over-expressing ACE2 (lenti-ACE2) will be used for pursuing four specific aims using a variety of integrated physiological, pharmacological and molecular approaches:
Specific Aim 1 will test the role of ACE2/Ang (1-7)/Mas in counteracting ACE/Ang II/AT1 in ischemic damage through regulating blood pressure and cerebral blood flow.
Specific Aim 2 will examine the role of ACE2/Ang (1-7)/Mas in counteracting ACE/Ang II/AT1 in ischemic damage through mechanisms independent of blood pressure and cerebral blood flow.
Specific Aim 3 will study the role of ACE2/Ang (1-7)/Mas in counteracting ACE/Ang II/AT1 in cerebral repair after ischemic stroke.
Specific Aim 4 will investigate the role of ACE2/Ang (1-7)/Mas in counteracting ACE/Ang II/AT1 in the efficacy of EPCs transplantation for promoting repair after ischemic stroke.
Ischemic stroke is the third leading cause of death in the United States. Currently, there are no effective drugs for reducing cerebral damage and promoting repair after ischemic stroke. The renin-angiotensin system (RAS) is a possible therapeutic target for ischemic stroke. There are two arms of RAS, the angiotensin (Ang) converting enzyme (ACE), Ang II and Ang AT1 receptor (ACE/Ang II/AT1 axis) and the Ang converting enzyme 2 (ACE2), Ang (1-7) and Mas receptor (ACE2/Ang (1-7)/Mas receptor axis). This proposal will test the hypothesis that the ACE2/Ang (1- 7)/Mas axis via counteracting the ACE/Ang II/AT1 plays important roles in acute cerebral ischemic damage and repair. The results of this project will provide new insights on the role of Ang II/Ang (1-7) balance in the pathophysiology of ischemic stroke, and thus facilitate the development of novel therapeutic targets for ischemic stroke.
|Chen, Yusen; Lu, Bing; Wang, Jinju et al. (2015) Circulating CD133+ CD34+ progenitor cells and plasma stromal-derived factor-1alpha: predictive role in ischemic stroke patients. J Stroke Cerebrovasc Dis 24:319-26|
|Chen, Jian-ying; An, Ran; Liu, Zhen-jun et al. (2014) Therapeutic effects of mesenchymal stem cell-derived microvesicles on pulmonary arterial hypertension in rats. Acta Pharmacol Sin 35:1121-8|
|Zheng, J; Li, G; Chen, S et al. (2014) Activation of the ACE2/Ang-(1-7)/Mas pathway reduces oxygen-glucose deprivation-induced tissue swelling, ROS production, and cell death in mouse brain with angiotensin II overproduction. Neuroscience 273:39-51|
|Zheng, Jiao-Lin; Li, Guang-Ze; Chen, Shu-Zhen et al. (2014) Angiotensin converting enzyme 2/Ang-(1-7)/mas axis protects brain from ischemic injury with a tendency of age-dependence. CNS Neurosci Ther 20:452-9|
|Wang, Yang-Kai; Shen, Du; Hao, Qiang et al. (2014) Overexpression of angiotensin-converting enzyme 2 attenuates tonically active glutamatergic input to the rostral ventrolateral medulla in hypertensive rats. Am J Physiol Heart Circ Physiol 307:H182-90|
|Chen, Ji; Zhao, Yuhui; Chen, Shuzhen et al. (2014) Neuronal over-expression of ACE2 protects brain from ischemia-induced damage. Neuropharmacology 79:550-8|
|Gu, Shenhong; Zhang, Wei; Chen, Ji et al. (2014) EPC-derived microvesicles protect cardiomyocytes from Ang II-induced hypertrophy and apoptosis. PLoS One 9:e85396|
|Zhao, Yu-Hui; Yuan, Bin; Chen, Ji et al. (2013) Endothelial progenitor cells: therapeutic perspective for ischemic stroke. CNS Neurosci Ther 19:67-75|
|Chen, Ji; Xiao, Xiang; Chen, Shuzhen et al. (2013) Angiotensin-converting enzyme 2 priming enhances the function of endothelial progenitor cells and their therapeutic efficacy. Hypertension 61:681-9|
|Chen, Ji; Chen, Shuzhen; Chen, Yusen et al. (2011) Circulating endothelial progenitor cells and cellular membrane microparticles in db/db diabetic mouse: possible implications in cerebral ischemic damage. Am J Physiol Endocrinol Metab 301:E62-71|