The objective of this proposal is to determine the role and mechanisms of kallistatin in repairing vascular injury. Endothelial damage plays a pivotal role in the development of vascular diseases. It has been shown that the number and migratory capacity of endothelial progenitor cells (EPCs) are decreased in patients with cardiovascular diseases. Therefore, restoration of EPC number and function is a promising approach to endothelial repair by providing a continuous source of replenishment for damaged and senescent vessels. Kallistatin, a plasma protein, was discovered in our laboratory. We have demonstrated that kallistatin exerts multiple protective effects against cardiovascular and renal dysfunction by inhibiting inflammation and oxidative stress in animal models and cultured cells. Importantly, kallistatin increases circulating EPC levels and reduces aortic oxidative stress in hypertensive rats, as well as promotes the migration and decreases the senescence of cultured EPCs. Our central hypothesis is that kallistatin prevents vascular damage by stimulating EPC mobilization and functional activity and reducing EPC senescence through decreased oxidative stress and enhanced nitric oxide production. We will pursue the following specific aims: 1) determine the mechanisms by which kallistatin promotes vascular repair by enhancing EPC migration, adhesion, tube formation and proliferation;2) determine the mechanisms by which kallistatin prevents vascular injury by inhibiting EPC senescence; and 3) determine the novel role of kallistatin in endothelial injury by using kallistatin administration and kallistatin depletion approaches in hypertensive rats, kallistatin transgenic mice and knockout mice. The outcomes of the proposed research are expected to have an important positive impact by providing a novel approach using kallistatin-based therapy to improve endothelial repair for vascular diseases.
The objective of this application is to investigate the role of kallistatin in endothelial injury associated with hypertension. Endothelial dysfunction correlates with major causes of morbidity and mortality in cardiovascular diseases. Reduced circulating endothelial progenitor cell (EPC) levels occur in conjunction with endothelial dysfunction and an increased risk of cardiovascular events. Kallistatin may exert an important novel role in protection against vascular damage by stimulating the mobilization, viability and functional activity of EPCs. The outcomes of the proposed research are expected to have an important positive impact by providing a novel approach using kallistatin-based therapy to improve endothelial repair for vascular diseases.
|Guo, Youming; Chao, Lee; Chao, Julie (2018) Kallistatin attenuates endothelial senescence by modulating Let-7g-mediated miR-34a-SIRT1-eNOS pathway. J Cell Mol Med 22:4387-4398|
|Chao, Julie; Guo, Youming; Li, Pengfei et al. (2017) Role of Kallistatin Treatment in Aging and Cancer by Modulating miR-34a and miR-21 Expression. Oxid Med Cell Longev 2017:5025610|
|Chao, Julie; Li, Pengfei; Chao, Lee (2017) Kallistatin suppresses cancer development by multi-factorial actions. Crit Rev Oncol Hematol 113:71-78|
|Chao, Julie; Li, Pengfei; Chao, Lee (2017) Kallistatin: double-edged role in angiogenesis, apoptosis and oxidative stress. Biol Chem 398:1309-1317|
|Chao, Julie; Bledsoe, Grant; Chao, Lee (2016) Protective Role of Kallistatin in Vascular and Organ Injury. Hypertension 68:533-41|
|Li, Pengfei; Guo, Youming; Bledsoe, Grant et al. (2016) Kallistatin induces breast cancer cell apoptosis and autophagy by modulating Wnt signaling and microRNA synthesis. Exp Cell Res 340:305-14|
|Lin, Wei-Chieh; Chen, Chang-Wen; Huang, Yu-Wen et al. (2015) Kallistatin protects against sepsis-related acute lung injury via inhibiting inflammation and apoptosis. Sci Rep 5:12463|
|Guo, Youming; Li, Pengfei; Bledsoe, Grant et al. (2015) Kallistatin inhibits TGF-?-induced endothelial-mesenchymal transition by differential regulation of microRNA-21 and eNOS expression. Exp Cell Res 337:103-10|
|Li, Pengfei; Guo, Youming; Bledsoe, Grant et al. (2015) Kallistatin treatment attenuates lethality and organ injury in mouse models of established sepsis. Crit Care 19:200|
|Gao, Lin; Li, Pengfei; Zhang, Jingmei et al. (2014) Novel role of kallistatin in vascular repair by promoting mobility, viability, and function of endothelial progenitor cells. J Am Heart Assoc 3:e001194|
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