Catalpol stimulates VEGF production via the JAK2/STAT3 pathway to improve angiogenesis in rats' stroke model.
BACKGROUND
Catalpol is the main active component of the radix from Rehmannia glutinosa Libosch, which has pleiotropic protective effects in neurodegenerative diseases, ischemic stroke, metabolic disorders and others


OBJECTIVE
Catalpol has been shown to have neuroprotective, neurorepair, and angiogenesis effects following ischemic brain injury. However, its molecular mechanisms are still poorly understood. In previous studies, the JAK2/STAT3 signaling pathway was found to play a role in neuroprotection and angiogenesis. This study investigated the role of catalpol in stimulating angiogenesis via the JAK2/STAT3 pathway after permanent focal cerebral ischemia (pMCAO).


METHODS
Rats were subjected to right middle cerebral artery occlusion through electrocoagulation and were treated with catalpol (5mg/kg), AG490 was also used to inhibit STAT3 phosphorylation (pSTAT3).


RESULTS
Following stroke, Catalpol improved the neuroethology deficit, increased the cerebral blood flow (CBF) of infarcted brain and upregulated EPO and EPOR. AG490 suppressed the phosphorylation of signal transducer and activator of transcription 3 (STAT3), ultimately inhibited VEGF mRNA expression, which reduced VEGF protein expression and inhibited stroke-induced angiogenesis. However, Catalpol enhanced stroke-induced STAT3 activation and subsequently restored STAT3 activity through the recovery of STAT3 binding to VEGF. Moreover, Catalpol reversed the effect of AG490 on STAT3 activation and nuclear translocation, restored the transcriptional activity of the VEGF promoter by recruiting STAT3 to the VEGF promoter, improved VEGF mRNA and protein expression, increased angiogenesis, reduced the difference in CBF between the infarcted and intact brain and ameliorated the neuroethology behaviors after stroke.


CONCLUSIONS
Catalpol affects neuroprotection and angiogenesis via the JAK2/STAT3 signaling pathway, which is mediated by STAT3 activation and VEGF expression. Catalpol may be used as a potential therapeutic drug for stroke.
Department of Emergency, the First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China.
Wan
W
Dong
Department of Pharmacy, The Seventh People's Hospital of Chengdu, Chengdu 610041, China.
Yang
Y
Xian
College of Pharmaceutical Sciences and Traditional Chinese Medicine, Southwest University, Chongqing 400715, China; Chongqing Engineering Research Center for Pharmacological Evaluation, Chongqing 400715, China; Engineering Research Center for Chongqing Pharmaceutical Process and Quality Control, Chongqing 400715, China.
Wang
W
Yuan
College of Pharmaceutical Sciences and Traditional Chinese Medicine, Southwest University, Chongqing 400715, China; Chongqing Engineering Research Center for Pharmacological Evaluation, Chongqing 400715, China; Engineering Research Center for Chongqing Pharmaceutical Process and Quality Control, Chongqing 400715, China. Electronic address: zhfbsci@126.com.
Zhu
Z
Huifeng
College of Pharmaceutical Sciences and Traditional Chinese Medicine, Southwest University, Chongqing 400715, China; Chongqing Engineering Research Center for Pharmacological Evaluation, Chongqing 400715, China; Engineering Research Center for Chongqing Pharmaceutical Process and Quality Control, Chongqing 400715, China.
Wang
W
Tao
Department of Pharmacy, The First People's Hospital of Neijiang, Neijiang 641000, China.
Liu
L
Zhiqiang
College of Pharmaceutical Sciences and Traditional Chinese Medicine, Southwest University, Chongqing 400715, China; Chongqing Engineering Research Center for Pharmacological Evaluation, Chongqing 400715, China; Engineering Research Center for Chongqing Pharmaceutical Process and Quality Control, Chongqing 400715, China.
Feng
F
Shan
College of Chemistry and Chemical Engineering, Chongqing University of Science & Technology, Chongqing 401331, China.
Fu
F
Ya
College of Pharmaceutical Sciences and Traditional Chinese Medicine, Southwest University, Chongqing 400715, China; Chongqing Engineering Research Center for Pharmacological Evaluation, Chongqing 400715, China; Engineering Research Center for Chongqing Pharmaceutical Process and Quality Control, Chongqing 400715, China.
Wang
W
Hongli
College of Pharmaceutical Sciences and Traditional Chinese Medicine, Southwest University, Chongqing 400715, China; Chongqing Engineering Research Center for Pharmacological Evaluation, Chongqing 400715, China; Engineering Research Center for Chongqing Pharmaceutical Process and Quality Control, Chongqing 400715, China.
Wang
W
Jinghuan
College of Pharmaceutical Sciences and Traditional Chinese Medicine, Southwest University, Chongqing 400715, China; Chongqing Engineering Research Center for Pharmacological Evaluation, Chongqing 400715, China; Engineering Research Center for Chongqing Pharmaceutical Process and Quality Control, Chongqing 400715, China.
Qin
Q
Lei
College of Pharmaceutical Sciences and Traditional Chinese Medicine, Southwest University, Chongqing 400715, China; Chongqing Engineering Research Center for Pharmacological Evaluation, Chongqing 400715, China; Engineering Research Center for Chongqing Pharmaceutical Process and Quality Control, Chongqing 400715, China.
Zou
Z
Li
College of Pharmaceutical Sciences and Traditional Chinese Medicine, Southwest University, Chongqing 400715, China; Chongqing Engineering Research Center for Pharmacological Evaluation, Chongqing 400715, China; Engineering Research Center for Chongqing Pharmaceutical Process and Quality Control, Chongqing 400715, China.
Qi
Q
Hongyi
D043925:Angiogenesis Inducing Agents / Q000494:pharmacology*; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D002536:Cerebral Arteries / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D002560:Cerebrovascular Circulation / Q000187:drug effects; D004195:Disease Models, Animal; D004921:Erythropoietin / Q000378:metabolism; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D057888:Iridoid Glucosides / Q000494:pharmacology*; D053614:Janus Kinase 2 / Q000378:metabolism*; D008297:Male; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D017467:Receptors, Erythropoietin / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D015533:Transcriptional Activation; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism*
D043925:Angiogenesis Inducing Agents; D057888:Iridoid Glucosides; D018696:Neuroprotective Agents; D012333:RNA, Messenger; D017467:Receptors, Erythropoietin; D050796:STAT3 Transcription Factor; C494088:Stat3 protein, rat; D042461:Vascular Endothelial Growth Factor A; C000599851:erythropoietin, rat; C467498:vascular endothelial growth factor A, rat; D004921:Erythropoietin; C078040:catalpol; C507927:Jak2 protein, rat; D053614:Janus Kinase 2
Angiogenesis; Catalpol; JAK2/STAT3; VEGF