PubMed:28973643 JSONTXT

{"target":"https://pubannotation.org/docs/sourcedb/PubMed/sourceid/28973643","sourcedb":"PubMed","sourceid":"28973643","source_url":"https://www.ncbi.nlm.nih.gov/pubmed/28973643","text":"Tacrolimus rescues the signaling and gene expression signature of endothelial ALK1 loss-of-function and improves HHT vascular pathology.\nHereditary hemorrhagic telangiectasia (HHT) is a highly debilitating and life-threatening genetic vascular disorder arising from endothelial cell (EC) proliferation and hypervascularization, for which no cure exists. Because HHT is caused by loss-of-function mutations in bone morphogenetic protein 9 (BMP9)-ALK1-Smad1/5/8 signaling, interventions aimed at activating this pathway are of therapeutic value. We interrogated the whole-transcriptome in human umbilical vein ECs (HUVECs) and found that ALK1 signaling inhibition was associated with a specific pro-angiogenic gene expression signature, which included a significant elevation of DLL4 expression. By screening the NIH clinical collections of FDA-approved drugs, we identified tacrolimus (FK-506) as the most potent activator of ALK1 signaling in BMP9-challenged C2C12 reporter cells. In HUVECs, tacrolimus activated Smad1/5/8 and opposed the pro-angiogenic gene expression signature associated with ALK1 loss-of-function, by notably reducing Dll4 expression. In these cells, tacrolimus also inhibited Akt and p38 stimulation by vascular endothelial growth factor, a major driver of angiogenesis. In the BMP9/10-immunodepleted postnatal retina-a mouse model of HHT vascular pathology-tacrolimus activated endothelial Smad1/5/8 and prevented the Dll4 overexpression and hypervascularization associated with this model. Finally, tacrolimus stimulated Smad1/5/8 signaling in C2C12 cells expressing BMP9-unresponsive ALK1 HHT mutants and in HHT patient blood outgrowth ECs. Tacrolimus repurposing has therefore therapeutic potential in HHT.","tracks":[{"project":"kaiyin_test","denotations":[{"id":"T10","span":{"begin":137,"end":174},"obj":"Disease"},{"id":"T3","span":{"begin":362,"end":365},"obj":"Disease"},{"id":"T1","span":{"begin":379,"end":395},"obj":"NegReg"},{"id":"T2","span":{"begin":396,"end":405},"obj":"Var"},{"id":"T9","span":{"begin":438,"end":469},"obj":"MPA"}],"relations":[{"id":"R1","pred":"ThemeOf","subj":"T9","obj":"T2"},{"id":"R2","pred":"CauseOf","subj":"T2","obj":"T1"},{"id":"R3","pred":"ThemeOf","subj":"T3","obj":"T1"}],"attributes":[{"subj":"T10","pred":"source","obj":"kaiyin_test"},{"subj":"T3","pred":"source","obj":"kaiyin_test"},{"subj":"T1","pred":"source","obj":"kaiyin_test"},{"subj":"T2","pred":"source","obj":"kaiyin_test"},{"subj":"T9","pred":"source","obj":"kaiyin_test"}]},{"project":"name_no","denotations":[{"id":"T10","span":{"begin":137,"end":174},"obj":"Disease"},{"id":"T3","span":{"begin":362,"end":365},"obj":"Disease"},{"id":"T1","span":{"begin":379,"end":395},"obj":"NegReg"},{"id":"T2","span":{"begin":396,"end":405},"obj":"Var"},{"id":"T9","span":{"begin":438,"end":469},"obj":"MPA"}],"relations":[{"id":"R1","pred":"ThemeOf","subj":"T9","obj":"T2"},{"id":"R2","pred":"CauseOf","subj":"T2","obj":"T1"},{"id":"R3","pred":"ThemeOf","subj":"T3","obj":"T1"}],"attributes":[{"subj":"T10","pred":"source","obj":"name_no"},{"subj":"T3","pred":"source","obj":"name_no"},{"subj":"T1","pred":"source","obj":"name_no"},{"subj":"T2","pred":"source","obj":"name_no"},{"subj":"T9","pred":"source","obj":"name_no"}]}],"config":{"attribute types":[{"pred":"source","value type":"selection","values":[{"id":"kaiyin_test","color":"#93a6ec","default":true},{"id":"name_no","color":"#c0ec93"}]}]}}