From the Institute of Vascular Medicine, Li Ka Shing Institute of Health Sciences (Y.Z., L.W., J.L., W.S.C., C.W.L., X.Y., Y.H.), School of Biomedical Sciences (J.L., Y.C., X.Y., Y.H.), School of Life Sciences (K.M.K.), Chinese University of Hong Kong, Hong Kong SAR, China; Department of Cardiovascular Sciences, Houston Methodist Research Institute, Houston, TX (X.Y.T., W.T.W.); and Institute of Cardiovascular Sciences, Peking University Health Science Center, Beijing, China (N.W.).
Arterioscler Thromb Vasc Biol. 2014 Jan;34(1):152-9. doi: 10.1161/ATVBAHA.113.302696. Epub 2013 Nov 7.
Bone morphogenic protein 4 (BMP4) is involved in the development of endothelial dysfunction in hypertension. This study investigated whether the inhibition of BMP4 signaling improves endothelial function in db/db diabetic mice.
Male db/db mice were treated with noggin via osmotic pump infusion (1 µg/[h·kg(-1)]) for 2 weeks. Adenovirus BMP4-short hairpin RNA was introduced via tail vein injection at a dosage of 10(9) pfu/mouse and its effects were examined 7 days after. Vasoreactivity was studied on wire and pressure myograph. Both noggin treatment and adenovirus BMP4-short hairpin RNA transduction improved endothelium-dependent relaxations in aortae and flow-mediated dilatation in mesenteric arteries of db/db mice. Ex vivo treatment with BMP4 inhibitors and adenovirus BMP4-short hairpin RNA rescued the impaired endothelium-dependent relaxations in db/db mouse aortae and reduced reactive oxygen species overproduction determined by dihydroethidium staining, CM-H2DCFDA fluorescence imaging, and chemiluminescence assay in db/db mouse aortae, and also in ex vivo cultured C57BL/6 mouse aortae or primary mouse aortic endothelial cells treated with high glucose. Likewise, activin receptor-like kinase 3 silencing by short hairpin RNA lentivirus improved endothelium-dependent relaxations in db/db mouse aortae accompanied by reactive oxygen species inhibition in endothelial cells. In addition, noggin reduced BMP4 upregulation in high-glucose-treated endothelial cells and in C57BL/6 mouse aortae and in aortae from db/db mice.
Inhibition of BMP4/activin receptor-like kinase 3/reactive oxygen species signaling improved endothelial function in diabetic mice through limiting oxidative stress in endothelium. Inhibiting BMP4 cascade can become another potential therapeutic strategy against diabetic vascular dysfunction.
骨形态发生蛋白 4（BMP4）参与高血压内皮功能障碍的发生。本研究旨在探讨抑制 BMP4 信号是否能改善 db/db 糖尿病小鼠的内皮功能。
雄性 db/db 小鼠经渗透泵输注 noggin（1μg/[h·kg(-1)]) 治疗 2 周。通过尾静脉注射腺病毒 BMP4-short hairpin RNA（10(9) pfu/只），7 天后检测其作用。在血管张力和压力肌描记器上研究血管反应性。noggin 处理和腺病毒 BMP4-short hairpin RNA 转导均改善了 db/db 小鼠主动脉的内皮依赖性舒张功能和肠系膜动脉的血流介导的扩张功能。BMP4 抑制剂和腺病毒 BMP4-short hairpin RNA 的离体处理挽救了 db/db 小鼠主动脉内皮依赖性舒张功能的损害，并减少了二氢乙啶染色、CM-H2DCFDA 荧光成像和化学发光测定确定的 db/db 小鼠主动脉中超氧化物的产生，还挽救了高糖处理的 C57BL/6 小鼠主动脉或原代小鼠主动脉内皮细胞中产生的超氧化物。同样，短发夹 RNA 慢病毒沉默激活素受体样激酶 3 也改善了 db/db 小鼠主动脉的内皮依赖性舒张功能，并抑制了内皮细胞中的活性氧。此外，noggin 降低了高糖处理的内皮细胞以及 C57BL/6 小鼠主动脉和 db/db 小鼠主动脉中 BMP4 的上调。
抑制 BMP4/激活素受体样激酶 3/活性氧信号通路通过限制内皮细胞中的氧化应激改善了糖尿病小鼠的内皮功能。抑制 BMP4 级联反应可能成为治疗糖尿病血管功能障碍的另一种潜在治疗策略。
