ZYZ-803, a novel hydrogen sulfide-nitric oxide conjugated donor, promotes angiogenesis via cross-talk between STAT3 and CaMKⅡ

• 来源期刊: 中国药理学报（英文版）
• 关键词: ZYZ-803 H2S NO human umbilical vein endothelial cells (HUVECs) angiogenesis STAT3 CaMKⅡ
• 年，卷（期）: 2020,（2）
• 页码范围: 218-228
• 页数: 11页
• 语种: 英文

摘要

Endothelial angiogenesis plays a vital role in recovery from chronic ischemic injuries.ZYZ-803 is a hybrid donor of hydrogen sulfide (H2S) and nitric oxide (NO).Previous studies showed that ZYZ-803 stimulated endothelial cell angiogenesis both in vitro and in vivo.In this study,we investigated whether the signal transducer and activator of transcription 3 (STAT3) and Ca2+/CaM-dependent protein kinase Ⅱ (CaMKⅡ) signaling was involved in ZYZ-803-induced angiogenesis.Treatment with ZYZ-803 (1 μM) significantly increased the phosphorylation of STAT3 (Tyr705) and CaMKⅡ (Thr286) in human umbilical vein endothelial cells (HUVECs),these two effects had a similar time course.Pretreatment with WP1066 (STAT3 inhibitor) or KN93 (CAMKⅡ inhibitor) blocked ZYZ-803-induced STAT3/CAMKⅡ activation and significantly suppressed the proliferation and migration of HUVECs.In addition,pretreatment with the inhibitors significantly decreased ZYZ-803-induced tube formations along with the outgrowths of branch-like microvessels in aortic rings.In the mice with femoral artery ligation,administration of ZYZ-803 significantly increased the blood perfusion and vascular density in the hind limb,whereas co-administration of WP1066 or KN93 abrogated ZYZ-803-induced angiogenesis.By using STAT3 siRNA,we further explored the cross-talk between STAT3 and CaMKⅡ in ZYZ-803-induced angiogenesis.We found that STAT3 knockdown suppressed ZYZ-803-induced HUVEC angiogenesis and affected CaMKⅡ expression.ZYZ-803 treatment markedly enhanced the interaction between CaMKⅡ and STAT3.ZYZ-803 treatment induced the nuclear translocation of STAT3.We demonstrated that both STAT3 and CaMKⅡ functioned as positive regulators in ZYZ-803-induced endothelial angiogenesis and STAT3 was important in ZYZ-803-induced CaMKⅡ activation,which highlights the beneficial role of ZYZ-803 in STAT3/CaMKll-related cardiovascular diseases.