Abstract
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/CaMKII-related cardiovascular diseases.
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Acknowledgements
This work was supported by grants from the National Natural Science Foundation of China (Nos. 81402956, 81573421, and 81330080), the Shanghai Committee of Science and Technology of China (Nos. 16431902000 and 19QA1401500), and the Shanghai Chenguang Program (No. 14CG03).
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YZZ, YCM, and YX designed the research; YX, TD, and RZ performed the research; LLC and BT provided technology support; YZZ, YCM, and YX analyzed the data and wrote the paper.
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Xiong, Y., Chang, Ll., Tran, B. et al. ZYZ-803, a novel hydrogen sulfide-nitric oxide conjugated donor, promotes angiogenesis via cross-talk between STAT3 and CaMKII. Acta Pharmacol Sin 41, 218–228 (2020). https://doi.org/10.1038/s41401-019-0255-3
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DOI: https://doi.org/10.1038/s41401-019-0255-3
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