Highlights

• ZYZ-803 is a newly synthesized hybrid molecule that simultaneously donates H₂S and NO, unlike previous single-gas donors.
• The study identifies a previously unreported cross-talk between STAT3 and CaMKII in angiogenesis triggered by ZYZ-803.
• ZYZ-803 promotes STAT3 nuclear translocation and enhances STAT3-CaMKII interaction, a mechanism not described before in H₂S-NO mediated signaling.

Summary

The study the pro-angiogenic mechanism of  ZYZ-803, a novel compound that donates both hydrogen sulfide (H₂S) and nitric oxide (NO), and its role in promoting angiogenesis—the formation of new blood vessels.

Using human endothelial cells (HUVECs) and mouse models of hind limb ischemia, the researchers found that ZYZ-803 activates both STAT3 and CaMKII signaling pathways, which are essential for angiogenesis.  ZYZ-803 treatment promoted endothelial cell proliferation, migration, and tube formation—key steps in angiogenesis—through phosphorylation of STAT3 (Tyr705) and CaMKII (Thr286). Pharmacological inhibition or genetic knockdown of either STAT3 or CaMKII significantly attenuated these pro-angiogenic effects, revealing functional cross-talk between the two pathways. Moreover, ZYZ-803 enhanced the physical interaction between CaMKII and STAT3 and facilitated STAT3 nuclear translocation.

These results indicate that ZYZ-803 promotes angiogenesis via coordinated H₂S/NO release and synergistic activation of the STAT3–CaMKII axis, underscoring its therapeutic potential in ischemic cardiovascular diseases.

Y. Xiong et al., “ZYZ-803, a novel hydrogen sulfide-nitric oxide conjugated donor, promotes angiogenesis via cross-talk between STAT3 and CaMKII,” Acta Pharmacol Sin, vol. 41, no. 2, pp. 218–228, Feb. 2020, doi: 10.1038/s41401-019-0255-3.