Sinomenine promotes flap survival by upregulating eNOS and eNOS-mediated autophagy via PI3K/AKT pathway

Large skin defects and surgical tissue reconstructions are frequently covered utilizing random flaps. The flap has the advantage of being designed according to the size and shape of a surgical wound. However, the necrosis of the distal part of the flap restricts the clinical application of flaps. Sinomenine (SIN) is the major active component of sinomenium acutum. SIN has been demonstrated to inhibit oxidative stress and stimulate autophagy in a cell, animal, and clinical studies. The protective and proliferative effects of sinomenium on HUVECs were evaluated by scratched test, CCK-8, and EDU assays. For the flap survival, we established a mouse random pattern flap model and observed the effects of SIN injected intraperitoneally. The survival area and blood flow intensity of the flap in sinomenium group were significantly increased compared to the control group. Our results demonstrate that SIN promotes flap survival. Sinomenium enhances eNOS expression in the flap and reduces the level of oxidative stress, promotes autophagy flux increase, reduces apoptosis, and promotes angiogenesis. Having a therapeutic benefit of SIN, Autophagy inhibitor 3-MA shows its critical role by reversing the beneficial effects of SIN, and the nitric oxide synthase inhibitor l-NAME both stimulated HUVECs that explore the relationship between autophagy flux and nitric oxide synthase. Furthermore, the mechanism in our study reveals the changes in the signal pathway of PI3K/AKT, the protective effect of SIN during antioxidant activity, the activation of eNOS through PI3K/AKT signaling pathway affects autophagy through the eNOS system, and promote the random flap survival.