Improving of endothelial cell dysfunction was a vital step in suppression the progression of atherosclerosis and preventing acute cardiovascular events, which bring out massive medical burden globally. Therefore, it was of great significance to actively explore the molecular mechanism of atherosclerosis in the prevention and treatment of cardiovascular diseases and related complications. In preview study, we had identified that Shh expression was suppressed in ox-LDL-induced HUVECs and in addition, Shh could improve endothelial apoptosis. In this study, we found that Shh could promote NO and eNOS expression, leading to a significant suppression of atherosclerotic plaques in ApoE−/− mice. Consistent with these data, Shh could improve endothelial cell dysfunction by promoting expression of NO and eNOS and inhibiting expression of ROS and inflammation in ox-LDL-induced HUVECs. These results suggest that Shh was a promising therapeutic target for atherosclerosis.
Endothelial cell dysfunction is a major pathogenetic contributor of early-stage atherosclerotic lesions which is characterized by endothelial cells maladapted including reducing of eNOS and NO expression and inducing ROS expression, resulting in promoting endothelial cells activated and inflammation whereas vasoconstriction. Under uncontrolled uptake of ox-LDL, impaired release of cholesterol, and excessive cholesterol esterification could result in accumulation of cholesterol esters stored as cytoplasmic lipid droplets and subsequently trigger endothelial dysfunction. Control of the homeostasis of endothelium has a critical importance in the pathogenesis of atherosclerosis, we observed that Shh exerted a protective effect by down-regulation ROS and promoted eNOS and NO releasing. Furthermore, we undertook an in vivo demonstrated that Shh could reduce the plaque lesion in HFD-diet ApoE−/− mice. These results provide strong evidence to support the notion that Shh contributed to a protective effect through increased eNOS and NO expression, as well as inhibited trafficking of cell surface molecules, thereby exerted anti-arteriosclerosis. Moreover, previous study has found that Shh could reduce the endothelial cell apoptosis associated with the NF-κB signaling. This remind us that this pathway may also be involved in the regulation of the endothelial cell dysfunction. Further work is needed before a definitive conclusion on this matter can be draw.
In recent years, scholars have found that Shh has neuroprotective effects on anti-oxidative stress and anti-apoptosis. In the cortical neuron damage induced by H2O2, Shh could promote the expression of anti-apoptotic gene Bcl-2 and inhibit the expression of pro-apoptotic gene Bax, and simultaneously up-regulate neurotrophic factor, vascular endothelial growth factor and brain-derived neurotrophic factor to protect cortical neurons from oxidative stress. In addition, Shh increased the activities of superoxide dismutase and glutathione peroxidase, and up-regulates the expression of Bcl-2 protein, which improved the ability of autistic patients to defend against oxidative stress. In previous study, in ox-LDL-induced HUVECs apoptosis model, we also found that Shh, as a protective protein, can inhibit the mitochondria-mediated apoptosis. And further, in this study we found that Shh have anti-inflammation and endothelial relaxing.
In short, these data suggest that Shh may attenuate ox-LDL induced endothelial cell dysfunction through down-regulation of expression of ROS and and up-regulation of expression of NO. Thus, improving of Shh expression to reduce the injury of cells in early lesions could be important for reducing the number and size of cells in atherosclerotic lesions.