Promotion of Endothelial Wound Healing by the Chalcones 4-hydroxyderricin and Xanthoangelol, and the Molecular Mechanism of This Effect

The two chalcones xanthoangelol (XA) and 4-hydroxyderricin (4HD) are major functional polyphenolic compounds in the edible herb Angelica keiskei, which is native to Japan. The compounds XA and 4HD are known to have anti-inflammatory and anti-diabetic functions although their beneficial effect on vascular disease is not clear. Atherosclerosis induced by lifestyle-related diseases such as obesity and hypertension is a serious vascular disease in which endothelial injury plays a major pathogenic role. Therefore, the healing of endothelial injury is considered important in preventing atherosclerosis. The present study examined whether XA and 4HD promote the wound healing of cultured porcine vascular endothelial cells (ECs) and analyzed the molecular mechanisms of their effect. Both compounds promoted endothelial wound healing, induced nitric oxide (NO) production, and increased heme oxygenase-1 (HO-1) expression as well as the phosphorylation level of endothelial NO synthase (eNOS). The wound healing promoted by these compounds was inhibited by pretreatment with the NOS inhibitor L-NMMA and HO-1 inhibitor ZnPPIX, respectively. ZnPPIX inhibited the phosphorylation of eNOS as well. XAand 4HD-dependent wound healing was also blocked by hemoglobin, a carbon monoxide (CO) absorbent. A CO-releasing molecule facilitated the wound healing, which was suppressed by pretreatment with L-NMMA. These results suggest that XA and 4HD stimulate wound healing by increasing HO-1 expression with subsequent CO production, which activates eNOS followed by NO generation. Our findings indicate that the two chalcones in Angelica keiskeimay have a preventative effect against atherosclerosis.