Honokiol attenuates oxidative stress and vascular calcification via the upregulation of heme oxygenase-1 in chronic kidney disease

Abstract

Vascular calcification (VC) is a common complication of chronic kidney disease (CKD), with oxidative stress identified as a key contributor to VC progression. Honokiol (HKL), a biphenolic compound derived from plants, has been found to be effective in treating various models of cardiovascular disease through the mitigation of oxidative stress. However, its effects on VC remain unexplored. To elucidate the effects of HKL on VC, a CKD rat model, a vitamin D₃-overload-induced mouse model of vascular calcification, and a high-phosphate-induced human vascular smooth muscle cell (VSMC) calcification model were established. Calcification levels were assessed using alizarin red staining, calcium quantification, and western blotting of osteogenic markers. Oxidative stress was assessed by measuring reactive oxygen species. Furthermore, transcriptome sequencing was employed to identify molecules and pathways affected by HKL. HKL was found to significantly reduce calcification in both in vivo and in vitro models. It also mitigated oxidative stress induced by high phosphate in human VSMCs. Mechanistically, HKL upregulated heme oxygenase-1 (HMOX-1), thereby inhibiting oxidative stress and reducing calcification. Pharmacological inhibition of HMOX-1 counteracted the protective effect of HKL against vascular calcification. In summary, the findings suggest that HKL ameliorates VC by upregulating HMOX-1 and decreasing oxidative stress.