Rosmarinic Acid Activates the Nrf2/ARE Signaling Pathway via the miR-25-3p/SIRT6 Axis to Inhibit Vascular Remodeling

Abstract

The vital pathological processes in intimal hyperplasia include aberrant vascular smooth muscle cells (VSMCs) proliferation, migration, and phenotypic switching. Rosmarinic acid (RA) is a natural phenolic acid compound. Nevertheless, the underlying mechanism of RA in neointimal hyperplasia is still unclear. Our analysis illustrated that miR-25-3p mimics significantly enhanced PDGF-BB-mediated VSMCs proliferation, migration, and phenotypic switching while RA partially weakened the effect of miR-25-3p. Mechanistically, we found that miR-25-3p directly targets sirtuin (SIRT6). The suppressive effect of the miR-25-3p inhibitor on PDGF-BB-induced VSMCs proliferation, migration, and phenotypic switch was partially eliminated by SIRT6 knockdown. The suppression of the PDGF-BB-stimulated Nrf2/ARE signaling pathway that was activated by the miR-25-3p inhibitor was exacerbated by the SIRT6 knockdown. In in vivo experiments, RA reduced the degree of intimal hyperplasia while miR-25-3p agomir partially reversed the suppressive effect of RA in vascular remodeling. Our results indicate that RA activates the Nrf2/ARE signaling pathway via the miR-25-3p/SIRT6 axis to inhibit vascular remodeling.

Tongxinluo capsule as a multi-functional traditional Chinese medicine in treating cardiovascular disease: A review of components, pharmacological mechanisms, and clinical applications

“…Endovascular proliferation is a natural repair process after vascular damage, but excessive proliferation can lead to the occurrence of vascular restenosis. Endometrial proliferation of blood vessels originates from the excessive proliferation, migration, and phenotypic transformation of smooth muscle cells in the intima of blood vessels, which are stimulated by local or circulatory oxidative stress and inflammatory factors [ 182 , 183 ]. The entire process includes endothelial damage, platelet aggregation, inflammatory cell infiltration, smooth muscle cell proliferation and migration to the subintima, etc [ 184 ] Endovascular hyperplasia is the central link in the pathological process of vascular remodeling.…”