Betulinaldehyde regulates VSMC phenotypic transition to alleviate vascular hyperplasia through PPARγ/mitochondria/ROS axis

Abstract

Aims

Betulinaldehyde (BA) demonstrates various biological activities both in vivo and in vitro, but its role in vascular remodeling has been little explored. Our network pharmacological analysis suggests that PPARγ serves as a significant regulatory target for BA. This study seeks to clarify the mechanisms associated with BA, thereby offering new perspective targets for addressing vascular remodeling.

Materials and methods

Network pharmacology analysis identified key genes linking BA to vascular remodeling. In vivo effects of BA were evaluated by H&E, immunohistochemical (IHC), and Masson staining. Vascular smooth muscle cells (VSMCs) function was examined using Western blotting, EdU incorporation, wound healing, and transwell assays. Mitochondrial alterations were assessed via electron microscopy, along with JC-1, ROS, and mitoSOX detection.

Key findings

In vivo experiments demonstrated that BA effectively alleviates intimal hyperplasia, collagen deposition, and the increase in the proliferation marker PCNA. Furthermore, BA effectively inhibits VSMC proliferation and migration induced by PDGF-BB. We further found that BA exerts its effects by regulating mitochondrial function through increasing PPARγ expression, which reduces ROS release and ultimately inhibits the progression of vascular remodeling. However, the inhibition or downregulation of PPARγ partially diminishes the therapeutic effects of BA, highlighting its crucial role in this process.

Significance

Our study suggests that BA mitigates vascular remodeling through PPARγ/mitochondria/ROS axis, which uncovers a novel mechanism linking BA to vascular remodeling. And BA's incentive function on PPARγ broadens its application in other diseases.