Dynamin-related protein 1 mediates the therapeutic effect of isoliquiritigenin in diabetic intimal hyperplasia via regulation of mitochondrial fission

Hypertens Res. 2024 Jul;47(7):1908-1924. doi: 10.1038/s41440-024-01681-z. Epub 2024 May 15.

Abstract

Phenotypic shift of vascular smooth muscle cells (VSMCs) plays a key role in intimal hyperplasia, especially in patients with diabetes mellitus (DM). This study aimed to investigate the role of dynamin-related protein 1 (DRP1) in mitochondrial fission-mediated VSMC phenotypic shift and to clarify whether DRP1 is the therapeutic target of isoliquiritigenin (ISL). Wire injury of carotid artery or platelet-derived growth factor treatment was performed in DM mice or high-glucose cultured human aortic smooth muscle cells (HASMCs), respectively. The effects of DRP1 silencing on DM-induced intimal hyperplasia were investigated both in vivo and in vitro. Phenotypic shift of HASMCs was evaluated by detection of reactive oxygen species (ROS) generation, cell viability, and related protein expressions. The effects of ISL on DM-induced intimal hyperplasia were evaluated both in vivo and in vitro. DRP1 silencing and ISL treatment attenuated DM-induced intimal hyperplasia with reduced ROS generation, cell viability, and VSMC dedifferentiation. The GTPase domain of DRP1 protein played a critical role in mitochondrial fission in DM-induced VSMC phenotypic shift. Cellular experiments showed that ISL inhibited mitochondrial fission and reduced the GTPase activity of DRP1, which was achieved by the directly binding to K216 of the DRP1 GTPase domain. ISL attenuated mouse intimal hyperplasia by reducing GTPase activity of DRP1 and inhibiting mitochondrial fission in vivo. In conclusion, increased GTPase activity of DRP1 aggregated DM-induced intimal hyperplasia by increasing mitochondrial fission-mediated VSMC phenotypic shift. ISL attenuated mouse intimal hyperplasia by reducing DRP1 GTPase activity and inhibiting mitochondrial fission of VSMCs.

Keywords: Dynamin-related protein 1; GTPase; Intimal hyperplasia; Mitochondrial fission; Vascular smooth muscle cells.

MeSH terms

  • Animals
  • Cells, Cultured
  • Chalcones* / pharmacology
  • Chalcones* / therapeutic use
  • Diabetes Mellitus, Experimental / drug therapy
  • Dynamins* / metabolism
  • Humans
  • Hyperplasia*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mitochondrial Dynamics* / drug effects
  • Muscle, Smooth, Vascular / drug effects
  • Muscle, Smooth, Vascular / metabolism
  • Muscle, Smooth, Vascular / pathology
  • Myocytes, Smooth Muscle / drug effects
  • Reactive Oxygen Species / metabolism
  • Tunica Intima / drug effects
  • Tunica Intima / metabolism
  • Tunica Intima / pathology

Substances

  • Dynamins
  • isoliquiritigenin
  • Chalcones
  • Reactive Oxygen Species
  • Dnm1l protein, mouse