Targeted inhibition of the GRK2/HIF-1α pathway is an effective strategy to alleviate synovial hypoxia and inflammation

Int Immunopharmacol. 2022 Dec;113(Pt A):109271. doi: 10.1016/j.intimp.2022.109271. Epub 2022 Nov 10.

Abstract

G-protein coupled receptor (GPCR) kinases (GRKs) and hypoxia-inducible factor-1α (HIF-1α) play key roles in rheumatoid arthritis (RA). Several studies have demonstrated that HIF-1α expression is positively regulated by GRK2, suggesting its posttranscriptional effects on HIF-1α. In this study, we review the role of HIF-1α and GRK2 in RA pathophysiology, focusing on their proinflammatory roles in immune cells and fibroblast-like synoviocytes (FLS).We then introduce several drugs that inhibit GRK2 and HIF-1α, and briefly outline their molecular mechanisms. We conclude by presenting gaps in knowledge and our prospects for the pharmacological potential of targeting these proteins and the relevant downstream signaling pathways.Future research is warranted and paramount for untangling these novel and promising roles for GRK2 and HIF-1α in RA.

Keywords: Drug therapy; GRK2; HIF-1α; RA.

Publication types

  • Review

MeSH terms

  • Arthritis, Rheumatoid* / drug therapy
  • Arthritis, Rheumatoid* / genetics
  • Arthritis, Rheumatoid* / immunology
  • G-Protein-Coupled Receptor Kinase 2* / antagonists & inhibitors
  • G-Protein-Coupled Receptor Kinase 2* / genetics
  • G-Protein-Coupled Receptor Kinase 2* / immunology
  • Humans
  • Hypoxia / genetics
  • Hypoxia / immunology
  • Hypoxia-Inducible Factor 1, alpha Subunit* / antagonists & inhibitors
  • Hypoxia-Inducible Factor 1, alpha Subunit* / genetics
  • Hypoxia-Inducible Factor 1, alpha Subunit* / immunology
  • Inflammation / drug therapy
  • Inflammation / genetics
  • Inflammation / immunology
  • Synoviocytes* / immunology

Substances

  • Hypoxia-Inducible Factor 1, alpha Subunit
  • GRK2 protein, human
  • G-Protein-Coupled Receptor Kinase 2
  • HIF1A protein, human