Chemokine Receptor CXCR-2 Initiates Atrial Fibrillation by Triggering Monocyte Mobilization in Mice

Hypertension. 2020 Aug;76(2):381-392. doi: 10.1161/HYPERTENSIONAHA.120.14698. Epub 2020 Jul 8.

Abstract

Atrial fibrillation (AF) is frequently associated with increased inflammatory response characterized by infiltration of monocytes/macrophages. The chemokine receptor CXCR-2 is a critical regulator of monocyte mobilization in hypertension and cardiac remodeling, but it is not known whether CXCR-2 is involved in the development of hypertensive AF. AF was induced by infusion of Ang II (angiotensin II; 2000 ng/kg per minute) for 3 weeks in male C57BL/6 wild-type mice, CXCR-2 knockout mice, bone marrow-reconstituted chimeric mice, and mice treated with the CXCR-2 inhibitor SB225002. Microarray analysis revealed that 4 chemokine ligands of CXCR-2 were significantly upregulated in the atria during 3 weeks of Ang II infusion. CXCR-2 expression and the number of CXCR2+ immune cells markedly increased in Ang II-infused atria in a time-dependent manner. Moreover, Ang II-infused wild-type mice had increased blood pressure, AF inducibility, atrial diameter, fibrosis, infiltration of macrophages, and superoxide production compared with saline-treated wild-type mice, whereas these effects were significantly attenuated in CXCR-2 knockout mice and wild-type mice transplanted with CXCR-2-deficient bone marrow cells or treated with SB225002. Moreover, circulating blood CXCL-1 levels and CXCR2+ monocyte counts were higher and associated with AF in human patients (n=31) compared with sinus rhythm controls (n=31). In summary, this study identified a novel role for CXCR-2 in driving monocyte infiltration of the atria, which accelerates atrial remodeling and AF after hypertension. Blocking CXCR-2 activation may serve as a new therapeutic strategy for AF.

Keywords: atrial fibrillation; chemokines; inflammation; monocytes; superoxides.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiotensin II
  • Animals
  • Atrial Fibrillation / chemically induced
  • Atrial Fibrillation / genetics
  • Atrial Fibrillation / metabolism*
  • Blood Pressure / drug effects
  • Blood Pressure / physiology*
  • Chemokine CXCL1 / blood
  • Macrophages / drug effects
  • Macrophages / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Monocytes / drug effects
  • Monocytes / metabolism*
  • Phenylurea Compounds / pharmacology
  • Receptors, Interleukin-8B / antagonists & inhibitors
  • Receptors, Interleukin-8B / genetics
  • Receptors, Interleukin-8B / metabolism*
  • Superoxides / metabolism

Substances

  • Chemokine CXCL1
  • Phenylurea Compounds
  • Receptors, Interleukin-8B
  • SB 225002
  • Superoxides
  • Angiotensin II