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

Abstract

<jats:p> 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 <jats:sup>+</jats:sup> 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 <jats:sup>+</jats:sup> 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. </jats:p>

Gallic Acid Ameliorates Angiotensin II-Induced Atrial Fibrillation by Inhibiting Immunoproteasome- Mediated PTEN Degradation in Mice

“…We next determined the effect of GA on NF-κB signaling and gap junction gene expression. In agreement with our recent studies ( Li et al, 2018 , 2019 ; Zhang et al, 2020 ), the protein expression levels of p-p65 and connexin 43 (Cx43) were upregulated in Ang II-treated atria, and this upregulation was reversed after GA treatment ( Figure 3E ).…”

“…C57BL/6 mice (male, 8–10 weeks of age, n = 200) were used to establish the model of AF by subcutaneous infusion of Ang II (2000 ng/kg/min; Sigma-Aldrich, St. Louis, MO, United States) or saline for 3 weeks as described previously ( Li et al, 2018 , 2019 ; Zhang et al, 2020 ). The tail-cuff system (Softron BP98A; Softron Tokyo, Japan) was used to assess the systolic blood pressure (SBP) as previously described ( Wang et al, 2016 , 2018 ; Zhang et al, 2020 ). All animal studies were approved by the Animal Care and Use Committee of Dalian Medical University (No.…”

“…A Millar 1.1 F octapolar EP catheter (Scisense, NY, United States) was guided into the right atrium and ventricle. AF Inducibility was gauged by applying a 5-s burst using the automated stimulator as described previously ( Li et al, 2018 , 2019 ; Zhang et al, 2020 ). The 1-lead body surface ECG and ≤4 intracardiac bipolar electrograms were recorded by the 15 A computer-based data acquisition system (GY6328B; HeNan HuaNan Medical Science and Technology, Co., Ltd.).…”

“…Two-dimensional M-mode echocardiography was performed on mice using a 30 MHz probe (Vevo 1100 system; VisualSonics, Toronto, ON, Canada) as described previously ( Wang et al, 2018 ; Chen et al, 2019 ; Yan et al, 2019 ; Zhang et al, 2020 ). The left atrium (LA) chamber dimensions were measured.…”

“…Atrial samples were fixed in 4% paraformaldehyde, embedded in paraffin, and then sectioned (5 μm). The staining of Hematoxylin and eosin (H&E) and Masson’s Trichrome were performed on the atrial sections in accordance with the standard procedure ( Li et al, 2018 , 2019 ; Zhang et al, 2020 ). The immunohistochemistry staining was performed with anti-α-smooth muscle actin (α-SMA) (1:200, Abcam, MA, United States) and anti-Mac-2 (1:200, Abcam) as described ( Wang et al, 2018 ).…”