Abstract
Hyperuricemia-induced cardiac remodeling is at least in part via pressure-dependent mechanisms, yet the pressure-independent mechanisms are not well understood. C-X-C motif chemokine ligand 1 (CXCL1) was upregulated in renal tubules from mice subjected to uric acid (UA)-induced nephropathy. Given that CXCL1 is a master chemokine responsible for the recruitment of macrophage by binding with its receptor C-X-C motif chemokine receptor 2 (CXCR2), we thus hypothesized that UA-induced cardiac injury is via promoting the recruitment of CXCR2 + macrophages into the heart, which enhances cardiac inflammation. Within a mouse model of UA injection (500 mg/kg, twice/day, 14 days), we measured the level of cardiac CXCL1. We also tested the efficacy of the CXCR2 antagonist on UA-induced cardiac inflammation and remodeling. We found a high plasma level of UA-induced upregulation of CXCL1 in heart tissues. CXCR2 antagonist relieved UA-induced cardiac hypertrophy and suppressed cardiac inflammation and fibrosis. The silencing of CXCR2 in human monocytes abolished the migration of UA-induced monocyte. Thus, the interventions against CXCL1/CXCR2 may be effective for the prevention and treatment of UA-induced cardiac hypertrophy and inflammatory responses.
Highlights
Uric acid (UA) is the end product of purine metabolism and contributes to the formation of gout (So and Thorens, 2010)
Our results provided a novel mechanism for C-XC motif chemokine ligand 1 (CXCL1)-mediated cardiac inflammation in response to uric acid (UA) stimulation
CXCL1 had a twofold increase at 14 days after UA injection vs. vehicle control (Figure 1B)
Summary
Uric acid (UA) is the end product of purine metabolism and contributes to the formation of gout (So and Thorens, 2010). Based on a shared cysteine motif, chemokines are classified into four distinct classes, such as C-C motif chemokine ligand (CCL1-28), C-X-C motif chemokine ligand (CXCL1-17), C-X3-C motif chemokine ligand 1 (CX3CL1), and X-C motif chemokine ligand 1 (XCL1-2). Chemokines exert their biological functions via binding with surface receptors on inflammatory cells, which are designated as C-C motif chemokine receptor (CCR), C-X-C motif chemokine receptor (CXCR), C-X3-C motif chemokine receptor (CX3CR), and XCR chemokine receptor (XCR). Inactivation of CXCL1 signaling by either a neutralizing antibody or deletion of either CXCL1 or CXCR2 resulted in less macrophage infiltration, reduced cytokine expression level, and preserved cardiac functions following angiotensin II (Ang II) infusion (Wang et al, 2018)
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