Right atrial CCR2macrophages mediate atrial fibrillation in rat with monocrotaline-induced pulmonary arterial hypertension.

Abstract

BACKGROUND: Atrial fibrillation (AF) is commonly observed in patients with pulmonary arterial hypertension (PAH), yet the mechanisms linking these conditions remain unclear. Current evidence suggests that right atrial fibrosis and right ventricular dysfunction contribute to increased AF susceptibility in PAH. This study investigates the role of right atrial CC chemokine receptor type 2 positive (CCR2) macrophages and CCR2macrophage-derived secreted phosphorylated protein 1(SPP1) in promoting AF susceptibility during the progression of right heart dysfunction in PAH. METHODS: PAH was induced in rats by monocrotaline (MCT). Two time points were examined: the compensatory phase of right ventricular function (3 weeks post-MCT) and the decompensatory phase (5 weeks post-MCT). To evaluate AF susceptibility, right ventricular function, right atrial fibrosis, and the infiltration of CCR2and CCR2SPP1macrophages. Starting 3 days after MCT injection, PAH rats received the CCR2 antagonist RS504393 until the 5-week endpoint. The intervention's effects were evaluated by the same methods. Additionally, in vitro studies examined how neutralizing the SPP1 secreted by bone marrow-derived macrophages (BMDMs) influenced cardiac fibroblasts (CFs). RESULTS: Between 3 and 5 weeks after MCT injection, AF susceptibility increased alongside worsening right atrial fibrosis and greater infiltration of macrophages, CCR2macrophages, and CCR2SPP1macrophages in the right atrium. RS504393 mitigated these effects. In vitro findings showed that SPP1 secreted by BMDMs promoted CFs proliferation, differentiation, and collagen production. CONCLUSION: CCR2macrophages mediate AF secondary to PAH via SPP1 secretion to affect CFs. Targeting CCR2macrophages and SPP1 represents a promising therapeutic approach for managing AF in PAH patients.