Chronic cardiac pain exacerbated atherosclerosis and increased monocyte numbers in blood and plaques compared with sham-operated mice through BTK-mediated epigenetic modifications.
Does chronic cardiac pain accelerate atherosclerosis in Apoe -/- mice?
Chronic cardiac pain accelerates atherosclerosis by promoting the recruitment of inflammatory monocytes into plaques via BTK-mediated epigenetic modifications.
Abstract Background Through neural-immune interactions, chronic pain is associated with an increased risk of cardiovascular disease and all-cause mortality. Cardiac pain is the most common clinical manifestation in patients with atherosclerotic cardiovascular disease, but whether cardiac pain will in turn promote atherosclerosis, the underlying mechanism is still unclear. Purpose We aimed to explore the specific inflammatory cellular mechanism of chronic cardiac pain accelerating atherosclerosis. Methods To investigate the effect of chronic cardiac pain on the development of atherosclerosis, apolipoprotein E deficient (Apoe -/-) mice were treated with either capsaicin on the ventricular surface or isoproterenol pumped subcutaneously. Changes in atherosclerotic plaque, systemic inflammation, and monocyte phenotype and function were assessed by immunohistochemistry, bone marrow transplantation, flow cytometry, RNA-seq, ATAC-seq, ChIP-seq, gene and protein analysis. The effect of T1-T5 dorsal root ganglion ablation on monocyte function and subsequent atherogenesis in mice was investigated in vivo. Results Chronic cardiac pain increased atherogenesis and monocyte numbers in blood and plaques compared with sham operated Apoe -/- mice. Bone marrow transplantation experiments further confirmed that chronic cardiac pain exacerbated atherosclerosis through immune cells. Mechanistically, chronic cardiac pain increases the expression of BTK in monocytes, and BTK promotes H3K36me3 epigenetic modification by phosphorylating SETD2, which ultimately promotes Cx3cr1 transcriptional expression. Myeloid cell-specific Btk knockout mice also showed less plaque and less infiltration of proinflammatory monocytes into the plaque. Furthermore, blocking cardiac nociceptive afferents by chemical ablation of T1-T5 dorsal root ganglia counteracted the upregulated systemic inflammation and atherosclerotic plaques in mice with chronic cardiac pain. Conclusion Chronic cardiac pain promotes the recruitment of inflammatory monocytes into plaques through epigenetic modifications and ultimately accelerates atherosclerosis. Our research proposing a new target for residual risk management in atherosclerotic cardiovascular disease.Schematic diagram
Dong et al. (Sat,) conducted a other in Atherosclerosis. Capsaicin on the ventricular surface or subcutaneous isoproterenol (chronic cardiac pain model) vs. Sham operation was evaluated on Atherosclerotic plaque, systemic inflammation, and monocyte phenotype and function. Chronic cardiac pain exacerbated atherosclerosis and increased monocyte numbers in blood and plaques compared with sham-operated mice through BTK-mediated epigenetic modifications.