Mechanical channel protein Piezo1 mediates macrophage polarization to exacerbate myocardial ischemia-reperfusion injury

Abstract Objective Macrophage polarization plays an important role in myocardial ischemia-reperfusion injury (MI/RI), but the mechanism driving macrophage polarization is not clear. As an important mechanical-gated channel protein, Piezo1 can mediate Ca2+ influx to affect the function of macrophages. However, the role and mechanism of macrophage Piezo1 in MI/RI remain elusive. Methods MI/RI model was established by ligation of the left anterior descending coronary artery in C57BL/6 mice. Piezo1 activation and macrophage Piezo1 knockdown mouse models were constructed by in vivo injection of Yoda1 (a Piezo1 specific agonist) and adeno-associated virus (F4/80-shPiezo1), respectively. In vitro , Yoda1 and siRNA were used to investigate the effect and mechanism of Piezo1 on macrophage polarization. Results The expression of Piezo1 in myocardial macrophages was increased after MI/RI. Activation of Piezo1 aggravated MI/RI, while macrophage-specific knockdown of Piezo1 alleviated the severity of MI/RI. Compared with the control group, inflammatory markers (TNFα, IL-1α, and IL-6) and M1-type macrophage markers (CD80, CD86, and NOS2) were significantly decreased in the myocardium of macrophage specific Piezo1 knockdown mice. In addition, the effect of Piezo1 activation on M1 polarization of macrophages was further determined in vitro. Mechanically, we found that the specific activation of Piezo1 induced a large amount of Ca2+ influx, resulting in the reduction of mitochondrial calmodulin (MCU) expression, the increase of mitochondrial oxidative stress level, and mitochondrial metabolic dysfunction, leading to the activation of downstream transcription factors Spi-1 and NF-κB, and finally promoting the M1 polarization of macrophages and the increase of proinflammatory cytokines. Conclusion Our results suggest that macrophage Piezo1 plays a key role in the inflammatory response of MI/RI, and the Piezo1-MCU-SPI1 /NF-κB signaling axis may be a potential therapeutic target for MI/RI.