Pannexin1 via P2rx7/amphiregulin contributes to cardiac fibrosis post myocardial infarction.

The primary pathological mechanism underlying ventricular remodeling and cardiac dysfunction following myocardial infarction (MI) is predominantly mediated by cardiomyocyte apoptosis. Pannexin1 (PANX1) channels, which open during apoptosis, facilitate the release of ATP from dying cells. However, the functional significance of PANX1 in mediating cardiomyocyte apoptosis and its contribution to myocardial infarction progression remain to be fully elucidated. To investigate the regulatory role of PANX1 in cardiomyocyte apoptosis following MI and elucidate its underlying molecular mechanisms. We conducted both in vivo and vitro studies. In vivo, we observed a significant elevation of PANX1 expression levels in post-MI mice, which facilitated macrophage recruitment and subsequently triggered upregulation of amphiregulin(AREG). In vitro, HL-1 cells exposure to hypoxia/reoxygenation (H/R) induced apoptosis, accompanying with the upregulation of PANX1, enhanced extracellular ATP release. And these alterations promoted the recruitment of RAW264.7 cells, subsequently elevating AREG levels. These effects were mitigated by the knockdown of PANX1. To confirm PANX1's role in MI hearts, AAV-9-PANX1-RNAi and negative control vectors were administered into the hearts of mice. Over 28 days post-MI, PANX1 knockdown significantly enhanced cardiac function and attenuated myocardial fibrosis. Our findings reveal that PANX1 plays a crucial role in facilitating a link between apoptotic cardiomyocyte and macrophage, contributing to modulate myocardial fibrosis and cardiac dysfunctional recovery post-MI via the AREG. Furthermore, the PANX1/P2rx7/AREG pathway is essential for facilitating a link between apoptotic cardiomyocytes and macrophages in mice following MI.