Mitochondrial pannexin1 controls cardiac sensitivity to ischaemia/reperfusion injury

Abstract

Aims No effective therapy is available in clinics to protect the heart from ischaemia/reperfusion (I/R) injury. Endothelial cells are activated after I/R, which may drive the inflammatory response by releasing ATP through pannexin1 (Panx1) channels. Here, we investigated the role of Panx1 in cardiac I/R. Methods and results Panx1 was found in cardiac endothelial cells, neutrophils, and cardiomyocytes. After in vivo I/R, serum Troponin-I, and infarct size were less pronounced in Panx1−/− mice, but leukocyte infiltration in the infarct area was similar between Panx1−/− and wild-type mice. Serum Troponin-I and infarct size were not different between mice with neutrophil-specific deletion of Panx1 and Panx1fl/fl mice, suggesting that cardioprotection by Panx1 deletion rather involved cardiomyocytes than the inflammatory response. Physiological cardiac function in wild-type and Panx1−/− hearts was similar. The time to onset of contracture and time to maximal contracture were delayed in Panx1−/− hearts, suggesting reduced sensitivity of these hearts to ischaemic injury. Moreover, Panx1−/− hearts showed better recovery of left ventricle developed pressure, cardiac contractility, and relaxation after I/R. Ischaemic preconditioning failed to confer further protection in Panx1−/− hearts. Panx1 was found in subsarcolemmal mitochondria (SSM). SSM in WT or Panx1−/− hearts showed no differences in morphology. The function of the mitochondrial permeability transition pore and production of reactive oxygen species in SSM was not affected, but mitochondrial respiration was reduced in Panx1−/− SSM. Finally, Panx1−/− cardiomyocytes had a decreased mitochondrial membrane potential and an increased mitochondrial ATP content. Conclusion Panx1−/− mice display decreased sensitivity to cardiac I/R injury, resulting in smaller infarcts and improved recovery of left ventricular function. This cardioprotective effect of Panx1 deletion seems to involve cardiac mitochondria rather than a reduced inflammatory response. Thus, Panx1 may represent a new target for controlling cardiac reperfusion damage.

Intercellular Communication in Airway Epithelial Cell Regeneration: Potential Roles of Connexins and Pannexins

“…Another fundamental question is to discriminate between the channel-dependent or channel-independent role of connexins and pannexins in repairing airway epithelial cells. In this context, a particular focus must be placed on their localization, as connexins and pannexins can be found in intracellular compartments [122,144,145]. The intracellular relocalization of connexins and pannexins depends on the regulation of their trafficking and degradation, which are controlled by phosphorylation, acetylation, glycosylation, and ubiquitination [12,146].…”

Cardiomyocyte PANX1 Controls Glycolysis and Neutrophil Recruitment in Hypertrophy

“…[31][32][33] Release of ATP from cardiomyocytes through PANX1, which caused fibroblast activation in vitro, has previously been described. 16 Moreover, global PANX1 deletion in mice decreased ischemic area in a model of cardiac ischemia-reperfusion injury, 34 while endothelial cellspecific deletion of PANX1 in mice decreased immune cell infiltration in a model of myocardial infarction. 35 Though much of the work done with PANX1 heavily implicates the role of PANX1-dependent ATP release, previous studies have demonstrated that a wide variety of metabolites can be released through PANX1.…”

Pannexin 1 Channels Control Cardiomyocyte Metabolism and Neutrophil Recruitment During Non-Ischemic Heart Failure

“…Release of ATP from cardiomyocytes through PANX1, which caused fibroblast activation in vitro, has previously been described 16 . Moreover, global PANX1 deletion in mice decreased ischemic area in a model of cardiac ischemia reperfusion injury 34 , while endothelial cell-specific deletion of PANX1 in mice decreased immune cell infiltration in a model of myocardial infarction 35 . While these prior studies have strongly implied PANX1 as a therapeutic target for cardiovascular diseases in general 36 , the role for PANX1 in cardiomyocytes specifically in the regulation of chronic cardiac pathologies, including heart failure, remains to be elucidated.…”