Increased Regional Pannexin1 (Px1) Channel Expression linked to Focal Ischemia is Pro‐Arrhythmic During Stress

Abstract

Mice with the hypertrophic cardiomyopathy‐linked TnT‐I79N mutation develop arrhythmias during physiological stress. In isolated hearts these arrhythmias are linked to regional ischemia (no decrease in global coronary flow) which causes regional hypoxia and cellular energy deprivation and results in regional conduction velocity slowing and increased arrhythmia susceptibility (84.7% vs 14.3% in control).To test if regional hypoxia/ischemia also occurred spontaneously in vivo in TnT‐I79N mice, we measured mRNA expression of genes up‐regulated by hypoxia (GLUT1, TUBB3, Px1) and found increased expression (0.3fold, 3fold, 10fold respectively). To determine the spatial distribution of Px1‐hypoxia marker we first subjected Px1 ‐βGal reporter mice to coronary ligation and demonstrate that Xgal staining is limited to the perfusion bed of the ligated artery. Then we crossed the TnT‐I79N with the Px1 reporter mice and found that Xgal staining increased in a spatially non‐uniform “patchy” distribution, consistent with focal ischemia. Px1 channels have been implicated in the regulation of vascular perfusion during hypoxia. Strikingly, ablation of Px1 in TnT‐I79N mice reduced the arrhythmia incidence in isolated hearts (to 36.4%) and prevented the focal energy deprivation during stress.Although the physiological role for the increase in Px1 after ischemia remains unclear, Px1 contributes to the increased arrhythmia susceptibility in TnT‐I79N mice. Hence, our data suggest that Px1 may be involved in the regulation of local coronary perfusion and is maladaptive during stress.