A Critical Role for Pannexin 1 in Heart Failure Induced by Acute and Chronic Isoproterenol Administration.

Pannexin 1 (Panx1), a ubiquitously expressed ATP release membrane channel, has been shown to play a role in inflammation and blood pressure regulation. Panx1 channel function is inhibited by spironolactone, a frontline therapy for heart failure patients. Despite this, the function of Panx1 in cardiomyocytes and a possible role in heart failure has not yet been studied. To investigate if Panx1 is involved in the development of cardiac dysfunction and fibrosis, we use a model of chronic adrenergic stimulation to induce heart failure in two novel mouse models. We have generated mice with constitutive deletion of Panx1 in cardiomyocytes by crossing mice expressing loxP-flanked alleles of Panx1 to mice expressing Cre recombinase under the control of the cardiomyocyte specific MyHC6 promoter (Panx1 ). Using the same approach with mice expressing the tamoxifen-inducible MerCreMer system under the control of the Tnnt2 promoter we generated mice with tamoxifen-inducible deletion of Panx1 in cardiomyocytes (Panx1 ). Constitutive deletion of Panx1 in cardiomyocytes had no effect on heart function at baseline as measured by echocardiography. However, after acute isoproterenol treatment (15 mg/kg/day, i.p.), Panx1 mice were protected from systolic and diastolic dysfunction and cardiac hypertrophy. In vitro, treatment of H9c2 cardiomyocytes with isoproterenol led to Panx1-dependent release of ATP. Furthermore, siRNA-mediated knock down of Panx1 in H9c2 cells attenuated basal and maximal extracellular acidification rate (a measure of glycolysis) after 24 hours of isoproterenol treatment, indicating a role for Panx1 in regulation of cardiomyocyte metabolism. Taken together, these data demonstrates that Panx1 deficiency protects against isoproterenol-induced cardiac dysfunction and pathological glycolytic shift in stressed cardiomyocytes. Further elucidating the role of Panx1 in cardiomyocytes in regulating cardiac function and fibrosis will identify a novel therapeutic target to prevent heart failure.