Abstract P2028: A Role For Pannexin 1 In Heart Failure Induced By Acute And Chronic Isoproterenol Administration

Abstract

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 an acute (14 day) and a chronic (28 day) model of adrenergic stimulation to induce heart failure in two novel mouse models: 1) 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 MyHC6-Cre ). 2) Using 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 Tnnt2-MerCreMer ). 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 MyHC6-Cre mice were protected from systolic and diastolic dysfunction and cardiac hypertrophy. Furthermore, after chronic administration of isoproterenol (15 mg/kg/day, osmotic pump) Panx1 MyHC6-Cre mice were still protected from cardiac hypertrophy compared to Panx1 fl/fl littermates. In vitro , treatment of H9c2 cardiomyocytes with isoproterenol led to Panx1-dependent release of ATP in a dose-dependent manner. This was demonstrated with both pharmacological blockade by spironolactone and siRNA-mediated knock-down of Panx1. Taken together, these data demonstrates that Panx1 deficiency in cardiomyocytes protects against isoproterenol-induced cardiac dysfunction and that ATP is released through Panx1 in response to isoproterenol. Further elucidating the role of Panx1 in cardiomyocytes in regulating cardiac function and fibrosis will identify Panx1 as a novel therapeutic target to prevent heart failure.