Abstract
Introduction: Induction of Sonic Hedgehog (Shh) in the myocardium post myocardial infarction promotes neovascularization and reduces infarct size. Shh signals through the 7-TM protein Smoothened (SMO), which we have found to couple to Gi proteins. Our goal is to investigate the effect of Shh on myocardial excitability and electrical remodeling and the role of SMO/Gi coupling. Methods and Results: We performed whole-cell patch clamp action potential and K+ currents measurements, biochemistry and volume-conducted ECG measurements in Langerdoff preparations using wild type and transgenic GiCT mice with inducible cardiomyocyte-specific impaired Gi protein signaling. In normal hearts and isolated cardiomyocytes, Shh reduced by 80% the isoproterenol-induced cAMP increase and protein kinase A (PKA) activation (p<0.01). Shh also induced a 2-2.5 fold prolongation of the action potential duration (APD) (p<0.001) and a reduction of the IK, slow (9.3±0.8 vs. 1.9±0.5 pA/pF; p<0.05). In Langerdorff-perfused hearts, Shh agonists induced a ~30% increase of the QT interval (p<0.01) and premature ventricular contractions (PVC) (0 out of 6 controls vs. 8 out of 8 Shh) and ventricular tachycardia (VT) (0 out of 6 controls vs. 7 out of 8 Shh), while pre-perfusion with KAAD-cyclopamine, a SMO inhibitor, reduced the arrhythmic episodes (PVC in 3 out of 8 and VT in 0 out 8). These effects we mediated by Gi proteins, as cAMP reduction, prolongation of the QT segment, and development of arrhythmias were abolished in hearts of GiCT mice. Conclusion: Our study demonstrates that acute Shh signaling in the heart leads to reshaping of the action potential (AP) and results in a dramatic increase of ventricular arrhythmias. Our data constitute the first evidence that acute, noncanonical Shh signaling may be implicated in the pathological electrical remodeling that sets the substrate for life-threatening arrhythmias in HF patients.
Published Version
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