Fibroblast KATP currents modulate myocyte electrophysiology in infarcted hearts

• Published in: American journal of physiology. Heart and circulatory physiology 2013-05, Vol.304 (9), p.H1231-H1239
• Main Authors: Benamer, Najate, Vasquez, Carolina, Mahoney, Vanessa M, Steinhardt, Maximilian J, Coetzee, William A, Morley, Gregory E
• Format: Article
• Language: English
• Subjects: Action Potentials - drug effects; Action Potentials - physiology; Animals; ATP-Binding Cassette Transporters - genetics; ATP-Binding Cassette Transporters - metabolism; Cardiac Excitation and Contraction; Fibroblasts - metabolism; Fibroblasts - physiology; Glyburide - pharmacology; Heart Ventricles - cytology; KATP Channels - agonists; KATP Channels - antagonists & inhibitors; KATP Channels - metabolism; KATP Channels - physiology; Male; Myocardial Infarction - metabolism; Myocardial Infarction - physiopathology; Myocytes, Cardiac - metabolism; Myocytes, Cardiac - physiology; Pinacidil - pharmacology; Potassium Channel Blockers - pharmacology; Potassium Channels, Inwardly Rectifying - genetics; Potassium Channels, Inwardly Rectifying - metabolism; Rats; Rats, Wistar; Receptors, Drug - genetics; Receptors, Drug - metabolism; RNA, Messenger - biosynthesis; RNA, Small Interfering; Sulfonylurea Receptors; Transcription, Genetic; Voltage-Sensitive Dye Imaging
• ISSN: 0363-6135; 1522-1539
• DOI: 10.1152/ajpheart.00878.2012

Cardiac metabolism remains altered for an extended period of time after myocardial infarction. Studies have shown fibroblasts from normal hearts express KATP channels in culture. It is unknown whether fibroblasts from infarcted hearts express KATP channels and whether these channels contribute to scar and border zone electrophysiology. KATP channel subunit expression levels were determined in fibroblasts isolated from normal hearts (Fb), and scar (sMI-Fb) and remote (rMI-Fb) regions of left anterior descending coronary artery (LAD) ligated rat hearts. Whole cell KATP current density was determined with patch clamp. Action potential duration (APD) was measured with optical mapping in myocyte-only cultures and heterocellular cultures with fibroblasts with and without 100 μmol/l pinacidil. Whole heart optical mapping was used to assess KATP channel activity following LAD ligation. Pinacidil activated a potassium current (35.4 ± 7.5 pA/pF at 50 mV) in sMI-Fb that was inhibited with 10 μmol/l glibenclamide. Kir6.2 and SUR2 transcript levels were elevated in sMI-Fb. Treatment with Kir6.2 short interfering RNA decreased KATP currents (87%) in sMI-Fb. Treatment with pinacidil decreased APD (26%) in co-cultures with sMI-Fb. APD values were prolonged in LAD ligated hearts after perfusion with glibenclamide. KATP channels are present in fibroblasts from the scar and border zones of infarcted hearts. Activation of fibroblast KATP channels could modulate the electrophysiological substrate beyond the acute ischemic event. Targeting fibroblast KATP channels could represent a novel therapeutic approach to modify border zone electrophysiology after cardiac injury.