Fibroblast K_ATP currents modulate myocyte electrophysiology in infarcted hearts

Abstract

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.

Fibroblast Electrical Remodeling in Heart Failure and Potential Effects on Atrial Fibrillation

“…Targeting ventricular fibroblast ion currents to produce antiarrhythmic electrophysiological changes in and around the infarct site may provide a new paradigm for the management of complex ventricular arrhythmias (43). Evidence suggests that modulating the fibroblast ATP-regulated K þ current may be exploited to alter border-zone electrophysiology in infarcted hearts (44).…”

The protective effect of ursodeoxycholic acid in an in vitro model of the human fetal heart occurs via targeting cardiac fibroblasts

“…5 infarcted heart model, pinacidil treatment increased whole-cell K ATP current which was blocked by glibenclamide (Benamer et al, 2013). It is thought that activation of fibroblast K ATP current would reduce the depolarizing effect on cardiomyocytes, which would subsequently prevent early after depolarisations.…”

“…Although K ATP channel subunits are abundant in cardiomyocytes, Benamer et al (2009Benamer et al ( , 2013 reported mRNA and protein expression of SUR2 and Kir6.1 as the two most prominently expressed subunits in mouse and rat ventricular fibroblasts (Benamer et al, 2013(Benamer et al, , 2009). Subsequently, they recorded current carried by the Kir6.1/SUR2 channel complex, which was shown to be sensitive to both pinacidil and glibenclamide.…”

“…Equally, hypoxic/ischaemic environments can cause down-regulation of ion channels involved in maintaining RMP (Benamer et al, 2013(Benamer et al, , 2009). In our study we saw a significant positive shift of membrane potential in human fetal fibroblasts [ Figure 8B], which is indicative of channel subunit reduction.…”

Cardiac Mechano-Gated Ion Channels and Arrhythmias

“…67 Of note, cardiac K ATP channels are also present and active in fibroblasts, suggesting that one must consider cardiac pre-/post-conditioning effects on cells other than just cardiomyocytes. 68–70 As with other K + channels, K ATP opening favours re-/hyperpolarization. While beneficial in preventing spurious excitation of resting cells, this also shortens the action potential (AP) duration (APD) and reduces the refractory period.…”