Ademuyiwa S Aromolaran1. 1. Cardiac Electrophysiology and Metabolism Research Group, VA New York Harbor Healthcare System, Research and Development Office, (151), 800 Poly Place, Brooklyn, NY, 11209, USA; Department of Cell Biology, State University of New York Downstate Medical Center, Brooklyn, NY, USA; Department of Physiology & Cellular Biophysics, Columbia University, New York, NY, USA. Electronic address: ademuyiwa.aromolaran@downstate.edu.
Abstract
OBJECTIVES: To develop an adult guinea pig model of lipotoxicity and explore the underlying mechanisms associated with changes in the expression of the delayed rectifier potassium current (IK). BACKGROUND: Lipotoxicity may represent a common link among metabolic disorders and a higher vulnerability to arrhythmias. METHODS: Whole-cell patch clamp, and palmitic acid (PA, a potent inducer of lipotoxicity), were used to assess mechanisms of short-term (∼50 days) high-fat diet (HFD) feeding on atrial electrophysiology in guinea pig hearts and myocytes. RESULTS: HFD fed guinea pigs were significantly heavier, displayed hypertriglyceridemia and hypercholesterolemia; but no signs of hyperglycemia or inflammation compared to low-fat diet fed controls. Increasing cardiac PA levels, resulted in shortened atrial action potential duration, and increased IK density. Inhibition of phosphoinositide 3-kinase (PI3K) prevented increases in IK due to PA. Acute (≥1hr) exposure of atrial myocytes to exogenous PA (1 mM) increased the density of the rapid delayed rectifier potassium current IKr, while it was decreased with the unsaturated oleic acid (OA, 1 mM). Serine-threonine protein phosphatase-2 (PP2A) inhibition with cantharidin reversed the effect of OA on IKr. CONCLUSION: Our data provide evidence of a novel lipotoxic guinea pig model with signs of vulnerability to arrhythmias. Inhibition of PA/PI3K/IK and/or activation of the OA/PP2A/IKr pathways may be therapeutically beneficial for lipotoxic arrhythmias.
OBJECTIVES: To develop an adult guinea pig model of lipotoxicity and explore the underlying mechanisms associated with changes in the expression of the delayed rectifier potassium current (IK). BACKGROUND: Lipotoxicity may represent a common link among metabolic disorders and a higher vulnerability to arrhythmias. METHODS: Whole-cell patch clamp, and palmitic acid (PA, a potent inducer of lipotoxicity), were used to assess mechanisms of short-term (∼50 days) high-fat diet (HFD) feeding on atrial electrophysiology in guinea pig hearts and myocytes. RESULTS: HFD fed guinea pigs were significantly heavier, displayed hypertriglyceridemia and hypercholesterolemia; but no signs of hyperglycemia or inflammation compared to low-fat diet fed controls. Increasing cardiac PA levels, resulted in shortened atrial action potential duration, and increased IK density. Inhibition of phosphoinositide 3-kinase (PI3K) prevented increases in IK due to PA. Acute (≥1hr) exposure of atrial myocytes to exogenous PA (1 mM) increased the density of the rapid delayed rectifier potassium current IKr, while it was decreased with the unsaturated oleic acid (OA, 1 mM). Serine-threonine protein phosphatase-2 (PP2A) inhibition with cantharidin reversed the effect of OA on IKr. CONCLUSION: Our data provide evidence of a novel lipotoxic guinea pig model with signs of vulnerability to arrhythmias. Inhibition of PA/PI3K/IK and/or activation of the OA/PP2A/IKr pathways may be therapeutically beneficial for lipotoxic arrhythmias.
Authors: Hester M Den Ruijter; Arie O Verkerk; Cees A Schumacher; Sander M Houten; Charly N W Belterman; Antonius Baartscheer; Ingeborg A Brouwer; Marc van Bilsen; Baukje de Roos; Ruben Coronel Journal: Circ Heart Fail Date: 2012-04-02 Impact factor: 8.790
Authors: Leena P Bharath; Ting Ruan; Youyou Li; Anindita Ravindran; Xin Wan; Jennifer Kim Nhan; Matthew Lewis Walker; Lance Deeter; Rebekah Goodrich; Elizabeth Johnson; Derek Munday; Robert Mueller; David Kunz; Deborah Jones; Van Reese; Scott A Summers; Pon Velayutham Anandh Babu; William L Holland; Quan-Jiang Zhang; E Dale Abel; J David Symons Journal: Diabetes Date: 2015-08-07 Impact factor: 9.461