Atrial AMP-activated protein kinase is critical for prevention of dysregulation of electrical excitability and atrial fibrillation
Kevin N. Su, Yina Ma, Marine Cacheux, Zeki Ilkan, Nour Raad, Grace K. Muller, Xiaohong Wu, Nicole Guerrera, Stephanie L. Thorn, Albert J. Sinusas, Marc Foretz, Benoit Viollet, Joseph G. Akar, Fadi G. Akar, Lawrence H. Young
Kevin N. Su, Yina Ma, Marine Cacheux, Zeki Ilkan, Nour Raad, Grace K. Muller, Xiaohong Wu, Nicole Guerrera, Stephanie L. Thorn, Albert J. Sinusas, Marc Foretz, Benoit Viollet, Joseph G. Akar, Fadi G. Akar, Lawrence H. Young
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Research Article Cardiology

Atrial AMP-activated protein kinase is critical for prevention of dysregulation of electrical excitability and atrial fibrillation

Abstract

Metabolic stress is an important cause of pathological atrial remodeling and atrial fibrillation. AMPK is a ubiquitous master metabolic regulator, yet its biological function in the atria is poorly understood in both health and disease. We investigated the impact of atrium-selective cardiac AMPK deletion on electrophysiological and structural remodeling in mice. Loss of atrial AMPK expression caused atrial changes in electrophysiological properties and atrial ectopic activity prior to the onset of spontaneous atrial fibrillation. Concomitant transcriptional downregulation of connexins and atrial ion channel subunits manifested with delayed left atrial activation and repolarization. The early molecular and electrophysiological abnormalities preceded left atrial structural remodeling and interstitial fibrosis. AMPK inactivation induced downregulation of transcription factors (Mef2c and Pitx2c) linked to connexin and ion channel transcriptional reprogramming. Thus, AMPK plays an essential homeostatic role in atria, protecting against adverse remodeling potentially by regulating key transcription factors that control the expression of atrial ion channels and gap junction proteins.

Authors

Kevin N. Su, Yina Ma, Marine Cacheux, Zeki Ilkan, Nour Raad, Grace K. Muller, Xiaohong Wu, Nicole Guerrera, Stephanie L. Thorn, Albert J. Sinusas, Marc Foretz, Benoit Viollet, Joseph G. Akar, Fadi G. Akar, Lawrence H. Young

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Figure 6

Decreased atrial potassium channel expression and prolonged electrophysiological repolarization in hearts from mice with atrial AMPK deletion.

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Decreased atrial potassium channel expression and prolonged electrophysi...
Atrial channel expression and high-resolution optical action potentials in AMPK double-KO sarcolipin-Cre Prkaa1fl/fl Prkaa2fl/fll (AMPK-dKO) and littermate control Prkaa1fl/fl Prkaa2fl/fl (CON) mice. (A) mRNA transcripts encoding the repolarizing Kv1.5 (Kcna5), Kv7.1 (Kcnq1), and the inward rectifier Kir2.1 (Kcnj2) channels in right atria (RA) and left atria (LA) from 1-week-old mice. (B) mRNA transcripts encoding the “funny current” (Hcn4) from 1-week-old mice. Values are mean ± SEM of n = 6 per group. (C) Representative Kir2.1 immunoblots from RA and LA from 4-week-old mice with corresponding densitometric quantification. Proteins were immunoblotted after transfer from the same gel used for Nav1.5 and GAPDH detection (in Figure 5C) and the GAPDH immunoblot was again used as the loading control for Kir2.1. Values are mean ± SEM of n = 4 per group. (D) Representative image of an ex vivo perfused heart from a 6-week-old CON mouse oriented to optimize the simultaneous mapping of the left atrial and ventricular surfaces during atrial pacing. (E) Representative LA and left ventricular (LV) optical action potential traces that document the ability to accurately resolve both depolarization and repolarization. Scale bar: 200 ms. (F) Quantification of LA and LV action potential duration (APD75) in hearts from 6-week-old mice. Values are mean ± SEM of n = 6–8 per group. *P < 0.05, **P < 0.01, ***P < 0.001 versus CON by unpaired Student’s t test.