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Overexpression of adenylyl cyclase type 5 (AC5) confers a proarrhythmic substrate to the heart

Zhenghang Zhao1, Gopal J Babu2, Hairuo Wen3

  • 1Department of Pharmacology, School of Medicine, Xi'an Jiaotong University, Xi'an, People's Republic of China; Department of Cell Biology and Molecular Medicine, Rutgers University-New Jersey Medical School, Newark, New Jersey;

American Journal of Physiology. Heart and Circulatory Physiology
|December 9, 2014
PubMed

Insights

Overexpression of adenylyl cyclase 5 (AC5) in the heart leads to calcium overload and promotes arrhythmias. This occurs through increased sarcoplasmic reticulum calcium and ryanodine receptor activity, triggering abnormal heart rhythms.

Area of Science:

  • Cardiology
  • Molecular Biology
  • Electrophysiology

Background:

  • Beta-adrenergic receptor (β-AR) signaling inhibition is a common arrhythmia treatment.
  • Adenylyl cyclase (AC) enzymes, particularly AC5 and AC6, mediate β-AR signaling in the heart.
  • Previous studies overlooked the role of AC5 and AC6 overexpression in cardiac arrhythmogenesis.

Purpose of the Study:

  • To investigate the proarrhythmic substrate in hearts overexpressing AC5 (AC5Tg mice).
  • To understand the mechanisms by which AC5 overexpression contributes to arrhythmias.

Main Methods:

  • Intracellular calcium ion (Ca(2+)i) imaging in ventricular myocytes from AC5Tg and wild-type (WT) mice.
  • Measurement of sarcoplasmic reticulum (SR) Ca(2+) content, fractional Ca(2+) release, and twitch Ca(2+) transient.
  • Assessment of action potential duration, spontaneous Ca(2+) waves, afterdepolarizations, and triggered action potentials.
  • Analysis of SERCA2a levels, oxidized Ca(2+)/calmodulin-dependent protein kinase II (CaMKII), phosphorylated ryanodine receptors (RyR), and reactive oxygen species.

Main Results:

  • AC5Tg myocytes exhibited significantly higher SR Ca(2+) content, fractional Ca(2+) release, and twitch Ca(2+) transient compared to WT, indicating Ca(2+) overload.
  • Action potential duration was prolonged in AC5Tg myocytes.
  • AC5Tg myocytes showed increased spontaneous Ca(2+) waves, particularly upon isoproterenol stimulation, leading to afterdepolarizations and triggered APs.
  • AC5Tg hearts had elevated SERCA2a, oxidized CaMKII, and phosphorylated RyR, alongside increased reactive oxygen species production after isoproterenol treatment.
  • Isoproterenol induced more severe arrhythmias in AC5Tg mice than in WT mice.

Conclusions:

  • AC5 overexpression promotes cardiac arrhythmogenesis.
  • Mechanisms involve sarcoplasmic reticulum Ca(2+) overload and hyperactivation of RyR via CaMKII phosphorylation.
  • This leads to spontaneous Ca(2+) waves and afterdepolarizations, contributing to arrhythmias.
Keywords:
adenylyl cyclase type 5arrhythmiascalcium handlingelectrophysiologyoverexpression

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