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

Zhenghang Zhao, Gopal J. Babu, Hairuo Wen, Nadezhda Fefelova, Richard Gordan, Xiangzhen Sui, Lin Yan, Dorothy E. Vatner, Stephen F. Vatner, Lai Hua Xie

Research output: Contribution to journalArticlepeer-review

14 Scopus citations

Abstract

Inhibition of (β-adrenergic receptor ((β-AR) signaling is one of the most common therapeutic approaches for patients with arrhythmias. Adenylyl cyclase (AC) is the key enzyme responsible for transducing (β-AR stimulation to increases in cAMP. The two major AC isoforms in the heart are types 5 and 6. Therefore, it is surprising that prior studies on overexpression of AC5 and AC6 in transgenic (Tg) mice have not examined mediation of arrhythmogenesis. Our goal was to examine the proarrhythmic substrate in AC5Tg hearts. Intracellular calcium ion (Ca2+i) was imaged in fluo-4 AM-loaded ventricular myocytes. The sarcoplasmic reticulum (SR) Ca2+ content, fractional Ca2+ release, and twitch Ca2+ transient were significantly higher in the AC5Tg vs. wild-type (WT) myocytes, indicating Ca2+ overload in AC5Tg myocytes. Action potential (AP) duration was significantly longer in AC5Tg than in WT myocytes. Additionally, AC5Tg myocytes developed spontaneous Ca2+ waves in a larger fraction compared with WT myocytes, particularly when cells were exposed to isoproterenol. The Ca2+ waves further induced afterdepolarizations and triggered APs. AC5Tg hearts had increased level of SERCA2a, oxidized Ca2+/calmodulin-dependent protein kinase II (CaMKII), and phosphorylation of ryanodine receptors (RyR) at the CaMKII site, especially after isoproterenol treatment. This was consistent with higher reactive oxygen species production in AC5Tg myocytes after isoproterenol treatment. Isoproterenol induced more severe arrhythmias in AC5Tg than in WT mice. We conclude that AC5 overexpression promotes arrhythmogenesis, by inducing SR Ca2+ overload and hyperactivation of RyR (phosphorylation by CaMKII), which in turn induces spontaneous Ca2+ waves and afterdepolarizations.

Original languageEnglish (US)
Pages (from-to)H240-H249
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume308
Issue number3
DOIs
StatePublished - 2015

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Keywords

  • Adenylyl cyclase type 5
  • Arrhythmias
  • Calcium handling
  • Electro-physiology
  • Overexpression

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