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

Zhao Z1, Babu GJ2, Wen H3, Fefelova N2, Gordan R2, Sui X2, Yan L2, Vatner DE2, Vatner SF2, Xie LH4.

Am J Physiol Heart Circ Physiol. 2015;308(3):H240-9.

Show Affiliations

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;

2Department of Cell Biology and Molecular Medicine, Rutgers University-New Jersey Medical School, Newark, New Jersey;

3Department of Cell Biology and Molecular Medicine, Rutgers University-New Jersey Medical School, Newark, New Jersey; Department of Reproductive and Genetic Toxicology, National Center for Safety Evaluation of Drugs, National Institutes for Food and Drug Control, Beijing, People’s Republic of China; and.

4Department of Cell Biology and Molecular Medicine, Rutgers University-New Jersey Medical School, Newark, New Jersey; School of Pharmacology, Xinxiang Medical University, Xixiang, People’s Republic of China [email protected]

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 adenylyl cyclase isoforms in the heart are types 5 and 6. Therefore, it is surprising that prior studies on  overexpression of adenylyl cyclase type 5 and adenylyl cyclase type 6 in transgenic (Tg) mice have not examined mediation of arrhythmogenesis. Our goal was to examine the proarrhythmic  substrate in AC5Tg hearts. Intracellular calcium ion (Ca(2+) i) was imaged in fluo-4 AM-loaded ventricular myocytes. The sarcoplasmic reticulum (SR) Ca(2+) content, fractional Ca(2+) release, and twitch Ca(2+) transient were significantly higher in the AC5Tg vs. wild-type (WT) myocytes, indicating Ca(2+) overload in AC5Tg myocytes. Action potential (AP) duration was significantly longer in AC5Tg than in WT myocytes. Additionally, AC5Tg myocytes developed spontaneous Ca(2+) waves in a larger fraction compared with WT myocytes, particularly when cells were exposed to isoproterenol. The Ca(2+) waves further induced after depolarizations and triggered APs. AC5Tg hearts had increased level of SERCA2a, oxidized Ca(2+)/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 adenylyl cyclase type 5 over expression promotes arrhythmogenesis, by inducing SR Ca(2+) overload and hyperactivation of RyR (phosphorylation  by CaMKII), which in turn induces spontaneous Ca(2+) waves and after depolarizations.

Copyright © 2015 the American Physiological Society.

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Figure Legend

 Type 5 adenylyl cyclase overexpression (AC5OE) facilitates arrhythmogenesis under adrenergic stress. Stimulation of b-adrenergic receptor (b-AR) by isoproterenol (Iso) activates protein kinase A (PKA).  AC5OE exacerbates SR Ca overload (via activation of Ca handling proteins) and ryanodine receptor (RyR) leak (via enhanced oxidative stress and CaMKII activation).  A higher arrhythmic propensity occurs only when the above two pathways work together synergistically (Å)  to induce early and delayed afterdepolarizations (EADs & DADs).

Overexpression of adenylyl cyclase type 5 (AC5) confers a proarrhythmic substrate heart. Global Medical Discovery