ArticleAmerican journal of physiology. Heart and circulatory physiology2015
Overexpression of adenylyl cyclase type 5 (AC5) confers a proarrhythmic substrate to the heart.
Article in American journal of physiology. Heart and circulatory physiology, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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17 citing papers in PubMed, 22 citations in OpenAlex.
- Annexin A4 Deficient Ventricular Myocytes Display Advanced Hypertrophy and Electrical Remodeling With Chronic β-Adrenoceptor Stimulation.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2026Article
- Potential Involvement of Ferroptosis in Duchenne Muscular Dystrophy-Associated Cardiomyopathy.Biomedicines · 2026Article
- p22Nature cardiovascular research · 2025Article
- Modulation of cardiac cAMP signaling by AMPK and its adjustments in pressure overload-induced myocardial dysfunction in rat and mouse.PloS one · 2023Article
- A microtubule-connexin-43 regulatory link suppresses arrhythmias and cardiac fibrosis in Duchenne muscular dystrophy mice.American journal of physiology. Heart and circulatory physiology · 2022Article
- In Vivo Cardiac-specific Expression of Adenylyl Cyclase 4 Gene Protects against Klotho Deficiency-induced Heart Failure.Translational research : the journal of laboratory and clinical medicine · 2022Article
- KHz-rate volumetric voltage imaging of the whole Zebrafish heart.Biophysical reports · 2022Article
- Calcium and Heart Failure: How Did We Get Here and Where Are We Going?International journal of molecular sciences · 2021Review
- Proteomic analysis of mitochondrial biogenesis in cardiomyocytes differentiated from human induced pluripotent stem cells.American journal of physiology. Regulatory, integrative and comparative physiology · 2021Article
- Cardiac adaptation and cardioprotection against arrhythmias and ischemia-reperfusion injury in mammalian hibernators.Pflugers Archiv : European journal of physiology · 2021Review
- Activation of TRPC (Transient Receptor Potential Canonical) Channel Currents in Iron Overloaded Cardiac Myocytes.Circulation. Arrhythmia and electrophysiology · 2021Article
- Iron Overload, Oxidative Stress and Calcium Mishandling in Cardiomyocytes: Role of the Mitochondrial Permeability Transition Pore.Antioxidants (Basel, Switzerland) · 2020Article
- Antioxidant defense and protection against cardiac arrhythmias: lessons from a mammalian hibernator (the woodchuck).FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2018Article
- The type VI adenylyl cyclase protects cardiomyocytes from β-adrenergic stress by a PKA/STAT3-dependent pathway.Journal of biomedical science · 2017Article
- Effect of densely ionizing radiation on cardiomyocyte differentiation from human-induced pluripotent stem cells.Physiological reports · 2017Article
- Cardiac Adenylyl Cyclase and Phosphodiesterase Expression Profiles Vary by Age, Disease, and Chronic Phosphodiesterase Inhibitor Treatment.Journal of cardiac failure · 2017Article
- Calm down when the heart is stressed: Inhibiting calmodulin-dependent protein kinase II for antiarrhythmias.Trends in cardiovascular medicine · 2015Article
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Authors and funding
10 authors at 5 institutions in 2 countries.
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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 (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 afterdepolarizations 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 AC5 overexpression promotes arrhythmogenesis, by inducing SR Ca(2+) overload and hyperactivation of RyR (phosphorylation by CaMKII), which in turn induces spontaneous Ca(2+) waves and afterdepolarizations.
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