PMID- 25485900
OWN - NLM
STAT- MEDLINE
DCOM- 20150402
LR  - 20200930
IS  - 1522-1539 (Electronic)
IS  - 0363-6135 (Print)
IS  - 0363-6135 (Linking)
VI  - 308
IP  - 3
DP  - 2015 Feb 1
TI  - Overexpression of adenylyl cyclase type 5 (AC5) confers a proarrhythmic substrate 
      to the heart.
PG  - H240-9
LID - 10.1152/ajpheart.00630.2014 [doi]
AB  - Inhibition of beta-adrenergic receptor (beta-AR) signaling is one of the most common 
      therapeutic approaches for patients with arrhythmias. Adenylyl cyclase (AC) is 
      the key enzyme responsible for transducing beta-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.
CI  - Copyright (c) 2015 the American Physiological Society.
FAU - Zhao, Zhenghang
AU  - Zhao Z
AD  - Department 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;
FAU - Babu, Gopal J
AU  - Babu GJ
AD  - Department of Cell Biology and Molecular Medicine, Rutgers University-New Jersey 
      Medical School, Newark, New Jersey;
FAU - Wen, Hairuo
AU  - Wen H
AD  - Department 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.
FAU - Fefelova, Nadezhda
AU  - Fefelova N
AD  - Department of Cell Biology and Molecular Medicine, Rutgers University-New Jersey 
      Medical School, Newark, New Jersey;
FAU - Gordan, Richard
AU  - Gordan R
AD  - Department of Cell Biology and Molecular Medicine, Rutgers University-New Jersey 
      Medical School, Newark, New Jersey;
FAU - Sui, Xiangzhen
AU  - Sui X
AD  - Department of Cell Biology and Molecular Medicine, Rutgers University-New Jersey 
      Medical School, Newark, New Jersey;
FAU - Yan, Lin
AU  - Yan L
AD  - Department of Cell Biology and Molecular Medicine, Rutgers University-New Jersey 
      Medical School, Newark, New Jersey;
FAU - Vatner, Dorothy E
AU  - Vatner DE
AD  - Department of Cell Biology and Molecular Medicine, Rutgers University-New Jersey 
      Medical School, Newark, New Jersey;
FAU - Vatner, Stephen F
AU  - Vatner SF
AD  - Department of Cell Biology and Molecular Medicine, Rutgers University-New Jersey 
      Medical School, Newark, New Jersey;
FAU - Xie, Lai-Hua
AU  - Xie LH
AD  - Department 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 xiela@njms.rutgers.edu.
LA  - eng
GR  - 5P01-AG-027211/AG/NIA NIH HHS/United States
GR  - R01-HL-106511/HL/NHLBI NIH HHS/United States
GR  - 5R01-HL-091781/HL/NHLBI NIH HHS/United States
GR  - R01 HL119464/HL/NHLBI NIH HHS/United States
GR  - 5R01-HL-033107/HL/NHLBI NIH HHS/United States
GR  - R01 HL097979/HL/NHLBI NIH HHS/United States
GR  - R01 HL106511/HL/NHLBI NIH HHS/United States
GR  - R01-HL-97979/HL/NHLBI NIH HHS/United States
GR  - R01-HL-093481/HL/NHLBI NIH HHS/United States
GR  - 5T32-HL-069752/HL/NHLBI NIH HHS/United States
GR  - 5R21-HL-097264/HL/NHLBI NIH HHS/United States
GR  - 1R01-HL-102472/HL/NHLBI NIH HHS/United States
GR  - 5R01-HL-095888/HL/NHLBI NIH HHS/United States
GR  - R01 HL093481/HL/NHLBI NIH HHS/United States
GR  - 1R01-HL-119464/HL/NHLBI NIH HHS/United States
GR  - 5P01-HL-069020/HL/NHLBI NIH HHS/United States
GR  - R01 HL102472/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20141205
PL  - United States
TA  - Am J Physiol Heart Circ Physiol
JT  - American journal of physiology. Heart and circulatory physiology
JID - 100901228
RN  - 0 (Cardiotonic Agents)
RN  - 0 (Isoenzymes)
RN  - 0 (Reactive Oxygen Species)
RN  - 0 (Ryanodine Receptor Calcium Release Channel)
RN  - EC 2.7.11.17 (Calcium-Calmodulin-Dependent Protein Kinase Type 2)
RN  - EC 3.6.3.8 (Sarcoplasmic Reticulum Calcium-Transporting ATPases)
RN  - EC 4.6.1.1 (Adenylyl Cyclases)
RN  - L628TT009W (Isoproterenol)
RN  - SY7Q814VUP (Calcium)
SB  - IM
MH  - Action Potentials
MH  - Adenylyl Cyclases/genetics/*metabolism
MH  - Animals
MH  - Arrhythmias, Cardiac/*metabolism
MH  - Calcium/metabolism
MH  - Calcium Signaling
MH  - Calcium-Calmodulin-Dependent Protein Kinase Type 2/genetics/metabolism
MH  - Cardiotonic Agents/pharmacology
MH  - Cells, Cultured
MH  - Heart Ventricles/cytology/metabolism
MH  - Isoenzymes/genetics/metabolism
MH  - Isoproterenol/pharmacology
MH  - Mice
MH  - Myocytes, Cardiac/drug effects/metabolism/physiology
MH  - Reactive Oxygen Species/metabolism
MH  - Ryanodine Receptor Calcium Release Channel/metabolism
MH  - Sarcoplasmic Reticulum Calcium-Transporting ATPases/genetics/metabolism
PMC - PMC4312946
OTO - NOTNLM
OT  - adenylyl cyclase type 5
OT  - arrhythmias
OT  - calcium handling
OT  - electrophysiology
OT  - overexpression
EDAT- 2014/12/09 06:00
MHDA- 2015/04/04 06:00
PMCR- 2016/02/01
CRDT- 2014/12/09 06:00
PHST- 2014/12/09 06:00 [entrez]
PHST- 2014/12/09 06:00 [pubmed]
PHST- 2015/04/04 06:00 [medline]
PHST- 2016/02/01 00:00 [pmc-release]
AID - ajpheart.00630.2014 [pii]
AID - H-00630-2014 [pii]
AID - 10.1152/ajpheart.00630.2014 [doi]
PST - ppublish
SO  - Am J Physiol Heart Circ Physiol. 2015 Feb 1;308(3):H240-9. doi: 
      10.1152/ajpheart.00630.2014. Epub 2014 Dec 5.