Ghent University Academic Bibliography

Advanced

The alpha1 isoform of soluble guanylate cyclase regulates cardiac contractility but is not required for ischemic preconditioning

Patrick Sips UGent, Peter Brouckaert UGent and Fumito Ichinose (2011) BASIC RESEARCH IN CARDIOLOGY. 106(4). p.635-643
abstract
Nitric oxide (NO)-dependent soluble guanylate cyclase (sGC) activation is an important component of cardiac signal transduction pathways, including the cardioprotective signaling cascade induced by ischemic preconditioning (IPC). The sGC alpha subunit, which binds to the common sGC beta 1 subunit, exists in two different isoforms, sGC alpha 1 and sGC alpha 2, but their relative physiological roles remain unknown. In the present study, we studied Langendorff-perfused isolated hearts of genetically engineered mice lacking functional sGC alpha 1 (sGC alpha 1KO mice), which is the predominant isoform in the heart. Our results show that the loss of sGC alpha 1 has a positive inotropic and lusitropic effect on basal cardiac function, indicating an important role for sGC alpha 1 in regulating basal myocardial contractility. Surprisingly, IPC led to a similar 35-40% reduction in infarct size and concomitant protein kinase C epsilon (PKC epsilon) phosphorylation in both wild-type (WT) and sGC alpha 1KO hearts subjected to 40 min of global ischemia and reperfusion. Inhibition of the activation of all sGC isoforms by 1H-[1,2,4] oxadiazolo[4,3-a]quinoxaline-1-one (ODQ, 10 mu mol/L) completely abolished the protection by IPC in WT and sGC alpha 1KO hearts. NO-stimulated cGMP production was severely attenuated in sGC alpha 1KO hearts compared to WT hearts, indicating that the sGC alpha 2 isoform only produces minute amounts of cGMP after NO stimulation. Taken together, our results indicate that although sGC alpha 1 importantly regulates cardiac contractility, it is not required for cardioprotection by IPC. Instead, our results suggest that possibly only minimal sGC activity, which in sGC alpha 1KO hearts is provided by the sGC alpha 2 isoform, is sufficient to transduce the cardioprotective signal induced by IPC via phosphorylation of PKC epsilon.
Please use this url to cite or link to this publication:
author
organization
year
type
journalArticle (original)
publication status
published
subject
keyword
Nitric oxide, NITRIC-OXIDE, Contractility, Isolated heart, Ischemic preconditioning, Soluble guanylate cyclase, ACTIVATION, CGMP, NO, ISOLATED HEART, LATE-PHASE, MYOCARDIAL-INFARCTION, VENTRICULAR MYOCYTES, PROTEIN-KINASE, REPERFUSION INJURY
journal title
BASIC RESEARCH IN CARDIOLOGY
Basic Res. Cardiol.
volume
106
issue
4
pages
635 - 643
Web of Science type
Article
Web of Science id
000291741700012
JCR category
CARDIAC & CARDIOVASCULAR SYSTEMS
JCR impact factor
7.348 (2011)
JCR rank
6/117 (2011)
JCR quartile
1 (2011)
ISSN
0300-8428
DOI
10.1007/s00395-011-0167-y
language
English
UGent publication?
yes
classification
A1
copyright statement
I have transferred the copyright for this publication to the publisher
id
1870627
handle
http://hdl.handle.net/1854/LU-1870627
date created
2011-08-08 16:58:05
date last changed
2017-02-03 12:29:16
@article{1870627,
  abstract     = {Nitric oxide (NO)-dependent soluble guanylate cyclase (sGC) activation is an important component of cardiac signal transduction pathways, including the cardioprotective signaling cascade induced by ischemic preconditioning (IPC). The sGC alpha subunit, which binds to the common sGC beta 1 subunit, exists in two different isoforms, sGC alpha 1 and sGC alpha 2, but their relative physiological roles remain unknown. In the present study, we studied Langendorff-perfused isolated hearts of genetically engineered mice lacking functional sGC alpha 1 (sGC alpha 1KO mice), which is the predominant isoform in the heart. Our results show that the loss of sGC alpha 1 has a positive inotropic and lusitropic effect on basal cardiac function, indicating an important role for sGC alpha 1 in regulating basal myocardial contractility. Surprisingly, IPC led to a similar 35-40\% reduction in infarct size and concomitant protein kinase C epsilon (PKC epsilon) phosphorylation in both wild-type (WT) and sGC alpha 1KO hearts subjected to 40 min of global ischemia and reperfusion. Inhibition of the activation of all sGC isoforms by 1H-[1,2,4] oxadiazolo[4,3-a]quinoxaline-1-one (ODQ, 10 mu mol/L) completely abolished the protection by IPC in WT and sGC alpha 1KO hearts. NO-stimulated cGMP production was severely attenuated in sGC alpha 1KO hearts compared to WT hearts, indicating that the sGC alpha 2 isoform only produces minute amounts of cGMP after NO stimulation. Taken together, our results indicate that although sGC alpha 1 importantly regulates cardiac contractility, it is not required for cardioprotection by IPC. Instead, our results suggest that possibly only minimal sGC activity, which in sGC alpha 1KO hearts is provided by the sGC alpha 2 isoform, is sufficient to transduce the cardioprotective signal induced by IPC via phosphorylation of PKC epsilon.},
  author       = {Sips, Patrick and Brouckaert, Peter and Ichinose, Fumito},
  issn         = {0300-8428},
  journal      = {BASIC RESEARCH IN CARDIOLOGY},
  keyword      = {Nitric oxide,NITRIC-OXIDE,Contractility,Isolated heart,Ischemic preconditioning,Soluble guanylate cyclase,ACTIVATION,CGMP,NO,ISOLATED HEART,LATE-PHASE,MYOCARDIAL-INFARCTION,VENTRICULAR MYOCYTES,PROTEIN-KINASE,REPERFUSION INJURY},
  language     = {eng},
  number       = {4},
  pages        = {635--643},
  title        = {The alpha1 isoform of soluble guanylate cyclase regulates cardiac contractility but is not required for ischemic preconditioning},
  url          = {http://dx.doi.org/10.1007/s00395-011-0167-y},
  volume       = {106},
  year         = {2011},
}

Chicago
Sips, Patrick, Peter Brouckaert, and Fumito Ichinose. 2011. “The Alpha1 Isoform of Soluble Guanylate Cyclase Regulates Cardiac Contractility but Is Not Required for Ischemic Preconditioning.” Basic Research in Cardiology 106 (4): 635–643.
APA
Sips, P., Brouckaert, P., & Ichinose, F. (2011). The alpha1 isoform of soluble guanylate cyclase regulates cardiac contractility but is not required for ischemic preconditioning. BASIC RESEARCH IN CARDIOLOGY, 106(4), 635–643.
Vancouver
1.
Sips P, Brouckaert P, Ichinose F. The alpha1 isoform of soluble guanylate cyclase regulates cardiac contractility but is not required for ischemic preconditioning. BASIC RESEARCH IN CARDIOLOGY. 2011;106(4):635–43.
MLA
Sips, Patrick, Peter Brouckaert, and Fumito Ichinose. “The Alpha1 Isoform of Soluble Guanylate Cyclase Regulates Cardiac Contractility but Is Not Required for Ischemic Preconditioning.” BASIC RESEARCH IN CARDIOLOGY 106.4 (2011): 635–643. Print.