Document Detail


Inhibition of Mas G-protein signaling improves coronary blood flow, reduces myocardial infarct size, and provides long-term cardioprotection.
MedLine Citation:
PMID:  22003054     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The Mas receptor is a class I G-protein-coupled receptor that is expressed in brain, testis, heart, and kidney. The intracellular signaling pathways activated downstream of Mas are still largely unknown. In the present study, we examined the expression pattern and signaling of Mas in the heart and assessed the participation of Mas in cardiac ischemia-reperfusion injury. Mas mRNA and protein were present in all chambers of human hearts, with cardiomyocytes and coronary arteries being sites of enriched expression. Expression of Mas in either HEK293 cells or cardiac myocytes resulted in constitutive coupling to the G(q) protein, which in turn activated phospholipase C and caused inositol phosphate accumulation. To generate chemical tools for use in probing the function of Mas, we performed a library screen and chemistry optimization program to identify potent and selective nonpeptide agonists and inverse agonists. Mas agonists activated G(q) signaling in a dose-dependent manner and reduced coronary blood flow in isolated mouse and rat hearts. Conversely, treatment of isolated rat hearts with Mas inverse agonists improved coronary flow, reduced arrhythmias, and provided cardioprotection from ischemia-reperfusion injury, an effect that was due, at least in part, to decreased cardiomyocyte apoptosis. Participation of Mas in ischemia-reperfusion injury was confirmed in Mas knockout mice, which had reduced infarct size relative to mice with normal Mas expression. These results suggest that activation of Mas during myocardial infarction contributes to ischemia-reperfusion injury and further suggest that inhibition of Mas-G(q) signaling may provide a new therapeutic strategy directed at cardioprotection.
Authors:
Tong Zhang; Zhuangjie Li; Huong Dang; Ruoping Chen; Chen Liaw; Thuy-Anh Tran; P Douglas Boatman; Daniel T Connolly; John W Adams
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Publication Detail:
Type:  Journal Article     Date:  2011-10-14
Journal Detail:
Title:  American journal of physiology. Heart and circulatory physiology     Volume:  302     ISSN:  1522-1539     ISO Abbreviation:  Am. J. Physiol. Heart Circ. Physiol.     Publication Date:  2012 Jan 
Date Detail:
Created Date:  2011-12-27     Completed Date:  2012-02-14     Revised Date:  2012-05-23    
Medline Journal Info:
Nlm Unique ID:  100901228     Medline TA:  Am J Physiol Heart Circ Physiol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  H299-311     Citation Subset:  IM    
Affiliation:
Arena Pharmaceuticals Incorporated, San Diego, California, USA.
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MeSH Terms
Descriptor/Qualifier:
Animals
Animals, Newborn
Apoptosis / drug effects
Cardiotonic Agents / chemistry,  pharmacology*
Coronary Circulation / drug effects*
Disease Models, Animal
Dose-Response Relationship, Drug
Drug Inverse Agonism
Enzyme Activation
GTP-Binding Protein alpha Subunits, Gq-G11 / metabolism*
HEK293 Cells
Humans
Inositol Phosphates / metabolism
Mice
Mice, Knockout
Molecular Structure
Myocardial Infarction / genetics,  metabolism,  pathology,  physiopathology,  prevention & control*
Myocardial Reperfusion Injury / genetics,  metabolism,  pathology,  physiopathology,  prevention & control*
Myocardium / metabolism*,  pathology
Proto-Oncogene Proteins / antagonists & inhibitors*,  genetics,  metabolism
RNA, Messenger / metabolism
Rats
Rats, Sprague-Dawley
Receptors, G-Protein-Coupled / antagonists & inhibitors*,  genetics,  metabolism
Signal Transduction / drug effects*
Time Factors
Transfection
Type C Phospholipases / metabolism
Ventricular Function, Left / drug effects
Chemical
Reg. No./Substance:
0/Cardiotonic Agents; 0/Inositol Phosphates; 0/Proto-Oncogene Proteins; 0/RNA, Messenger; 0/Receptors, G-Protein-Coupled; 0/proto-oncogene proteins c-mas-1; EC 3.1.4.-/Type C Phospholipases; EC 3.6.5.1/GTP-Binding Protein alpha Subunits, Gq-G11

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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