Inhibition of Mas G-protein signaling improves coronary blood flow, reduces myocardial infarct size, and provides long-term cardioprotection

Autor: P. Douglas Boatman, Huong T. Dang, Adams John W, Daniel T. Connolly, Zhuangjie Li, Chen W. Liaw, Ruoping Chen, Thuy-Anh Tran, Tong Zhang
Rok vydání: 2012
Předmět:
Time Factors
Physiology
Myocardial Infarction
Apoptosis
Proto-Oncogene Mas
Ventricular Function
Left
Receptors
G-Protein-Coupled
Rats
Sprague-Dawley
Mice
Myocardial infarction
Receptor
Mice
Knockout
Cardioprotection
Kidney
Molecular Structure
biology
Cell biology
medicine.anatomical_structure
Gq alpha subunit
Cardiology and Cardiovascular Medicine
Signal Transduction
medicine.medical_specialty
Cardiotonic Agents
Drug Inverse Agonism
G protein
Inositol Phosphates
Myocardial Reperfusion Injury
Transfection
Coronary Circulation
Proto-Oncogene Proteins
Physiology (medical)
Internal medicine
medicine
Animals
Humans
RNA
Messenger
G protein-coupled receptor
Dose-Response Relationship
Drug
business.industry
Myocardium
medicine.disease
Rats
Enzyme Activation
Disease Models
Animal
HEK293 Cells
Endocrinology
Animals
Newborn
Type C Phospholipases
biology.protein
GTP-Binding Protein alpha Subunits
Gq-G11
business
Reperfusion injury
Zdroj: American Journal of Physiology-Heart and Circulatory Physiology. 302:H299-H311
ISSN: 1522-1539
0363-6135
Popis: 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 Gq 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 Gq 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-Gq signaling may provide a new therapeutic strategy directed at cardioprotection.
Databáze: OpenAIRE
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