title: Gαi2- and Gαi3-deficient mice display opposite severity of myocardial ischemia reperfusion injury.
abstract: G-protein-coupled receptors (GPCRs) are the most abundant receptors in the heart and therefore are common targets for cardiovascular therapeutics. The activated GPCRs transduce their signals via heterotrimeric G-proteins. The four major families of G-proteins identified so far are specified through their α-subunit: Gαi, Gαs, Gαq and G12/13. Gαi-proteins have been reported to protect hearts from ischemia reperfusion injury. However, determining the individual impact of Gαi2 or Gαi3 on myocardial ischemia injury has not been clarified yet. Here, we first investigated expression of Gαi2 and Gαi3 on transcriptional level by quantitative PCR and on protein level by immunoblot analysis as well as by immunofluorescence in cardiac tissues of wild-type, Gαi2-, and Gαi3-deficient mice. Gαi2 was expressed at higher levels than Gαi3 in murine hearts, and irrespective of the isoform being knocked out we observed an up regulation of the remaining Gαi-protein. Myocardial ischemia promptly regulated cardiac mRNA and with a slight delay protein levels of both Gαi2 and Gαi3, indicating important roles for both Gαi isoforms. Furthermore, ischemia reperfusion injury in Gαi2- and Gαi3-deficient mice exhibited opposite outcomes. Whereas the absence of Gαi2 significantly increased the infarct size in the heart, the absence of Gαi3 or the concomitant upregulation of Gαi2 dramatically reduced cardiac infarction. In conclusion, we demonstrate for the first time that the genetic ablation of Gαi proteins has protective or deleterious effects on cardiac ischemia reperfusion injury depending on the isoform being absent.
authors.affiliation: Department of Anesthesiology and Intensive Care Medicine, Institute of Experimental and Clinical Pharmacology and Toxicology, Eberhard Karls University Hospitals and Clinics, and Interfaculty Center of Pharmacogenomics and Drug Research, Tuebingen, Germany.
authors.forename: David
authors.initials: D
authors.lastname: Köhler
authors.affiliation: Department of Pharmacology and Experimental Therapy, Institute of Experimental and Clinical Pharmacology and Toxicology, Eberhard Karls University Hospitals and Clinics, and Interfaculty Center of Pharmacogenomics and Drug Research, Tuebingen, Germany.
authors.forename: Vasudharani
authors.initials: V
authors.lastname: Devanathan
authors.affiliation: Department of Anesthesiology and Intensive Care Medicine, Institute of Experimental and Clinical Pharmacology and Toxicology, Eberhard Karls University Hospitals and Clinics, and Interfaculty Center of Pharmacogenomics and Drug Research, Tuebingen, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Bernardo de Oliveira Franz
authors.affiliation: Department of Pharmacology and Experimental Therapy, Institute of Experimental and Clinical Pharmacology and Toxicology, Eberhard Karls University Hospitals and Clinics, and Interfaculty Center of Pharmacogenomics and Drug Research, Tuebingen, Germany.
authors.forename: Therese
authors.initials: T
authors.lastname: Eldh
authors.affiliation: Department of Pharmacology and Experimental Therapy, Institute of Experimental and Clinical Pharmacology and Toxicology, Eberhard Karls University Hospitals and Clinics, and Interfaculty Center of Pharmacogenomics and Drug Research, Tuebingen, Germany.
authors.forename: Ana
authors.initials: A
authors.lastname: Novakovic
authors.affiliation: Department of Anesthesiology and Intensive Care Medicine, Institute of Experimental and Clinical Pharmacology and Toxicology, Eberhard Karls University Hospitals and Clinics, and Interfaculty Center of Pharmacogenomics and Drug Research, Tuebingen, Germany.
authors.forename: Judith M
authors.initials: JM
authors.lastname: Roth
authors.affiliation: Department of Anesthesiology and Intensive Care Medicine, Institute of Experimental and Clinical Pharmacology and Toxicology, Eberhard Karls University Hospitals and Clinics, and Interfaculty Center of Pharmacogenomics and Drug Research, Tuebingen, Germany.
authors.forename: Tiago
authors.initials: T
authors.lastname: Granja
authors.affiliation: Laboratory of Neurobiology, Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, North Carolina, United States of America.
authors.forename: Lutz
authors.initials: L
authors.lastname: Birnbaumer
authors.affiliation: Department of Anesthesiology and Intensive Care Medicine, Institute of Experimental and Clinical Pharmacology and Toxicology, Eberhard Karls University Hospitals and Clinics, and Interfaculty Center of Pharmacogenomics and Drug Research, Tuebingen, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Rosenberger
authors.affiliation: Department of Pharmacology and Experimental Therapy, Institute of Experimental and Clinical Pharmacology and Toxicology, Eberhard Karls University Hospitals and Clinics, and Interfaculty Center of Pharmacogenomics and Drug Research, Tuebingen, Germany.
authors.forename: Sandra
authors.initials: S
authors.lastname: Beer-Hammer
authors.affiliation: Department of Pharmacology and Experimental Therapy, Institute of Experimental and Clinical Pharmacology and Toxicology, Eberhard Karls University Hospitals and Clinics, and Interfaculty Center of Pharmacogenomics and Drug Research, Tuebingen, Germany.
authors.forename: Bernd
authors.initials: B
authors.lastname: Nürnberg
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D051960:GTP-Binding Protein alpha Subunit, Gi2 / Q000096:biosynthesis* / Q000235:genetics; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000096:biosynthesis* / Q000235:genetics; D015971:Gene Expression Regulation, Enzymologic; D051379:Mice; D008817:Mice, Mutant Strains; D009124:Muscle Proteins / Q000096:biosynthesis* / Q000235:genetics; D015428:Myocardial Reperfusion Injury / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D009206:Myocardium / Q000201:enzymology* / Q000473:pathology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics
chemical_list: D009124:Muscle Proteins; D012333:RNA, Messenger; D051960:GTP-Binding Protein alpha Subunit, Gi2; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; C498016:Gnai2 protein, mouse; C417708:Gnai3 protein, mouse