title: Overexpression of the muscle-specific protein, melusin, protects from cardiac ischemia/reperfusion injury.
abstract: Melusin is a muscle-specific protein which interacts with β1 integrin cytoplasmic domain and acts as chaperone protein. Its overexpression induces improved resistance to cardiac overload delaying left ventricle dilation and reducing the occurrence of heart failure. Here, we investigated possible protective effect of melusin overexpression against acute ischemia/reperfusion (I/R) injury with or without Postconditioning cardioprotective maneuvers. Melusin transgenic (Mel-TG) mice hearts were subjected to 30-min global ischemia followed by 60-min reperfusion. Interestingly, infarct size was reduced in Mel-TG mice hearts compared to wild-type (WT) hearts (40.3 ± 3.5 % Mel-TG vs. 59.5 ± 3.8 % WT hearts; n = 11 animals/group; P < 0.05). The melusin protective effect was also demonstrated by measuring LDH release, which was 50 % lower in Mel-TG compared to WT. Mel-TG hearts had a higher baseline level of AKT, ERK1/2 and GSK3β phosphorylation, and displayed increased phospho-kinases level after I/R compared to WT mice. Post-ischemic Mel-TG hearts displayed also increased levels of the anti-apoptotic factor phospho-BAD. Importantly, pharmacological inhibition of PI3K/AKT (Wortmannin) and ERK1/2 (U0126) pathways abrogated the melusin protective effect. Notably, HSP90, a chaperone known to protect heart from I/R injury, showed high levels of expression in the heart of Mel-TG mice suggesting a possible collaboration of this molecule with AKT/ERK/GSK3β pathways in the melusin-induced protection. Postconditioning, known to activate AKT/ERK/GSK3β pathways, significantly reduced IS and LDH release in WT hearts, but had no additive protective effects in Mel-TG hearts. These findings implicate melusin as an enhancer of AKT and ERK pathways and as a novel player in cardioprotection from I/R injury.
authors.affiliation: Dipartimento di Scienze Cliniche e, Biologiche Università di Torino, Ospedale S. Luigi, Regione Gonzole, 10, 10043, Orbassano, TO, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Penna
authors.forename: Mara
authors.initials: M
authors.lastname: Brancaccio
authors.forename: Francesca
authors.initials: F
authors.lastname: Tullio
authors.forename: Cristina
authors.initials: C
authors.lastname: Rubinetto
authors.forename: Maria-Giulia
authors.initials: MG
authors.lastname: Perrelli
authors.forename: Carmelina
authors.initials: C
authors.lastname: Angotti
authors.forename: Pasquale
authors.initials: P
authors.lastname: Pagliaro
authors.forename: Guido
authors.initials: G
authors.lastname: Tarone
mesh_terms: D000818:Animals; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D004789:Enzyme Activation; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism; D008297:Male; D008822:Mice, Transgenic; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism*; D009203:Myocardial Infarction / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D015428:Myocardial Reperfusion Injury / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors; D015854:Up-Regulation
chemical_list: D003598:Cytoskeletal Proteins; D018841:HSP90 Heat-Shock Proteins; C122158:Itgb1bp2 protein, mouse; D009124:Muscle Proteins; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D058539:Phosphatidylinositol 3-Kinase; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D051057:Proto-Oncogene Proteins c-akt; C535148:Mapk1 protein, mouse; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D038362:Glycogen Synthase Kinase 3