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Overexpression of the muscle-specific protein, melusin, protects from cardiac ischemia/reperfusion injury

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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.

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Acknowledgments

This work was supported by funding from Telethon grant GGP12047 to GT, MIUR Prin 2010RNXM9C_002 to GT; MIUR PRIN 2010J8RYS7_007 to MB and ex-60 % to PP.

Conflict of interest

Mara Brancaccio and Guido Tarone are scientific cofounders and consultants for Target Heart Biotec, a company that develops melusin recombinant protein as a drug to counteract heart failure.

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Authors and Affiliations

  1. Dipartimento di Scienze Cliniche e, Biologiche Università di Torino, Ospedale S. Luigi, Regione Gonzole, 10, 10043, Orbassano, TO, Italy

    Claudia Penna, Francesca Tullio, Maria-Giulia Perrelli, Carmelina Angotti & Pasquale Pagliaro

  2. National Institute for Cardiovascular Research, Bologna, Italy

    Claudia Penna, Francesca Tullio, Maria-Giulia Perrelli, Carmelina Angotti & Pasquale Pagliaro

  3. Department of Molecular Biotechnology and Health Sciences, University of Torino, Turin, Italy

    Mara Brancaccio, Cristina Rubinetto & Guido Tarone

  4. Molecular Biotechnology Center, University of Torino, Turin, Italy

    Mara Brancaccio, Cristina Rubinetto & Guido Tarone

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  1. Claudia Penna
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Correspondence to Pasquale Pagliaro.

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C. Penna, M. Brancaccio, P. Pagliaro, and G. Tarone contributed equally to this work.

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Penna, C., Brancaccio, M., Tullio, F. et al. Overexpression of the muscle-specific protein, melusin, protects from cardiac ischemia/reperfusion injury. Basic Res Cardiol 109, 418 (2014). https://doi.org/10.1007/s00395-014-0418-9

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