• Pietro Arina, Matteo Sorge, Andrea Gallo, Vittoria Di Mauro, Nicoletta Vitale, Paola Cappello, Luca Brazzi, Maria Barandalla-Sobrados, James Cimino, V Marco Ranieri, Fiorella Altruda, Mervyn Singer, Daniele Catalucci, Mara Brancaccio, and Vito Fanelli.
• Department of Anesthesia and Critical Care, AOU Città Della Salute e della Scienza di Torino, University of Turin, Turin, Italy.
• Shock. 2022 Jun 1; 57 (6): 318325318-325.

AimSepsis-induced cardiomyopathy is commonplace and carries an increased risk of death. Melusin, a cardiac muscle-specific chaperone, exerts cardioprotective function under varied stressful conditions through activation of the AKT pathway. The objective of this study was to determine the role of melusin in the pathogenesis of lipopolysaccharide (LPS)-induced cardiac dysfunction and to explore its signaling pathway for the identification of putative therapeutic targets.Methods And ResultsProspective, randomized, controlled experimental study in a research laboratory. Melusin overexpressing (MelOV) and wild-type (MelWT) mice were used. MelOV and MelWT mice were injected intraperitoneally with LPS. Cardiac function was assessed using trans-thoracic echocardiography. Myocardial expression of L-type calcium channel (LTCC), phospho-Akt and phospho-Gsk3-b were also measured. In separate experiments, wild-type mice were treated post-LPS challenge with the allosteric Akt inhibitor Arq092 and a mimetic peptide (R7W-MP) targeting the LTCC. The impact of these therapies on protein-protein interactions, cardiac function, and survival was assessed. MelOV mice had limited derangement in cardiac function after LPS challenge. Protection was associated with higher Akt and Gsk3-b phosphorylation and restored LTCC density. Pharmacological inhibition of Akt activity reversed melusin-dependent cardiac protection. Treatment with R7W-MP preserved cardiac function in wild-type mice after LPS challenge and significantly improved survival.ConclusionsThis study identifies AKT / Melusin as a key pathway for preserving cardiac function following LPS challenge. The cell-permeable mimetic peptide (R7W-MP) represents a putative therapeutic for sepsis-induced cardiomyopathy.Copyright © 2022 by the Shock Society.

45 keywords...

hide…