title: Endotoxemia Engages the RhoA Kinase Pathway to Impair Cardiac Function By Altering Cytoskeleton, Mitochondrial Fission, and Autophagy.
abstract: OBJECTIVE
  The RhoA/ROCK pathway controls crucial biological processes involved in cardiovascular pathophysiology, such as cytoskeleton dynamics, vascular smooth muscle contraction, and inflammation. In this work, we tested whether Rho kinase inhibition would beneficially impact cardiac cytoskeleton organization, bioenergetics, and autophagy in experimental endotoxemia induced by lipopolysaccharides (LPSs) in mice.
  
  
  RESULTS
  Fasudil, a potent ROCK inhibitor, prevented LPS-induced cardiac inflammation, oxidative stress, cytoskeleton disarray, and mitochondrial injury. ROCK inhibition prevented phosphorylation of cofilin and dynamin-related protein-1, which promotes stabilization-polymerization of F-actin and mediates mitochondrial fission, respectively. Pyr1, which exclusively alters actin dynamics, prevented LPS-induced myocardial dysfunction, suggesting that beneficial impact of ROCK inhibition was not mainly related to pleiotropic effects of fasudil on cardiac inflammation and oxidative stress. Fasudil reduced mitochondrial fragmentation, stimulated initiation of autophagy, and elicited cardioprotection in LPS heart. Mdivi-1, a potent mitochondria fission inhibitor, converted cardioprotective autophagy to an inefficient form due to cargo loading failure in which autophagic vacuoles fail to trap cytosolic cargo, despite their formation at enhanced rates and lysosomal elimination.
  
  
  METHODS
  In experimental endotoxemia, cardioprotection by RhoA/ROCK inhibition may be related to changes in actin cytoskeleton reorganization and mitochondrial homeostasis. Improvement of LPS-induced mitochondrial dysfunction by fasudil was attributed to inhibition of ROCK-dependent Drp1 phosphorylation and activation of autophagic processes that can limit mitochondrial fragmentation and enhance degradation of damaged mitochondria, respectively.
  
  
  CONCLUSIONS
  Fasudil prevented LPS-induced heart oxidative stress, abnormal F-actin distribution, and oxidative phosphorylation, which concur to improve cardiac contractile and bioenergetic function. We suggest that fasudil may represent a valuable therapy for patients with sepsis.
authors.affiliation: 1 Department of Physiology, School of Medicine , Lille, France .|2 INSERM U995/Team "Glycation: from inflammation to aging, " Lille University , France .|3 Critical Care Medicine , CHRU Lille, Lille, France .
authors.forename: Sebastien
authors.initials: S
authors.lastname: Preau
authors.affiliation: 1 Department of Physiology, School of Medicine , Lille, France .|2 INSERM U995/Team "Glycation: from inflammation to aging, " Lille University , France .
authors.forename: Florian
authors.initials: F
authors.lastname: Delguste
authors.affiliation: 2 INSERM U995/Team "Glycation: from inflammation to aging, " Lille University , France .|4 School of Medicine, Shanghai Jiao Tong University , Shanghai, China .
authors.forename: Yichi
authors.initials: Y
authors.lastname: Yu
authors.affiliation: 5 INSERM U1096 Institute for Research and Innovation in Biomedicine, University of Rouen , France .
authors.forename: Isabelle
authors.initials: I
authors.lastname: Remy-Jouet
authors.affiliation: 5 INSERM U1096 Institute for Research and Innovation in Biomedicine, University of Rouen , France .
authors.forename: Vincent
authors.initials: V
authors.lastname: Richard
authors.affiliation: 3 Critical Care Medicine , CHRU Lille, Lille, France .
authors.forename: Fabienne
authors.initials: F
authors.lastname: Saulnier
authors.affiliation: 2 INSERM U995/Team "Glycation: from inflammation to aging, " Lille University , France .
authors.forename: Eric
authors.initials: E
authors.lastname: Boulanger
authors.affiliation: 1 Department of Physiology, School of Medicine , Lille, France .|2 INSERM U995/Team "Glycation: from inflammation to aging, " Lille University , France .
authors.forename: Remi
authors.initials: R
authors.lastname: Neviere
mesh_terms: D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives / Q000494:pharmacology; D051339:Actin Depolymerizing Factors / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001343:Autophagy / Q000187:drug effects; D002121:Calcium Channel Blockers / Q000494:pharmacology; D003599:Cytoskeleton / Q000378:metabolism / Q000648:ultrastructure; D019446:Endotoxemia / Q000378:metabolism*; D015870:Gene Expression; D006321:Heart / Q000503:physiopathology*; D008070:Lipopolysaccharides / Q000009:adverse effects; D008297:Male; D051379:Mice; D063154:Mitochondrial Dynamics / Q000187:drug effects; D009200:Myocardial Contraction / Q000187:drug effects; D009205:Myocarditis / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D009206:Myocardium / Q000378:metabolism* / Q000648:ultrastructure; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism; D012518:Sarcomeres / Q000378:metabolism / Q000648:ultrastructure; D015398:Signal Transduction; D054460:rho-Associated Kinases / Q000378:metabolism*
chemical_list: D051339:Actin Depolymerizing Factors; D002121:Calcium Channel Blockers; D008070:Lipopolysaccharides; D017382:Reactive Oxygen Species; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D054460:rho-Associated Kinases; C049347:fasudil