title: Rho kinase as a therapeutic target in cardiovascular disease.
abstract: Rho kinase (ROCK) belongs to the AGC (PKA/PKG/PKC) family of serine/threonine kinases and is a major downstream effector of the small GTPase RhoA. ROCK plays central roles in the organization of the actin cytoskeleton and is involved in a wide range of fundamental cellular functions such as contraction, adhesion, migration, proliferation and gene expression. Two ROCK isoforms, ROCK1 and ROCK2, are assumed to be functionally redundant, based largely on the major common activators, the high degree of homology within the kinase domain and studies from overexpression with kinase constructs and chemical inhibitors (e.g., Y27632 and fasudil), which inhibit both ROCK1 and ROCK2. Extensive experimental and clinical studies support a critical role for the RhoA/ROCK pathway in the vascular bed in the pathogenesis of cardiovascular diseases, in which increased ROCK activity mediates vascular smooth muscle cell hypercontraction, endothelial dysfunction, inflammatory cell recruitment and vascular remodeling. Recent experimental studies, using ROCK inhibitors or genetic mouse models, indicate that the RhoA/ROCK pathway in myocardium contributes to cardiac remodeling induced by ischemic injury or persistent hypertrophic stress, thereby leading to cardiac decompensation and heart failure. This article, based on recent molecular, cellular and animal studies, focuses on the current understanding of ROCK signaling in cardiovascular diseases and in the pathogenesis of heart failure.
authors.affiliation: Riley Heart Research Centre, Wells Centre for Pediatric Research, Department of Pediatrics, Indiana University, School of Medicine, Indianapolis, IN, USA.
authors.forename: Michelle
authors.initials: M
authors.lastname: Surma
authors.forename: Lei
authors.initials: L
authors.lastname: Wei
authors.forename: Jianjian
authors.initials: J
authors.lastname: Shi
mesh_terms: D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000577:Amides / Q000627:therapeutic use*; D017209:Apoptosis; D002318:Cardiovascular Diseases / Q000188:drug therapy* / Q000503:physiopathology*; D003324:Coronary Artery Disease / Q000503:physiopathology; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D006333:Heart Failure / Q000378:metabolism; D006801:Humans; D008297:Male; D032383:Myocytes, Cardiac / Q000502:physiology; D020033:Protein Isoforms; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011725:Pyridines / Q000627:therapeutic use*; D014664:Vasodilation / Q000502:physiology; D054460:rho-Associated Kinases / Q000187:drug effects / Q000502:physiology*
chemical_list: D000577:Amides; D004791:Enzyme Inhibitors; D020033:Protein Isoforms; D047428:Protein Kinase Inhibitors; D011725:Pyridines; C108830:Y 27632; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; C515851:ROCK1 protein, human; C515852:ROCK2 protein, human; D054460:rho-Associated Kinases; C049347:fasudil