title: Hypertension impairs myocardin function: a novel mechanism facilitating arterial remodelling.
abstract: OBJECTIVE
  Hypertension evokes detrimental changes in the arterial vessel wall that facilitate stiffening and thus lead to a further rise in mean blood pressure, eventually causing heart failure. The underlying pathophysiological remodelling process is elicited by an increase in wall stress (WS) and is strictly dependent on the activation of vascular smooth muscle cells (SMC). However, it remains unclear as to why these cells fail to maintain their contractile and quiescent phenotype in a hypertensive environment.
  
  
  RESULTS
  In this context, we reveal that the knockdown of myocardin--a pivotal transcriptional determinant of the contractile SMC phenotype--is sufficient to induce SMC proliferation. In line with this observation, immunofluorescence analysis of the media of remodelling arteries from hypertensive mice demonstrated a significant decrease in the abundance of myocardin and an increase in SMC proliferation. Subsequent analyses of isolated perfused mouse arteries and human cultured SMCs exposed to cyclic stretch (i.e. mimicking one component of WS) suggested that this biomechanical force facilitates serine phosphorylation of myocardin. Furthermore, this biomechanical stimulus promotes rapid translocation of myocardin from the nucleus to the cytoplasm, inhibits its mRNA expression, and causes proteasomal degradation of the cytoplasmic protein.
  
  
  CONCLUSIONS
  Collectively, these findings suggest that hypertension negates the activity of myocardin in SMCs on multiple levels, hence eliminating a crucial determinant of SMC quiescence. This mechanism may control the initial switch from the contractile towards the synthetic SMC phenotype during hypertension and may offer an interesting novel approach to prevent cardiovascular disease.
authors: Institute of Physiology and Pathophysiology, Division of Cardiovascular Physiology,  University of Heidelberg, Im Neuenheimer Feld 326, 69120 Heidelberg,  Germany.
authors: Larissa
authors: L
authors: Pfisterer
authors: Anja
authors: A
authors: Feldner
authors: Markus
authors: M
authors: Hecker
authors: Thomas
authors: T
authors: Korff
mesh_terms: D000818:Animals; D001158:Arteries / Q000503:physiopathology*; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation; D002478:Cells, Cultured; D003593:Cytoplasm / Q000378:metabolism; D015536:Down-Regulation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D006973:Hypertension / Q000503:physiopathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000502:physiology*; D009687:Nuclear Proteins / Q000378:metabolism*; D010641:Phenotype; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D015534:Trans-Activators / Q000378:metabolism*; D000096985:Calponins; D000099251:Myocardin
chemical_list: D002135:Calcium-Binding Proteins; D048049:Extracellular Signal-Regulated MAP Kinases; D008840:Microfilament Proteins; D009687:Nuclear Proteins; D046988:Proteasome Endopeptidase Complex; D012333:RNA, Messenger; D015534:Trans-Activators; D000096985:Calponins; D000099251:Myocardin