title: Cardiac-specific mindin overexpression attenuates cardiac hypertrophy via blocking AKT/GSK3β and TGF-β1-Smad signalling.
abstract: OBJECTIVE
  Mindin is a secreted extracellular matrix protein, an integrin ligand, and an angiogenesis inhibitor, other examples of which are all key players in the progression of cardiac hypertrophy. However, its function during cardiac hypertrophy remains unclear. This study was aimed to identify the effect of mindin on cardiac hypertrophy and the underlying mechanisms.
  
  
  RESULTS
  A significant down-regulation of mindin expression was observed in human failing hearts. To further investigate the role of mindin in cardiac hypertrophy, we used cultured neonatal rat cardiomyocytes with gain and loss of mindin function and cardiac-specific Mindin-overexpressing transgenic (TG) mice. In cultured cardiomyocytes, mindin negatively regulated angiotensin II (Ang II)-mediated hypertrophic growth, as detected by [(3)H]-Leucine incorporation, cardiac myocyte area, and hypertrophic marker protein levels. Cardiac hypertrophy in vivo was produced by aortic banding (AB) or Ang II infusion in TG mice and their wild-type controls. The extent of cardiac hypertrophy was evaluated by echocardiography as well as by pathological and molecular analyses of heart samples. Mindin overexpression in the heart markedly attenuated cardiac hypertrophy, fibrosis, and left ventricular dysfunction in mice in response to AB or Ang II. Further analysis of the signalling events in vitro and in vivo indicated that these beneficial effects of mindin were associated with the interruption of AKT/glycogen synthase kinase 3β (GSK3β) and transforming growth factor (TGF)-β1-Smad signalling.
  
  
  CONCLUSIONS
  The present study demonstrates for the first time that mindin serves as a novel mediator that protects against cardiac hypertrophy and the transition to heart failure by blocking AKT/GSK3β and TGF-β1-Smad signalling.
authors.affiliation: Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, China.
authors.forename: Ling
authors.initials: L
authors.lastname: Yan
authors.forename: Xiang
authors.initials: X
authors.lastname: Wei
authors.forename: Qi-Zhu
authors.initials: QZ
authors.lastname: Tang
authors.forename: Jinghua
authors.initials: J
authors.lastname: Feng
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
authors.forename: Chen
authors.initials: C
authors.lastname: Liu
authors.forename: Zhou-Yan
authors.initials: ZY
authors.lastname: Bian
authors.forename: Lian-Feng
authors.initials: LF
authors.lastname: Zhang
authors.forename: Manyin
authors.initials: M
authors.lastname: Chen
authors.forename: Xue
authors.initials: X
authors.lastname: Bai
authors.forename: Ai-Bing
authors.initials: AB
authors.lastname: Wang
authors.forename: John
authors.initials: J
authors.lastname: Fassett
authors.forename: Yingjie
authors.initials: Y
authors.lastname: Chen
authors.forename: You-Wen
authors.initials: YW
authors.lastname: He
authors.forename: Qinglin
authors.initials: Q
authors.lastname: Yang
authors.forename: Peter P
authors.initials: PP
authors.lastname: Liu
authors.forename: Hongliang
authors.initials: H
authors.lastname: Li
mesh_terms: D000818:Animals; D006332:Cardiomegaly / Q000517:prevention & control*; D004452:Echocardiography; D016326:Extracellular Matrix Proteins / Q000502:physiology*; D005355:Fibrosis; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000037:antagonists & inhibitors; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors*; D000071679:Glycogen Synthase Kinase 3 beta; D006439:Hemodynamics; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009206:Myocardium / Q000473:pathology; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000502:physiology*; D051785:Smad Proteins / Q000037:antagonists & inhibitors* / Q000502:physiology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D053773:Transforming Growth Factor beta1 / Q000037:antagonists & inhibitors* / Q000502:physiology
chemical_list: D016326:Extracellular Matrix Proteins; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; D051785:Smad Proteins; D053773:Transforming Growth Factor beta1; C121491:mindin; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; C000605508:Gsk3b protein, rat; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D038362:Glycogen Synthase Kinase 3