title: Disruption of mindin exacerbates cardiac hypertrophy and fibrosis.
abstract: Cardiac hypertrophy is a response of the myocardium to increased workload and is characterised by an increase of myocardial mass and an accumulation of extracellular matrix (ECM). As an ECM protein, an integrin ligand, and an angiogenesis inhibitor, all of which are key players in cardiac hypertrophy, mindin is an attractive target for therapeutic intervention to treat or prevent cardiac hypertrophy and heart failure. In this study, we investigated the role of mindin in cardiac hypertrophy using littermate Mindin knockout (Mindin ( -/- )) and wild-type (WT) mice. Cardiac hypertrophy was induced by aortic banding (AB) or angiotensin II (Ang II) infusion in Mindin ( -/- ) and WT mice. The extent of cardiac hypertrophy was quantitated by echocardiography and by pathological and molecular analyses of heart samples. Mindin ( -/- ) mice were more susceptible to cardiac hypertrophy and fibrosis in response to AB or Ang II stimulation than wild type. Cardiac function was also markedly exacerbated during both systole and diastole in Mindin ( -/- ) mice in response to hypertrophic stimuli. Western blot assays further showed that the activation of AKT/glycogen synthase kinase 3β (GSK3β) signalling in response to hypertrophic stimuli was significantly increased in Mindin ( -/- ) mice. Moreover, blocking AKT/GSK3β signalling with a pharmacological AKT inhibitor reversed cardiac abnormalities in Mindin ( -/- ) mice. Our data show that mindin, as an intrinsic cardioprotective factor, prevents maladaptive remodelling and the transition to heart failure by blocking AKT/GSK3β signalling.
authors.affiliation: Department of Cardiology, Renmin Hospital of Wuhan University, JieFang Road 238, Wuhan 430060, People's Republic of China.
authors.forename: Zhou-Yan
authors.initials: ZY
authors.lastname: Bian
authors.forename: Xiang
authors.initials: X
authors.lastname: Wei
authors.forename: Shan
authors.initials: S
authors.lastname: Deng
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: Ding-Sheng
authors.initials: DS
authors.lastname: Jiang
authors.forename: Ling
authors.initials: L
authors.lastname: Yan
authors.forename: Lian-Feng
authors.initials: LF
authors.lastname: Zhang
authors.forename: Manyin
authors.initials: M
authors.lastname: Chen
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; D015153:Blotting, Western; D006332:Cardiomegaly / Q000235:genetics / Q000378:metabolism*; D004452:Echocardiography; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism*; D005355:Fibrosis / Q000235:genetics / Q000378:metabolism*; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009206:Myocardium / Q000473:pathology*
chemical_list: D016326:Extracellular Matrix Proteins; C121491:mindin