title: Activin receptor-like kinase 7 mediates high glucose-induced H9c2 cardiomyoblast apoptosis through activation of Smad2/3.
abstract: Cardiomyocyte apoptosis is an important pathological change of diabetic cardiomyopathy. How the elevated glucose levels cause cell apoptosis remains unknown. The aim of our study was to investigate whether activin receptor-like kinase 7 (ALK7)-Smad2/3 signaling pathway plays an important role in high glucose-induced cardiomyocyte apoptosis. H9c2 cardiomyoblasts and neonatal rat cardiomyocytes were treated with 33mmol/l glucose. The expression of ALK7, Smad2 and Smad3 were inhibited by small interfering RNA respectively. The level of ALK7, total Smad2/3, phosphorylated Smad2/3, B-cell lymphoma-2 (Bcl-2) and cleaved Caspase3 were evaluated using western blot. The apoptosis rate was detected by flow cytometer. High glucose treatment caused the apoptosis of H9c2 cardiomyocyte and the inhibition of Smad2 or Smad3 attenuated this apoptosis. ALK7 existed in both H9c2 cardiomyoblasts and neonatal rat cardiomyocytes and high ambient glucose upregulated its expression. The increased expression level of cleaved Caspase3 and apoptosis rate and decreased expression of Bcl-2 were reversed after ALK7 was inhibited. The expression of phosphorylated Smad2/3 also decreased after the knockdown of ALK7. Our findings suggest that ALK7 mediates high ambient glucose-induced H9c2 cardiomyoblasts apoptosis through the activation of Smad2/3.
authors.affiliation: The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Qilu Hospital of Shandong University, Ji'nan, Shandong Province, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Liu
authors.forename: Wen-yuan
authors.initials: WY
authors.lastname: Ding
authors.forename: Jing
authors.initials: J
authors.lastname: Zhao
authors.forename: Zhi-hao
authors.initials: ZH
authors.lastname: Wang
authors.forename: Ming
authors.initials: M
authors.lastname: Zhong
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.forename: Yu-guo
authors.initials: YG
authors.lastname: Chen
authors.forename: Yun
authors.initials: Y
authors.lastname: Zhang
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.forename: Meng-xiong
authors.initials: MX
authors.lastname: Tang
mesh_terms: D030201:Activin Receptors, Type I / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D002460:Cell Line; D058065:Diabetic Cardiomyopathies / Q000378:metabolism* / Q000473:pathology; D005947:Glucose / Q000008:administration & dosage*; D032386:Myoblasts, Cardiac / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D051899:Smad2 Protein / Q000378:metabolism*; D051900:Smad3 Protein / Q000378:metabolism*; D014162:Transfection; D015854:Up-Regulation
chemical_list: D051899:Smad2 Protein; C497784:Smad2 protein, rat; D051900:Smad3 Protein; C497787:Smad3 protein, rat; D030201:Activin Receptors, Type I; C486044:Acvr1c protein, rat; D005947:Glucose
keywords: ALK; ActRII; Activin receptor-like kinase 7; Apoptosis; B-cell lymphoma-2; BMPs; Bcl-2; Cardiomyocyte; DCM; DMEM; Dulbecco's modiﬁed Eagle's medium; FBS; GDF; Glucose; Smad2/3; TGF-β; X-linked inhibitor of apoptosis protein; XIAP; activin receptor-like kinase; activin type II receptors; bone morphogenetic proteins; diabetic cardiomyopathy; fetal bovine serum; growth and differentiation factors; siRNA; small interfering RNA; transforming growth factor-β