title: Helix B surface peptide attenuates diabetic cardiomyopathy via AMPK-dependent autophagy.
abstract: BACKGROUND
  Erythropoietin (EPO) has been reported to exert protective effects on a host of damaged tissues. However, the erythropoietic effect of this hormone can result in high risks of thrombosis, stroke, and hypertension, remarkably limiting the clinical use of EPO. Helix B surface peptide (HBSP) is a small peptide derived from the helix-B domain of EPO. Surprisingly, HBSP retains the tissue protective properties of EPO without altering the hematocrit. Thus, we evaluated the possible role of HBSP on diabetic cardiomyopathy.
  
  
  METHODS
  Diabetes was induced in mice by intraperitoneal injections of streptozocin (STZ). Mice were randomly treated with normal saline or HBSP. Cardiac function, fibrosis, apoptosis, and myocardial mitochondrial morphology were examined. For in vitro experiments, H9C2 myoblast cells were randomly grouped as normal glucose (NG, 5 mM), NG+HBSP (100 nM), high glucose (HG, 33 mM), HG+HBSP (100 nM), HG+HBSP+3-methyladenine (3-MA, 10 mM), HG+rapamycin (Rapa, 100 nM), and HG+HBSP+Compound C (CC, 10 mM). Autophagosomes, LC3 dots, apoptosis and mitochondria membrane potential (MMP) of H9C2 cells were examined.The expressions of LC3, p62, p-AMPK (Thr172) and p-mTOR (Ser2448) were examined by Western blot.
  
  
  RESULTS
  HBSP markedly improved cardiac function, attenuated cardiac interstitial fibrosis, inhibited myocardial apoptosis, and ameliorated mitochondrial ultrastructure in mice with diabetic cardiomyopathy. HG reduced autophagy in H9C2 cells. HBSP enhanced autophagy in HG-treated H9C2 cells. HBSP reduced the apoptosis index of HG-treated H9C2 cells. HBSP increased the MMP of HG-treated H9C2 cells. HBSP increased the levels of p-AMPK (Thr172), and reduced p-mTOR (Ser2448) in HG-treated H9C2 cells, and the increase of p-AMPK (Thr172) was accompanied by the stimulation of autophagy. Autophagy inhibitor 3-MA and AMPK inhibitor CC mitigated HBSP-induced beneficial effect, whereas autophagy inducer Rapa alleviated the HG-induced cell apoptosis.
  
  
  CONCLUSIONS
  HBSP attenuates diabetic cardiomyopathy via autophagy mediated by AMPK-dependent pathway. HBSP may be a potential therapeutic intervention for diabetic cardiomyopathy.
authors.affiliation: Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
authors.forename: Chen
authors.initials: C
authors.lastname: Lin
authors.affiliation: Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
authors.forename: Mingming
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai, China.
authors.forename: Yingmei
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
authors.forename: Kejian
authors.initials: K
authors.lastname: Yang
authors.affiliation: Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
authors.forename: Jianqiang
authors.initials: J
authors.lastname: Hu
authors.affiliation: Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
authors.forename: Rui
authors.initials: R
authors.lastname: Si
authors.affiliation: Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
authors.forename: Guoyong
authors.initials: G
authors.lastname: Zhang
authors.affiliation: Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
authors.forename: Beilei
authors.initials: B
authors.lastname: Gao
authors.affiliation: Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
authors.forename: Xiang
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
authors.forename: Chennian
authors.initials: C
authors.lastname: Xu
authors.affiliation: Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
authors.forename: Congye
authors.initials: C
authors.lastname: Li
authors.affiliation: Department of Cardiology, Tangdu Hospital, Fourth Military Medical University, Xi'an, China.
authors.forename: Qimeng
authors.initials: Q
authors.lastname: Hao
authors.affiliation: Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, China. Electronic address: docguo196@163.com.
authors.forename: Wenyi
authors.initials: W
authors.lastname: Guo
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis; D001343:Autophagy / Q000187:drug effects*; D045744:Cell Line, Tumor; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism / Q000628:therapy*; D058065:Diabetic Cardiomyopathies / Q000378:metabolism / Q000628:therapy*; D004452:Echocardiography; D004921:Erythropoietin / Q000737:chemistry*; D006400:Hematocrit; D015850:Interleukin-6 / Q000378:metabolism; D008297:Male; D008564:Membrane Potentials; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000473:pathology; D009206:Myocardium / Q000473:pathology; D010446:Peptide Fragments / Q000737:chemistry*; D051381:Rats; D013311:Streptozocin; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D015850:Interleukin-6; D010446:Peptide Fragments; D014409:Tumor Necrosis Factor-alpha; C585201:glutaminyl-glutamyl-glutaminyl-leucyl-glutamyl-arginyl-alanyl-leucyl-asparagyl-seryl-serine; C577686:interleukin-6, mouse; D004921:Erythropoietin; D013311:Streptozocin; D055372:AMP-Activated Protein Kinases
keywords: Apoptosis; Autophagy; Diabetic cardiomyopathy; Helix B surface peptide