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: Chen Lin, Mingming Zhang, Yingmei Zhang, Kejian Yang, Jianqiang Hu, Rui Si, Guoyong Zhang, Beilei Gao, Xiang Li, Chennian Xu, Congye Li, Qimeng Hao, Wenyi Guo
• Journal: Biochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 482 Issue 4 Pg. 665-671 (Jan 22 2017) ISSN: 1090-2104 [Electronic] United States
• PMID: 27865838 (Publication Type: Journal Article)
• Copyright: Copyright © 2016 Elsevier Inc. All rights reserved.

Chemical References

• Interleukin-6
• Peptide Fragments
• Tumor Necrosis Factor-alpha
• glutaminyl-glutamyl-glutaminyl-leucyl-glutamyl-arginyl-alanyl-leucyl-asparagyl-seryl-serine
• interleukin-6, mouse
• Erythropoietin
• Streptozocin
• AMP-Activated Protein Kinases

Topics

• AMP-Activated Protein Kinases (metabolism)
• Animals
• Apoptosis
• Autophagy (drug effects)
• Cell Line, Tumor
• Diabetes Mellitus, Experimental (metabolism, therapy)
• Diabetic Cardiomyopathies (metabolism, therapy)
• Echocardiography
• Erythropoietin (chemistry)
• Hematocrit
• Interleukin-6 (metabolism)
• Male
• Membrane Potentials
• Mice
• Mice, Inbred C57BL
• Mitochondria (pathology)
• Myocardium (pathology)
• Peptide Fragments (chemistry)
• Rats
• Streptozocin
• Tumor Necrosis Factor-alpha (metabolism)