title: Vasonatrin peptide attenuates myocardial ischemia-reperfusion injury in diabetic rats and underlying mechanisms.
abstract: Diabetes mellitus increases morbidity/mortality of ischemic heart disease. Although atrial natriuretic peptide and C-type natriuretic peptide reduce the myocardial ischemia-reperfusion damage in nondiabetic rats, whether vasonatrin peptide (VNP), the artificial synthetic chimera of atrial natriuretic peptide and C-type natriuretic peptide, confers cardioprotective effects against ischemia-reperfusion injury, especially in diabetic patients, is still unclear. This study was designed to investigate the effects of VNP on ischemia-reperfusion injury in diabetic rats and to further elucidate its mechanisms. The high-fat diet-fed streptozotocin-induced diabetic Sprague-Dawley rats were subjected to ischemia-reperfusion operation. VNP treatment (100 μg/kg iv, 10 min before reperfusion) significantly improved the instantaneous first derivation of left ventricle pressure (±LV dP/dtmax) and LV systolic pressure and reduced LV end-diastolic pressure, apoptosis index, caspase-3 activity, plasma creatine kinase (CK), and lactate dehydrogenase (LDH) activities. Moreover, VNP inhibited endoplasmic reticulum (ER) stress by suppressing glucose-regulated protein 78 (GRP78) and C/EBP homologous protein (CHOP). These effects were mimicked by 8-bromine-cyclic guanosinemonophosphate (8-Br-cGMP), a cGMP analog, whereas they were inhibited by KT-5823, the selective inhibitor of PKG. In addition, pretreatment with tauroursodeoxycholic acid (TUDCA), a specific inhibitor of ER stress, could not further promote the VNP's cardioprotective effect in diabetic rats. In vitro H9c2 cardiomyocytes were subjected to hypoxia/reoxygenation and incubated with or without VNP (10(-8) mol/l). Gene knockdown of PKG1α with siRNA blunted VNP inhibition of ER stress and apoptosis, while overexpression of PKG1α resulted in significant decreased ER stress and apoptosis. VNP protects the diabetic heart against ischemia-reperfusion injury by inhibiting ER stress via the cGMP-PKG signaling pathway. These results suggest that VNP may have potential therapeutic value for the diabetic patients with ischemic heart disease.
authors.affiliation: Experiment Teaching Center, Fourth Military Medical University, Xi'an, China;
authors.forename: Zhenwei
authors.initials: Z
authors.lastname: Shi
authors.affiliation: Department of Physiology, Fourth Military Medical University, Xi'an, China;
authors.forename: Feng
authors.initials: F
authors.lastname: Fu
authors.affiliation: Experiment Teaching Center, Fourth Military Medical University, Xi'an, China;
authors.forename: Liming
authors.initials: L
authors.lastname: Yu
authors.affiliation: Department of Physiology, Fourth Military Medical University, Xi'an, China;
authors.forename: Wenjuan
authors.initials: W
authors.lastname: Xing
authors.affiliation: Department of Cardiology, Tangdu Hospital, Fourth Military Medical University, Xi'an, China; and.
authors.forename: Feifei
authors.initials: F
authors.lastname: Su
authors.affiliation: Experiment Teaching Center, Fourth Military Medical University, Xi'an, China;
authors.forename: Xiangyan
authors.initials: X
authors.lastname: Liang
authors.affiliation: Experiment Teaching Center, Fourth Military Medical University, Xi'an, China;
authors.forename: Ru
authors.initials: R
authors.lastname: Tie
authors.affiliation: Experiment Teaching Center, Fourth Military Medical University, Xi'an, China;
authors.forename: Lele
authors.initials: L
authors.lastname: Ji
authors.affiliation: Department of Physiology, Fourth Military Medical University, Xi'an, China;
authors.forename: Miaozhang
authors.initials: M
authors.lastname: Zhu
authors.affiliation: Experimental Center, The Second Affiliated Hospital, School of Medicine, Xi'an Medical University, Xi'an, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Yu
authors.affiliation: Experiment Teaching Center, Fourth Military Medical University, Xi'an, China; hfzhang@fmmu.edu.cn.
authors.forename: Haifeng
authors.initials: H
authors.lastname: Zhang
mesh_terms: D000818:Animals; D017209:Apoptosis; D009320:Atrial Natriuretic Factor / Q000494:pharmacology* / Q000627:therapeutic use; D002227:Carbazoles / Q000494:pharmacology; D053148:Caspase 3 / Q000378:metabolism; D015687:Cell Hypoxia; D002460:Cell Line; D003402:Creatine Kinase / Q000097:blood; D006152:Cyclic GMP / Q000031:analogs & derivatives / Q000494:pharmacology; D062965:Cyclic GMP-Dependent Protein Kinase Type I / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000378:metabolism*; D059865:Endoplasmic Reticulum Stress; D006352:Heart Ventricles / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D015428:Myocardial Reperfusion Injury / Q000150:complications / Q000188:drug therapy / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013655:Taurochenodeoxycholic Acid / Q000494:pharmacology; D051742:Transcription Factor CHOP / Q000378:metabolism; D016276:Ventricular Function / Q000187:drug effects
chemical_list: D002227:Carbazoles; C497251:Ddit3 protein, rat; C073601:KT 5823; C068986:ventricular natriuretic peptide, eel; D051742:Transcription Factor CHOP; C016276:8-bromocyclic GMP; D013655:Taurochenodeoxycholic Acid; C031655:ursodoxicoltaurine; D009320:Atrial Natriuretic Factor; D062965:Cyclic GMP-Dependent Protein Kinase Type I; D003402:Creatine Kinase; D053148:Caspase 3; D006152:Cyclic GMP
keywords: PKG; diabetes; endoplasmic reticulum stress; myocardial ischemia-reperfusion injury; vasonatrin peptide