title: Neuregulin-1 attenuates mitochondrial dysfunction in a rat model of heart failure.
abstract: BACKGROUND
  Mitochondrial dysfunction plays a pivotal role in the progression of left ventricular (LV) remodeling and heart failure (HF). Recombinant human neuregulin-1 (rhNRG-1) improves cardiac function in models of experimental HF and in clinical trials; however, its impact on mitochondrial function during chronic HF remains largely unknown. The purpose of this study was to investigate whether rhNRG-1 could attenuate the functional and structural changes that occur in cardiac mitochondria in a rat model of HF induced by myocardial infarction.
  
  
  METHODS
  Sixty adult rats underwent sham or coronary ligation to induce HF. Four weeks after ligation, 29 animals with LV ejective fraction ≤ 50% were randomized to receive either vehicle or rhNRG-1 (10 µg×kg(-1)×d(-1), I.V.) for 10 days, another 12 sham-operated animals were given no treatment. Echocardiography was used to determine physiological changes. Mitochondrial membrane potential (MMP), respiratory function and tissue adenosine triphosphate (ATP) production were analyzed. Cytochrome c expression and cardiomyocyte apoptosis were determined. Oxidative stress was evaluated by reactive oxygen species production using fluorescence assays and gene expression of glutathione peroxidase measured by real-time quantitative PCR.
  
  
  RESULTS
  Compared with sham-operated animals, vehicle treated HF rats exhibited severe LV remodeling and dysfunction, significant mitochondrial dysfunction, increased mitochondrial cytochrome c release, increased myocyte apoptosis and enhanced oxidative stress. Short-term treatment with rhNRG-1 significantly attenuated LV remodeling and cardiac function. Concomitant with this change, mitochondrial dysfunction was significantly attenuated; with ATP production, MMP and respiratory function restored, cytochrome c release and apoptosis inhibited, and oxidative stress reduced.
  
  
  CONCLUSIONS
  The present study demonstrated that rhNRG-1 can significantly improve LV remodeling and cardiac function in the failing heart, this beneficial effect is related to reducing mitochondrial dysfunction, myocyte apoptosis and oxidative stress.
authors.affiliation: Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing 100029, China.
authors.forename: Yong-fang
authors.initials: YF
authors.lastname: Guo
authors.forename: Xiao-xia
authors.initials: XX
authors.lastname: Zhang
authors.forename: Yong
authors.initials: Y
authors.lastname: Liu
authors.forename: Hong-yan
authors.initials: HY
authors.lastname: Duan
authors.forename: Bing-zhang
authors.initials: BZ
authors.lastname: Jie
authors.forename: Xue-si
authors.initials: XS
authors.lastname: Wu
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D004452:Echocardiography; D006333:Heart Failure; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism*; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D020890:Neuregulin-1 / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D020890:Neuregulin-1; D017382:Reactive Oxygen Species