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. CONCLUSION: 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.
BACKGROUND:Mitochondrial dysfunction plays a pivotal role in the progression of left ventricular (LV) remodeling and heart failure (HF). Recombinant humanneuregulin-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. CONCLUSION: 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: Jeffrey E Cohen; Brendan P Purcell; John W MacArthur; Anbin Mu; Yasuhiro Shudo; Jay B Patel; Christopher M Brusalis; Alen Trubelja; Alexander S Fairman; Bryan B Edwards; Mollie S Davis; George Hung; William Hiesinger; Pavan Atluri; Kenneth B Margulies; Jason A Burdick; Y Joseph Woo Journal: Circ Heart Fail Date: 2014-06-05 Impact factor: 8.790
Authors: Michael F Hill; Amish V Patel; Abigail Murphy; Holly M Smith; Cristi L Galindo; Laura Pentassuglia; Xuyang Peng; Carrie G Lenneman; Oghenerukevwe Odiete; David B Friedman; Marvin W Kronenberg; Siyuen Zheng; Zhongming Zhao; Yanna Song; Frank E Harrell; Maya Srinivas; Anindita Ganguly; Jennifer Iaci; Tom J Parry; Anthony O Caggiano; Douglas B Sawyer Journal: PLoS One Date: 2013-02-21 Impact factor: 3.240
Authors: Cristi L Galindo; Ehab Kasasbeh; Abigail Murphy; Sergey Ryzhov; Sean Lenihan; Farhaan A Ahmad; Philip Williams; Amy Nunnally; Jamie Adcock; Yanna Song; Frank E Harrell; Truc-Linh Tran; Tom J Parry; Jen Iaci; Anindita Ganguly; Igor Feoktistov; Matthew K Stephenson; Anthony O Caggiano; Douglas B Sawyer; John H Cleator Journal: J Am Heart Assoc Date: 2014-10-23 Impact factor: 5.501