Tingting Liu1, Le Chen1, Eunjung Kim2, Diana Tran3, Brett S Phinney3, Anne A Knowlton4. 1. Molecular & Cellular Cardiology, Cardiovascular Division, University of California - Davis, Davis, CA, USA. 2. Clinical Research, St. Mary's Hospital of Daejeon Catholic University, Daejeon, Republic of Korea. 3. Proteomics Core Facility, University of California - Davis, Davis, CA, USA. 4. Molecular & Cellular Cardiology, Cardiovascular Division, University of California - Davis, Davis, CA, USA; Pharmacology Department, University of California - Davis, Davis, CA, USA; VA Medical Center Sacramento, CA, USA. Electronic address: aaknowlton@ucdavis.edu.
Abstract
AIMS: Mitochondrial dysfunction is an important part of the decline in cardiac function in heart failure. We hypothesized for hypothesized that there would be specific abnormalities in mitochondrial function and proteome with the progression of ischemic heart failure (HF). MAIN METHODS: We used a high left anterior descending artery (LAD) ligation in 3-4month old male rats to generate HF. Rats were studied 9weeks post-ligation. KEY FINDINGS: Electron microscopy of left ventricle samples showed mitochondrial changes including decreased size, increased number, abnormal distribution, and cristae loss. Mitochondria in ischemic HF exhibited decreased total ATP, impaired mitochondrial respiration, as well as reduced complex I activity. Analysis of LV mitochondrial proteins by mass spectrometry was performed, and 31 differentially expressed proteins (p<0.05) of more than 500 total proteins were identified. Of these proteins, 15 were up-regulated and 16 were down-regulated in the failing heart. A set of complex I proteins was significantly decreased, consistent with the impairment of complex I activity. There were distinct changes in mitochondrial function and proteome in ischemic HF. Although there were similarities, the distinction between the reported proteomic changed with TAC pressure overload induced HF and ischemic HF in the current study suggested different pathological mechanisms. SIGNIFICANCE: Specific changes in mitochondrial protein expression, which correlate with changes in mitochondrial function, have been identified in ischemic HF for the first time.
AIMS: Mitochondrial dysfunction is an important part of the decline in cardiac function in heart failure. We hypothesized for hypothesized that there would be specific abnormalities in mitochondrial function and proteome with the progression of ischemic heart failure (HF). MAIN METHODS: We used a high left anterior descending artery (LAD) ligation in 3-4month old male rats to generate HF. Rats were studied 9weeks post-ligation. KEY FINDINGS: Electron microscopy of left ventricle samples showed mitochondrial changes including decreased size, increased number, abnormal distribution, and cristae loss. Mitochondria in ischemic HF exhibited decreased total ATP, impaired mitochondrial respiration, as well as reduced complex I activity. Analysis of LV mitochondrial proteins by mass spectrometry was performed, and 31 differentially expressed proteins (p<0.05) of more than 500 total proteins were identified. Of these proteins, 15 were up-regulated and 16 were down-regulated in the failing heart. A set of complex I proteins was significantly decreased, consistent with the impairment of complex I activity. There were distinct changes in mitochondrial function and proteome in ischemic HF. Although there were similarities, the distinction between the reported proteomic changed with TAC pressure overload induced HF and ischemic HF in the current study suggested different pathological mechanisms. SIGNIFICANCE: Specific changes in mitochondrial protein expression, which correlate with changes in mitochondrial function, have been identified in ischemic HF for the first time.
Authors: Andrej Shevchenko; Igor Chernushevic; Anna Shevchenko; Matthias Wilm; Matthias Mann Journal: Mol Biotechnol Date: 2002-01 Impact factor: 2.695
Authors: James P Stice; Le Chen; Se-Chan Kim; J S Jung; A L Tran; T T Liu; Anne A Knowlton Journal: Endocrinology Date: 2011-02-08 Impact factor: 4.736
Authors: M R Voss; J N Stallone; Min Li; R N M Cornelussen; P Knuefermann; A A Knowlton Journal: Am J Physiol Heart Circ Physiol Date: 2003-04-24 Impact factor: 4.733
Authors: Lei Wu; Xin Guo; Steven D Hartson; Mary Abby Davis; Hui He; Denis M Medeiros; Weiqun Wang; Stephen L Clarke; Edralin A Lucas; Brenda J Smith; Johannes von Lintig; Dingbo Lin Journal: Mol Nutr Food Res Date: 2017-02-09 Impact factor: 5.914
Authors: Yan Huang; Corey Powers; Satish K Madala; Kenneth D Greis; Wendy D Haffey; Jeffrey A Towbin; Enkhsaikhan Purevjav; Sabzali Javadov; Arnold W Strauss; Zaza Khuchua Journal: PLoS One Date: 2015-06-01 Impact factor: 3.240
Authors: Bruna Paola Murino Rafacho; Priscila Portugal Dos Santos; Andréa de Freitas Gonçalves; Ana Angélica Henrique Fernandes; Katashi Okoshi; Fernanda Chiuso-Minicucci; Paula S Azevedo; Leonardo Antonio Mamede Zornoff; Marcos Ferreira Minicucci; Xiang-Dong Wang; Sergio Alberto Rupp de Paiva Journal: PLoS One Date: 2017-05-11 Impact factor: 3.240