Rui Liu1,2, Fangxu Sun3, Parvin Forghani1, Lawrence C Armand1, Antonio Rampoldi1, Dong Li1, Ronghu Wu3, Chunhui Xu1,4. 1. From the, Department of Pediatrics, (RL, PF, LCA, AR, DL, CX), Emory University School of Medicine and Children's Healthcare of Atlanta, Atlanta, Georgia. 2. Department of Pediatrics, (RL), the Third Xiangya Hospital of Central South University, Changsha, China. 3. School of Chemistry and Biochemistry and the Petit Institute for Bioengineering and Bioscience, (FS, RW), Georgia Institute of Technology, Atlanta, Georgia. 4. Wallace H. Coulter Department of Biomedical Engineering, (CX), Georgia Institute of Technology and Emory University, Atlanta, Georgia.
Abstract
BACKGROUND: Alcohol use in pregnancy increases the risk of abnormal cardiac development, and excessive alcohol consumption in adults can induce cardiomyopathy, contractile dysfunction, and arrhythmias. Understanding molecular mechanisms underlying alcohol-induced cardiac toxicity could provide guidance in the development of therapeutic strategies. METHODS: We have performed proteomic and bioinformatic analysis to examine protein alterations globally and quantitatively in cardiomyocytes derived from human-induced pluripotent stem cells (hiPSC-CMs) treated with ethanol (EtOH). Proteins in both cell lysates and extracellular culture media were systematically quantitated. RESULTS: Treatment with EtOH caused severe detrimental effects on hiPSC-CMs as indicated by significant cell death and deranged Ca2+ handling. Treatment of hiPSC-CMs with EtOH significantly affected proteins responsible for stress response (e.g., GPX1 and HSPs), ion channel-related proteins (e.g. ATP1A2), myofibril structure proteins (e.g., MYL2/3), and those involved in focal adhesion and extracellular matrix (e.g., ILK and PXN). Proteins involved in the TNF receptor-associated factor 2 signaling (e.g., CPNE1 and TNIK) were also affected by EtOH treatment. CONCLUSIONS: The observed changes in protein expression highlight the involvement of oxidative stress and dysregulation of Ca2+ handling and contraction while also implicating potential novel targets in alcohol-induced cardiotoxicity. These findings facilitate further exploration of potential mechanisms, discovery of novel biomarkers, and development of targeted therapeutics against EtOH-induced cardiotoxicity.
BACKGROUND: Alcohol use in pregnancy increases the risk of abnormal cardiac development, and excessive alcohol consumption in adults can induce cardiomyopathy, contractile dysfunction, and arrhythmias. Understanding molecular mechanisms underlying alcohol-induced cardiac toxicity could provide guidance in the development of therapeutic strategies. METHODS: We have performed proteomic and bioinformatic analysis to examine protein alterations globally and quantitatively in cardiomyocytes derived from human-induced pluripotent stem cells (hiPSC-CMs) treated with ethanol (EtOH). Proteins in both cell lysates and extracellular culture media were systematically quantitated. RESULTS: Treatment with EtOH caused severe detrimental effects on hiPSC-CMs as indicated by significant cell death and deranged Ca2+ handling. Treatment of hiPSC-CMs with EtOH significantly affected proteins responsible for stress response (e.g., GPX1 and HSPs), ion channel-related proteins (e.g. ATP1A2), myofibril structure proteins (e.g., MYL2/3), and those involved in focal adhesion and extracellular matrix (e.g., ILK and PXN). Proteins involved in the TNF receptor-associated factor 2 signaling (e.g., CPNE1 and TNIK) were also affected by EtOH treatment. CONCLUSIONS: The observed changes in protein expression highlight the involvement of oxidative stress and dysregulation of Ca2+ handling and contraction while also implicating potential novel targets in alcohol-induced cardiotoxicity. These findings facilitate further exploration of potential mechanisms, discovery of novel biomarkers, and development of targeted therapeutics against EtOH-induced cardiotoxicity.
Authors: Vinay Swaminathan; Joseph Mathew Kalappurakkal; Shalin B Mehta; Pontus Nordenfelt; Travis I Moore; Nobuyasu Koga; David A Baker; Rudolf Oldenbourg; Tomomi Tani; Satyajit Mayor; Timothy A Springer; Clare M Waterman Journal: Proc Natl Acad Sci U S A Date: 2017-10-03 Impact factor: 11.205
Authors: Donald E White; Pierre Coutu; Yan-Fen Shi; Jean-Claude Tardif; Stanley Nattel; René St Arnaud; Shoukat Dedhar; William J Muller Journal: Genes Dev Date: 2006-09-01 Impact factor: 11.361