title: Insulin-like growth factor-1 prevents loss of electrochemical gradient in cardiac muscle mitochondria via activation of PI 3 kinase/Akt pathway.
abstract: Insulin-like growth factor-1 (IGF 1) suppresses myocardial apoptosis and improves myocardial function in experimental models of cardiomyopathy. Apoptosis is triggered by mitochondria dysfunction and subsequent activation of caspases. We had previously shown that IGF 1 inhibited cardiomyocyte apoptosis via suppression of caspase, however, how IGF 1 and its signaling pathway modulates mitochondria function in cardiac muscle is not yet known. In this study we investigated how IGF 1 signaling modulates mitochondria membrane depolarization in the cardiomyocytes treated with doxorubicin. Doxorubicin rapidly induced loss of mitochondria electrochemical gradient and triggered mitochondria depolarization in primary cardiomyocytes, whereas addition of IGF 1 restored mitochondria electrochemical gradient. The effects of IGF 1 was blocked by a chemical inhibitor of PI 3 kinase and a dominant negative Akt, suggesting that IGF 1 signaling to mitochondria involves the PI 3 kinase-Akt pathway. Transducing cardiomyocytes with constitutive active PI 3 kinase partially restored the mitochondria electrochemical gradient in doxorubicin-treated cells. These findings provide direct evidence that IGF 1 modulation of mitochondria function is mediated through activation of PI 3 kinase and Akt. Additional experiments using agonist and antagonist of mitochondria K(ATP) channel suggest that IGF 1 signaling to mitochondria membrane does not directly involve K(ATP) channel. These findings suggest that cytosolic signaling to mitochondria may play a fundamental role in the cardiotoxic actions of doxorubicin and cardioprotective actions of IGF 1.
authors.affiliation: Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Med Sci I, Rm C240, University of California, Irvine, CA 92697, USA.
authors.forename: Hui-Chin
authors.initials: HC
authors.lastname: Lai
authors.forename: Tsun-Jui
authors.initials: TJ
authors.lastname: Liu
authors.forename: Chih-Tai
authors.initials: CT
authors.lastname: Ting
authors.forename: Prem M
authors.initials: PM
authors.lastname: Sharma
authors.forename: Ping H
authors.initials: PH
authors.lastname: Wang
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D003981:Diazoxide / Q000494:pharmacology; D004317:Doxorubicin / Q000494:pharmacology; D004563:Electrochemistry; D005822:Genetic Vectors; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D008564:Membrane Potentials; D008565:Membrane Proteins / Q000502:physiology; D008929:Mitochondria, Heart / Q000187:drug effects / Q000502:physiology*; D009206:Myocardium / Q000201:enzymology* / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D015221:Potassium Channels; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D051381:Rats; D015398:Signal Transduction; D013997:Time Factors
chemical_list: D003981:Diazoxide; D004317:Doxorubicin; D007334:Insulin-Like Growth Factor I; D008565:Membrane Proteins; D019869:Phosphatidylinositol 3-Kinases; D015221:Potassium Channels; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; C117780:mitochondrial K(ATP) channel; C494920:Akt1 protein, rat