title: Myocardial 14-3-3η protein protects against mitochondria mediated apoptosis.
abstract: There is a definite cardioprotective role for 14-3-3η protein against pressure overload induced cardiac hypertrophy and streptozotocin induced cardiac dysfunction in type 1 diabetes mellitus (DM). But it is not conclusive whether it has any influence on mitochondrial mediated cardiomyocyte apoptosis in type 2 DM. In order to test this hypothesis, we have used C57BL6/J (WT) mice with cardiac specific dominant negative mutation of 14-3-3η protein (DN 14-3-3η). Both WT and DN 14-3-3η mice were fed with high fat diet (HFD) for 12weeks. Their body weight and blood glucose levels were measured weekly and compared with standard diet (SD) fed mice. By the end of 12weeks, echocardiography was performed. Frozen myocardial sections were prepared to stain the apoptotic cardiomyocytes using TUNEL staining. DN 14-3-3η mice fed with HFD showed cardiac dysfunction as identified by the decreased fractional shortening and ejection fraction and increased cardiomyocyte apoptosis in TUNEL staining. Western blotting analysis using mitochondrial fraction of the ventricular tissue homogenates showed a significant reduction in the level of cytochrome c suggesting its translocation into cytoplasm, which may be crucial in inducing cardiomyocyte apoptosis. In addition, DN 14-3-3η mice depicted significantly increased levels of NADPH oxidase subunits suggesting oxidative stress, a significant reduction in phospho apoptosis signal-regulating kinase-1 (p-Ask-1) and increase in Ask-1 and phospho c-Jun N-terminal kinase (p-JNK) levels suggesting activation of Ask-1/JNK signaling. These results suggest that 14-3-3η has a protective role against mitochondria mediated cardiomyocyte apoptosis with the involvement of Ask-1/JNK signaling during HFD induced type 2 DM.
authors.affiliation: Department of Clinical Pharmacology, Faculty of Pharmaceutical Sciences, Niigata University of Pharmacy and Applied Life Sciences, Niigata City 956-8603, Japan.
authors.forename: Remya
authors.initials: R
authors.lastname: Sreedhar
authors.affiliation: Department of Clinical Pharmacology, Faculty of Pharmaceutical Sciences, Niigata University of Pharmacy and Applied Life Sciences, Niigata City 956-8603, Japan.
authors.forename: Somasundaram
authors.initials: S
authors.lastname: Arumugam
authors.affiliation: Department of Cardiovascular Sciences, Houston Methodist Research Institute, Houston, TX 77030, USA.
authors.forename: Rajarajan A
authors.initials: RA
authors.lastname: Thandavarayan
authors.affiliation: J.K.K. Nattraja College of Pharmacy, Natarajapuram, Komarapalayam, Namakkal District, 638183 Tamil Nadu, India.
authors.forename: Vijayasree V
authors.initials: VV
authors.lastname: Giridharan
authors.affiliation: Department of Clinical Pharmacology, Faculty of Pharmaceutical Sciences, Niigata University of Pharmacy and Applied Life Sciences, Niigata City 956-8603, Japan.
authors.forename: Vengadeshprabhu
authors.initials: V
authors.lastname: Karuppagounder
authors.affiliation: Department of Clinical Pharmacology, Faculty of Pharmaceutical Sciences, Niigata University of Pharmacy and Applied Life Sciences, Niigata City 956-8603, Japan.
authors.forename: Vigneshwaran
authors.initials: V
authors.lastname: Pitchaimani
authors.affiliation: Department of Clinical Pharmacology, Faculty of Pharmaceutical Sciences, Niigata University of Pharmacy and Applied Life Sciences, Niigata City 956-8603, Japan.
authors.forename: Rejina
authors.initials: R
authors.lastname: Afrin
authors.affiliation: Department of Clinical Pharmacology, Faculty of Pharmaceutical Sciences, Niigata University of Pharmacy and Applied Life Sciences, Niigata City 956-8603, Japan.
authors.forename: Shizuka
authors.initials: S
authors.lastname: Miyashita
authors.affiliation: Department of Clinical Pharmacology, Faculty of Pharmaceutical Sciences, Niigata University of Pharmacy and Applied Life Sciences, Niigata City 956-8603, Japan.
authors.forename: Mayumi
authors.initials: M
authors.lastname: Nomoto
authors.affiliation: Department of Clinical Pharmacology, Faculty of Pharmaceutical Sciences, Niigata University of Pharmacy and Applied Life Sciences, Niigata City 956-8603, Japan.
authors.forename: Meilei
authors.initials: M
authors.lastname: Harima
authors.affiliation: Department of Pharmacology, College of Pharmacy, King Khalid University, Abha, Kingdom of Saudi Arabia.
authors.forename: Narasimman
authors.initials: N
authors.lastname: Gurusamy
authors.affiliation: Department of Gastroenterology, Niigata University Graduate School of Medical and Dental Sciences, Niigata City 951-8510, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Suzuki
authors.affiliation: Department of Clinical Pharmacology, Faculty of Pharmaceutical Sciences, Niigata University of Pharmacy and Applied Life Sciences, Niigata City 956-8603, Japan. Electronic address: watanabe@nupals.ac.jp.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Watanabe
mesh_terms: D048948:14-3-3 Proteins / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis; D001786:Blood Glucose / Q000378:metabolism; D045304:Cytochromes c / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism; D059305:Diet, High-Fat / Q000009:adverse effects; D048031:JNK Mitogen-Activated Protein Kinases; D048848:MAP Kinase Kinase Kinase 5 / Q000378:metabolism; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000378:metabolism*; D009206:Myocardium / Q000166:cytology* / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism; D018384:Oxidative Stress; D015398:Signal Transduction
chemical_list: D048948:14-3-3 Proteins; D001786:Blood Glucose; D045304:Cytochromes c; D048031:JNK Mitogen-Activated Protein Kinases; D048848:MAP Kinase Kinase Kinase 5
keywords: 14-3-3η protein; Apoptosis signal-regulating kinase-1; Cardiomyocyte apoptosis; Cytochrome c; Diabetes mellitus; High fat diet