title: Nicotine plus a high-fat diet triggers cardiomyocyte apoptosis.
abstract: Cigarette smoking is an important risk factor for diabetes, cardiovascular disease and non-alcoholic fatty liver disease. The health risk associated with smoking can be aggravated by obesity. Smoking might also trigger cardiomyocyte (CM) apoptosis. Given that CM apoptosis has been implicated as a potential mechanism in the development of cardiomyopathy and heart failure, we characterize the key signaling pathways in nicotine plus high-fat diet (HFD)-induced CM apoptosis. Adult C57BL6 male mice were fed a normal diet (ND) or HFD and received twice-daily intraperitoneal (IP) injections of nicotine (0.75 mg/kg body weight [BW]) or saline for 16 weeks. An additional group of nicotine-treated mice on HFD received twice-daily IP injections of mecamylamine (1 mg/kg BW), a non-selective nicotinic acetylcholine receptor antagonist, for 16 weeks. Nicotine when combined with HFD led to a massive increase in CM apoptosis that was fully prevented by mecamylamine treatment. Induction of CM apoptosis was associated with increased oxidative stress and activation of caspase-2-mediated intrinsic pathway signaling coupled with inactivation of AMP-activated protein kinase (AMPK). Furthermore, nicotine treatment significantly (P < 0.05) attenuated the HFD-induced decrease in fibroblast growth factor 21 (FGF21) and silent information regulator 1 (SIRT1). We conclude that nicotine, when combined with HFD, triggers CM apoptosis through the generation of oxidative stress and inactivation of AMPK together with the activation of caspase-2-mediated intrinsic apoptotic signaling independently of FGF21 and SIRT1.
authors.affiliation: Division of Endocrinology, Metabolism and Molecular Medicine, Department of Internal Medicine, Charles R. Drew University of Medicine and Science, 1731 E. 120th Street, Los Angeles, CA 90059, USA.|David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Indrani
authors.initials: I
authors.lastname: Sinha-Hikim
authors.affiliation: Division of Endocrinology, Metabolism and Molecular Medicine, Department of Internal Medicine, Charles R. Drew University of Medicine and Science, 1731 E. 120th Street, Los Angeles, CA 90059, USA.|David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Theodore C
authors.initials: TC
authors.lastname: Friedman
authors.affiliation: Division of Endocrinology, Metabolism and Molecular Medicine, Department of Internal Medicine, Charles R. Drew University of Medicine and Science, 1731 E. 120th Street, Los Angeles, CA 90059, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Falz
authors.affiliation: Division of Endocrinology, Metabolism and Molecular Medicine, Department of Internal Medicine, Charles R. Drew University of Medicine and Science, 1731 E. 120th Street, Los Angeles, CA 90059, USA.
authors.forename: Victor
authors.initials: V
authors.lastname: Chalfant
authors.affiliation: Division of Endocrinology, Metabolism and Molecular Medicine, Department of Internal Medicine, Charles R. Drew University of Medicine and Science, 1731 E. 120th Street, Los Angeles, CA 90059, USA.
authors.forename: Mohammad Kamrul
authors.initials: MK
authors.lastname: Hasan
authors.affiliation: Division of Endocrinology, Metabolism and Molecular Medicine, Department of Internal Medicine, Charles R. Drew University of Medicine and Science, 1731 E. 120th Street, Los Angeles, CA 90059, USA.
authors.forename: Jorge
authors.initials: J
authors.lastname: Espinoza-Derout
authors.affiliation: Division of Endocrinology, Metabolism and Molecular Medicine, Department of Internal Medicine, Charles R. Drew University of Medicine and Science, 1731 E. 120th Street, Los Angeles, CA 90059, USA.
authors.forename: Desean L
authors.initials: DL
authors.lastname: Lee
authors.affiliation: Division of Endocrinology, Metabolism and Molecular Medicine, Department of Internal Medicine, Charles R. Drew University of Medicine and Science, 1731 E. 120th Street, Los Angeles, CA 90059, USA.
authors.forename: Carl
authors.initials: C
authors.lastname: Sims
authors.affiliation: Division of Endocrinology, Metabolism and Molecular Medicine, Department of Internal Medicine, Charles R. Drew University of Medicine and Science, 1731 E. 120th Street, Los Angeles, CA 90059, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Tran
authors.affiliation: VA San Diego Health Care System and University of California, San Diego, Calif., USA.
authors.forename: Sushil K
authors.initials: SK
authors.lastname: Mahata
authors.affiliation: Division of Endocrinology, Metabolism and Molecular Medicine, Department of Internal Medicine, Charles R. Drew University of Medicine and Science, 1731 E. 120th Street, Los Angeles, CA 90059, USA. amiyasinhahikim@cdrewu.edu.|David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA 90095, USA. amiyasinhahikim@cdrewu.edu.
authors.forename: Amiya P
authors.initials: AP
authors.lastname: Sinha-Hikim
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D020169:Caspases / Q000378:metabolism; D059305:Diet, High-Fat; D005346:Fibroblast Growth Factors / Q000378:metabolism; D007150:Immunohistochemistry; D008297:Male; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D032383:Myocytes, Cardiac / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology / Q000648:ultrastructure; D009538:Nicotine / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D056564:Sirtuin 1 / Q000378:metabolism
chemical_list: C414620:fibroblast growth factor 21; D005346:Fibroblast Growth Factors; D009538:Nicotine; D055372:AMP-Activated Protein Kinases; D020169:Caspases; D056564:Sirtuin 1
keywords: Cardiomyocyte apoptosis; High-fat diet; Mouse; Nicotine; Oxidative stress