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Nicotine plus a high-fat diet triggers cardiomyocyte apoptosis

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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.

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Acknowledgments

This work was supported by the Diversity Promoting Institution Drug Abuse Research Program (DIDARP) grant (R24DA017298) and the Accelerating Excellence in Translational Science (AXIS) grant (2U54MD007598) from the National Institutes of Health (NIH). We also thank the Technology Core of the AXIS grant (2U54MD007598) from NIH for tissue preparation and for hematoxylin and eosin staining.

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Authors and Affiliations

  1. 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

    Indrani Sinha-Hikim, Theodore C. Friedman, Mark Falz, Victor Chalfant, Mohammad Kamrul Hasan, Jorge Espinoza-Derout, Desean L. Lee, Carl Sims, Peter Tran & Amiya P. Sinha-Hikim

  2. David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA 90095, USA

    Indrani Sinha-Hikim, Theodore C. Friedman & Amiya P. Sinha-Hikim

  3. VA San Diego Health Care System and University of California, San Diego, Calif., USA

    Sushil K. Mahata

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  1. Indrani Sinha-Hikim
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  2. Theodore C. Friedman
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  11. Amiya P. Sinha-Hikim
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Sinha-Hikim, I., Friedman, T.C., Falz, M. et al. Nicotine plus a high-fat diet triggers cardiomyocyte apoptosis. Cell Tissue Res 368, 159–170 (2017). https://doi.org/10.1007/s00441-016-2536-1

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