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Exogenous midkine administration prevents cardiac remodeling in pacing-induced congestive heart failure of rabbits

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Abstract

Midkine (MK), a heparin-binding growth factor, has been shown to prevent cardiac remodeling after ischemic injury through its anti-apoptotic effect. Cell apoptosis is central to the pathophysiology of cardiac remodeling in congestive heart failure (CHF) of ischemic as well as non-ischemic origin. We hypothesized that MK exerts the anti-apoptotic cardioprotective effect in CHF of non-ischemic etiology. MK protein or vehicle (normal saline) was subcutaneously administered in tachycardia-induced CHF rabbits (right ventricular pacing, 350 beats/min, 4 weeks). The vehicle-treated rabbits (n = 19, control) demonstrated severe CHF and high mortality rate, whereas MK (n = 16) demonstrated a well-compensated state and a lower mortality rate. In echocardiography, left ventricular (LV) end-diastolic dimension decreased in MK versus control, whereas LV systolic function increased. In histological analysis (picrosirius red staining), MK decreased collagen deposition area compared with control. TUNEL staining showed that MK prevented cell apoptosis and minimized myocyte loss in the CHF rabbit ventricle, associated with activation of PI3-K/Akt signaling, producing a parallel decrease of Bax/Bcl-2 ratio. MK prevented progression of cardiac remodeling in the CHF rabbit, likely by activation of anti-apoptotic signaling. Exogenous MK application might be a novel therapeutic strategy for CHF due to non-ischemic origin.

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Acknowledgments

We thank Drs. Yukiomi Tsuji and Arihiro Sumida for technical advice and assistance in animal experiments. This work was supported by the Ministry of Education, Culture, Sports, Sciences and Technology, Japan.

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Department of Cardiovascular Research, Research Institute of Environmental Medicine, Nagoya University, Furo-cho, Chikusa-ku, Nagoya, 464-8601, Japan

    Masahide Harada, Mayumi Hojo, Kaichiro Kamiya & Mitsuru Horiba

  2. Department of Cardiology, Fujita Health University School of Medicine, 1-98 Dengakugakubo, Kutsukake-cho, Toyoake, 470-1192, Japan

    Masahide Harada

  3. Department of Biochemistry, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8560, Japan

    Kenji Kadomatsu

  4. Department of Cardiology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8560, Japan

    Toyoaki Murohara

  5. Nagoya University, Furo-cho, Chikusa-ku, Nagoya, 464-8601, Japan

    Itsuo Kodama

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  1. Masahide Harada
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  2. Mayumi Hojo
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  7. Mitsuru Horiba
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Correspondence to Masahide Harada.

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Harada, M., Hojo, M., Kamiya, K. et al. Exogenous midkine administration prevents cardiac remodeling in pacing-induced congestive heart failure of rabbits. Heart Vessels 31, 96–104 (2016). https://doi.org/10.1007/s00380-014-0569-5

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  • DOI: https://doi.org/10.1007/s00380-014-0569-5

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