title: Exogenous midkine administration prevents cardiac remodeling in pacing-induced congestive heart failure of rabbits.
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.
authors.affiliation: Department of Cardiovascular Research, Research Institute of Environmental Medicine, Nagoya University, Furo-cho, Chikusa-ku, Nagoya, 464-8601, Japan. masahideharada@yahoo.ca.|Department of Cardiology, Fujita Health University School of Medicine, 1-98 Dengakugakubo, Kutsukake-cho, Toyoake, 470-1192, Japan. masahideharada@yahoo.ca.
authors.forename: Masahide
authors.initials: M
authors.lastname: Harada
authors.affiliation: Department of Cardiovascular Research, Research Institute of Environmental Medicine, Nagoya University, Furo-cho, Chikusa-ku, Nagoya, 464-8601, Japan.
authors.forename: Mayumi
authors.initials: M
authors.lastname: Hojo
authors.affiliation: Department of Cardiovascular Research, Research Institute of Environmental Medicine, Nagoya University, Furo-cho, Chikusa-ku, Nagoya, 464-8601, Japan.
authors.forename: Kaichiro
authors.initials: K
authors.lastname: Kamiya
authors.affiliation: Department of Biochemistry, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8560, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Kadomatsu
authors.affiliation: Department of Cardiology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8560, Japan.
authors.forename: Toyoaki
authors.initials: T
authors.lastname: Murohara
authors.affiliation: Nagoya University, Furo-cho, Chikusa-ku, Nagoya, 464-8601, Japan.
authors.forename: Itsuo
authors.initials: I
authors.lastname: Kodama
authors.affiliation: Department of Cardiovascular Research, Research Institute of Environmental Medicine, Nagoya University, Furo-cho, Chikusa-ku, Nagoya, 464-8601, Japan.
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Horiba
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002304:Cardiac Pacing, Artificial / Q000009:adverse effects*; D016207:Cytokines / Q000008:administration & dosage*; D004195:Disease Models, Animal; D004452:Echocardiography; D006333:Heart Failure / Q000188:drug therapy*; D006352:Heart Ventricles / Q000503:physiopathology; D008297:Male; D000078792:Midkine; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000473:pathology*; D011817:Rabbits; D013610:Tachycardia; D020257:Ventricular Remodeling / Q000187:drug effects*
chemical_list: D016207:Cytokines; D000078792:Midkine
keywords: Apoptosis; Cardiomyopathy; Heart failure; Midkine