ATTENUATION OF ISCHEMIC MYOCARDIAL INJURY AND DYSFUNCTION BY CARDIAC FIBROBLAST-DERIVED FACTOR(S)

[Original Article]

ATTENUATION OF ISCHEMIC MYOCARDIAL INJURY AND DYSFUNCTION BY
CARDIAC FIBROBLAST-DERIVED FACTOR(S)

KAZUHIKO NAKAZATO^1),*, WAKAKO NAGANUMA^1),*, KAZUEI OGAWA¹⁾,
HIROYUKI YAOITA¹⁾, SHINYA MIZUNO²⁾, TOSHIKAZU NAKAMURA²⁾
and YUKIO MARUYAMA¹⁾

¹⁾Department of Cardiology and Hematology, Fukushima Medical University, Fukushima, Japan, ²⁾Division of Molecular Regenerative Medicine, Department of Biochemistry and Molecular Biology, Osaka University Graduate School of Medicine, Osaka, Japan

(Received March 26, 2009, accepted November 9, 2009)

Abstract: Fibroblasts, the majority of non-cardiomyocytes in the heart, are known to release several kinds of substances such as cytokines and hormones that affect cell and tissue functions. We hypothesized that undefined substance(s) derived from cardiac fibroblasts may have the potential to protect against ischemic myocardium. To assess our hypothesis, using rats, we investigated:1) the effect of cardiac fibroblast-conditioned medium (CM) on the viability of hypoxic cardiomyocytes in vitro, 2) the effect of CM on left ventricular (LV) function in global ischemia-reperfusion in an ex vivo model, 3) the mechanism underlying cardioprotection by CM. Seventy-two hours after starting a hypoxic culture, the viability of cardiomyocytes was higher (P<0.05) in the CM treated group (41.4%) compared to the control (20.5%). In Langendorff's preparation, 30 min after ischemia-reperfusion, LV end-diastolic pressure was lower, and LV developed pressure and −LVdP/dt were higher (P<0.01 or P<0.05) in the CM group than in the control, although coronary flow did not differ between the two groups. Pretreatment with a protein kinase C inhibitor or a mitochondrial ATP-sensitive K⁺ channel blocker attenuated these changes of LV function in the CM group. Such cardioprotection was achieved by a fraction of the CM having a molecular weight (MW) > 50,000, but not by that of the CM with a lower MW. In addition, a specific antibody against hepatocyte growth factor (HGF, MW is 84,000) did not reduce the cardioprotection afforded by CM. There may be an unknown cardioprotective substance other than HGF in rats, which mimics ischemic preconditioning and has MW>50,000.

Key words: Cardiomyocytes, Fibroblast, Ischemia, Hypoxia, Rat

中里和彦，永沼和香子，小川一英，矢尾板裕幸，水野信哉，中村敏一，丸山幸夫

*Both authors contributed equally to this work.
Corresponding author:Kazuhiko Nakazato
E-mail address:nakazato@fmu. ac. jp
http://fmu.ac.jp/home/lib/F-igaku/
http://www.sasappa.co.jp/online/