TY - JOUR
T1 - Myocardial protective effect of FR167653; a novel cytokine inhibitor in ischemic-reperfused rat heart
AU - Aleshin, Alexey
AU - Sawa, Yoshiki
AU - Ono, Masamichi
AU - Funatsu, Toshihiro
AU - Miyagawa, Shigeru
AU - Matsuda, Hikaru
N1 - Funding Information:
The experiments were performed in adherence with ‘Principles of Laboratory Animal Care’ formulated by the National Society for Medical Research and the ‘Guide for the Care and Use of Laboratory Animals’ published in the National Institutes of Health (NIH Pub N. 85-23, revised 1985).
PY - 2004/11
Y1 - 2004/11
N2 - Objectives: In this study, a newly synthesized cytokine inhibitor FR167653 was investigated using a rat heart ischemia-reperfusion model to prove its myocardial protective effect and its role in the inhibition of cytokine production in ischemic myocardium. Methods: Studies were performed with isolated, Langendorff-perfused Lewis rat hearts (n=80) which were either treated with FR167653 or untreated, as the control group, and subjected to ischemia-reperfusion. Results: Reperfusion followed by 30 min of 37°C ischemia induced marked myocardial cytokine expression and activated p38MAPK. FR167653 administered before ischemia and during reperfusion significantly reduced ischemia-activated myocardial TNFα mRNA expression (190±97 vs. 4805±3017, P=0.024) as well as TNFα production (0 vs. 9.6±2.5 ng/ml, P<0.05) and also inhibited p38 MAPK activation. Its administration improved recovery of cardiac contractile function during reperfusion: LVDP (130±18 vs. 82±21 mmHg (P=0.002)), max/min dP/dt (2812±328/-2283±216 vs. 1520±424/-1325±237 mmHg/s, P=0.003). CPK leakage was significantly reduced in FR167653 treated hearts versus untreated hearts (54±6 vs. 0.5±0.1, P<0.05) and reduction of coronary flow was improved (110±13 vs. 77±11%) 1 h after beginning of reperfusion (P<0.05). Moreover, FR administration attenuated the number of TUNEL positive cardiomyocytes (3±1 vs. 9±2%). Conclusion: These data demonstrated positive inotropic and antiapoptotic effects of a newly synthesized compound (FR167653) of cytokine inhibitors and its inhibitory effect on myocardial TNFα production and p38 MAPK activation in ischemic-reperfused rat heart. This suggested that cytokine inhibition is significant as a method for myocardial protection against ischemia-reperfusion injury.
AB - Objectives: In this study, a newly synthesized cytokine inhibitor FR167653 was investigated using a rat heart ischemia-reperfusion model to prove its myocardial protective effect and its role in the inhibition of cytokine production in ischemic myocardium. Methods: Studies were performed with isolated, Langendorff-perfused Lewis rat hearts (n=80) which were either treated with FR167653 or untreated, as the control group, and subjected to ischemia-reperfusion. Results: Reperfusion followed by 30 min of 37°C ischemia induced marked myocardial cytokine expression and activated p38MAPK. FR167653 administered before ischemia and during reperfusion significantly reduced ischemia-activated myocardial TNFα mRNA expression (190±97 vs. 4805±3017, P=0.024) as well as TNFα production (0 vs. 9.6±2.5 ng/ml, P<0.05) and also inhibited p38 MAPK activation. Its administration improved recovery of cardiac contractile function during reperfusion: LVDP (130±18 vs. 82±21 mmHg (P=0.002)), max/min dP/dt (2812±328/-2283±216 vs. 1520±424/-1325±237 mmHg/s, P=0.003). CPK leakage was significantly reduced in FR167653 treated hearts versus untreated hearts (54±6 vs. 0.5±0.1, P<0.05) and reduction of coronary flow was improved (110±13 vs. 77±11%) 1 h after beginning of reperfusion (P<0.05). Moreover, FR administration attenuated the number of TUNEL positive cardiomyocytes (3±1 vs. 9±2%). Conclusion: These data demonstrated positive inotropic and antiapoptotic effects of a newly synthesized compound (FR167653) of cytokine inhibitors and its inhibitory effect on myocardial TNFα production and p38 MAPK activation in ischemic-reperfused rat heart. This suggested that cytokine inhibition is significant as a method for myocardial protection against ischemia-reperfusion injury.
KW - Apoptosis
KW - Cytokines
KW - Heart preservation
KW - Ischemia-reperfusion
KW - Myocardial injury
UR - http://www.scopus.com/inward/record.url?scp=7244239237&partnerID=8YFLogxK
U2 - 10.1016/j.ejcts.2004.06.021
DO - 10.1016/j.ejcts.2004.06.021
M3 - Article
C2 - 15519192
AN - SCOPUS:7244239237
SN - 1010-7940
VL - 26
SP - 974
EP - 980
JO - European Journal of Cardio-thoracic Surgery
JF - European Journal of Cardio-thoracic Surgery
IS - 5
ER -