- Email: [email protected]
Modified susceptibility to reperfusion injury in daunorubicin-treated rat hearts
ABSTRACTS / Journal of Molecular and Cellular Cardiology 44 (2008) 711–825
Conclusion(s): Since early and later stages of atherosclerosis are associated with increased cell proliferation or with cell apoptosis, respectively, our results on NPI may identify a new mechanistic target for oxLDL during atherosclerosis. The data support the contention that the nucleus and NPI may represent a novel therapeutic target to control diseases that have cell proliferation as a central feature. Supported by CIHR, HSFC, and NSERC. Keywords: Oxidized low density lipoproteins; Nuclear protein import; Vascular smooth muscle cells
751
Conclusion: Daunorubicin depressed left ventricular function but increased myocardial tolerance to reperfusion-induced ventricular arrhythmias. These findings indicate that stress stimuli induced by a cytotoxic drug in an early stage of cardiomyopathy might trigger a biological adaptation — preconditioning-like protection. Supported by UK 19/2007, SKS 2007. Keywords: Daunorubicin; Myocardial ischemia/reperfusion injury; Rat doi:10.1016/j.yjmcc.2008.02.096
doi:10.1016/j.yjmcc.2008.02.095
Abstract No. 96 Abstract No. 95 Modified susceptibility to reperfusion injury in daunorubicin-treated rat hearts Adriana Adameovaa,⁎, Zuzana Maslenovaa, Katarina Turcekovaa, Jana Kmecovaa, Magdalena Kuzelovaa, Tana Ravingerovab, Pavel Sveca, Jan Klimasa. aFaculty of Pharmacy, Comenius University, Bratislava, Slovak Republic. bInstitute of Heart Research SAS, Bratislava, Slovak Republic ⁎ Corresponding author. Department of Pharmacology and Toxicology, Faculty of Pharmacy, Comenius University, Bratislava, Odbojárov 10, 832 32, Slovak Republic. Tel.: +421 2 50 117 366; fax: +421 2 50 117 100.
Daunorubicin treatment, effective in leukaemias, is limited due to its cardiotoxicity manifested by cardiomyopathy and congestive heart failure. Although daunorubicin itself may induce acute arrhythmias, relatively little is known about the susceptibility of daunorubicin-treated hearts to ischaemia/reperfusion injury. In Wistar rats (10-week old) treated with daunorubicin (D) for 14 days (3 mg/kg, i.p., every 48 h), as well as in the control ones, we tested in vivo: 1) left ventricular function using catheterization and 2) severity of ventricular arrhythmias induced by 10 min reperfusion following 6 min ischaemia (occlusion/ reperfusion of left anterior descending artery). Left ventricle pressure and the rates of contraction and relaxation were diminished by 15–40% in daunorubicin-treated rats (P b 0.05). Daunorubicin increased QRS amplitude and reduced the incidence of the most life-threatening arrhythmia, ventricular fibrillation. Similarly, the severity of reperfusion arrhythmias, expressed by arrhythmia score, was significantly lower in the treated group.
Table 1 Group
Control D-treated
QRS (mV)
0.77 ± 0.017 1.06 ± 0.04⁎
Incidence (%) VT
tVF
100 80
100 40⁎
Arrhythmia score
5 ± 0.00 3.20 ± 0.7⁎
T-type Ca2+ channel antagonists attenuated aldosterone, endothelin-1, and angiotensin-II-induced IL-18 expressions in rat cardiomyocytes Takashi Doi⁎, Tsuyoshi Sakoda, Toshio Naka, Takahumi Akagami, Mitsumasa Ohyanagi. Department of Internal Medicine, Hyogo College of Medicine, Japan ⁎ Corresponding author. 1-1, Mukogawa-cho, Nishinomya City, Hyogo College of Medicine, Division of Coronary Heart Disease, Japan. Tel.: +81 798 45 6553; fax: +81 798 45 6551. E-mail address: [email protected]
Interleukin-18 (IL-18) is a proinflammatory cytokine with multiple functions. Aldosterone is recognized as an important risk factor for cardiovascular diseases with myocardial hypertrophy and fibrosis with pathological remodeling. Endothelin-1 (ET-1) and Angiotensin-II (Ang-II) have been reported to be potent hypertrophy-promoting factors through Rho/Rho-kinase pathway. Ca2+ is an important factor in cardiac hypertrophy and cardiac remodeling. In the present study, we examined the effect of L-, T-type Ca2+ channel antagonists on Aldosterone-, ET-1- and Ang-II-induced IL-18 expression in rat cardiomyocytes. Aldosterone and ET-1 and Ang-II induced IL-18 mRNA and protein expression. T-type Ca2+ channel antagonists, Mibefradil and Efonidipine led to a significant reduction in Aldosterone-, ET-1-, and Ang-II-induced IL-18 expression. However, L-type Ca2+ channel antagonist, Nifedipine did not inhibit these reactions. Aldosterone-, ET-1-, and Ang-II-induced IL-18 expressions were inhibited not only by the ET-1 receptor antagonist, BQ123 and the Ang-II receptor antagonist, Olmesartan, but also by the HMG Co-A reductase Simvastatin and RhoA inhibitor, C3 toxin and Rho-kinase inhibitor, Fasudil. Aldosterone, ET-1 and Ang-II induced Rhokinase activities. Aldosterone-, ET-1-, and Ang-II-induced Rhokinase activities were prevented by the Mibefradil and Efonidipine but not by Nifedipine. These results indicate that Mibefradil and Efonidipine attenuated Aldosterone-, ET-1-, and Ang-II-induced IL-18 expressions at the level between ET-1 or Ang-II receptor and Rho-kinase. Inhibition of IL-18 expression induced by Aldosterone, ET-1 or Ang-II might be one of the
Conclusion(s): Since early and later stages of atherosclerosis are associated with increased cell proliferation or with cell apoptosis, respectively, our results on NPI may identify a new mechanistic target for oxLDL during atherosclerosis. The data support the contention that the nucleus and NPI may represent a novel therapeutic target to control diseases that have cell proliferation as a central feature. Supported by CIHR, HSFC, and NSERC. Keywords: Oxidized low density lipoproteins; Nuclear protein import; Vascular smooth muscle cells
751
Conclusion: Daunorubicin depressed left ventricular function but increased myocardial tolerance to reperfusion-induced ventricular arrhythmias. These findings indicate that stress stimuli induced by a cytotoxic drug in an early stage of cardiomyopathy might trigger a biological adaptation — preconditioning-like protection. Supported by UK 19/2007, SKS 2007. Keywords: Daunorubicin; Myocardial ischemia/reperfusion injury; Rat doi:10.1016/j.yjmcc.2008.02.096
doi:10.1016/j.yjmcc.2008.02.095
Abstract No. 96 Abstract No. 95 Modified susceptibility to reperfusion injury in daunorubicin-treated rat hearts Adriana Adameovaa,⁎, Zuzana Maslenovaa, Katarina Turcekovaa, Jana Kmecovaa, Magdalena Kuzelovaa, Tana Ravingerovab, Pavel Sveca, Jan Klimasa. aFaculty of Pharmacy, Comenius University, Bratislava, Slovak Republic. bInstitute of Heart Research SAS, Bratislava, Slovak Republic ⁎ Corresponding author. Department of Pharmacology and Toxicology, Faculty of Pharmacy, Comenius University, Bratislava, Odbojárov 10, 832 32, Slovak Republic. Tel.: +421 2 50 117 366; fax: +421 2 50 117 100.
Daunorubicin treatment, effective in leukaemias, is limited due to its cardiotoxicity manifested by cardiomyopathy and congestive heart failure. Although daunorubicin itself may induce acute arrhythmias, relatively little is known about the susceptibility of daunorubicin-treated hearts to ischaemia/reperfusion injury. In Wistar rats (10-week old) treated with daunorubicin (D) for 14 days (3 mg/kg, i.p., every 48 h), as well as in the control ones, we tested in vivo: 1) left ventricular function using catheterization and 2) severity of ventricular arrhythmias induced by 10 min reperfusion following 6 min ischaemia (occlusion/ reperfusion of left anterior descending artery). Left ventricle pressure and the rates of contraction and relaxation were diminished by 15–40% in daunorubicin-treated rats (P b 0.05). Daunorubicin increased QRS amplitude and reduced the incidence of the most life-threatening arrhythmia, ventricular fibrillation. Similarly, the severity of reperfusion arrhythmias, expressed by arrhythmia score, was significantly lower in the treated group.
Table 1 Group
Control D-treated
QRS (mV)
0.77 ± 0.017 1.06 ± 0.04⁎
Incidence (%) VT
tVF
100 80
100 40⁎
Arrhythmia score
5 ± 0.00 3.20 ± 0.7⁎
T-type Ca2+ channel antagonists attenuated aldosterone, endothelin-1, and angiotensin-II-induced IL-18 expressions in rat cardiomyocytes Takashi Doi⁎, Tsuyoshi Sakoda, Toshio Naka, Takahumi Akagami, Mitsumasa Ohyanagi. Department of Internal Medicine, Hyogo College of Medicine, Japan ⁎ Corresponding author. 1-1, Mukogawa-cho, Nishinomya City, Hyogo College of Medicine, Division of Coronary Heart Disease, Japan. Tel.: +81 798 45 6553; fax: +81 798 45 6551. E-mail address: [email protected]
Interleukin-18 (IL-18) is a proinflammatory cytokine with multiple functions. Aldosterone is recognized as an important risk factor for cardiovascular diseases with myocardial hypertrophy and fibrosis with pathological remodeling. Endothelin-1 (ET-1) and Angiotensin-II (Ang-II) have been reported to be potent hypertrophy-promoting factors through Rho/Rho-kinase pathway. Ca2+ is an important factor in cardiac hypertrophy and cardiac remodeling. In the present study, we examined the effect of L-, T-type Ca2+ channel antagonists on Aldosterone-, ET-1- and Ang-II-induced IL-18 expression in rat cardiomyocytes. Aldosterone and ET-1 and Ang-II induced IL-18 mRNA and protein expression. T-type Ca2+ channel antagonists, Mibefradil and Efonidipine led to a significant reduction in Aldosterone-, ET-1-, and Ang-II-induced IL-18 expression. However, L-type Ca2+ channel antagonist, Nifedipine did not inhibit these reactions. Aldosterone-, ET-1-, and Ang-II-induced IL-18 expressions were inhibited not only by the ET-1 receptor antagonist, BQ123 and the Ang-II receptor antagonist, Olmesartan, but also by the HMG Co-A reductase Simvastatin and RhoA inhibitor, C3 toxin and Rho-kinase inhibitor, Fasudil. Aldosterone, ET-1 and Ang-II induced Rhokinase activities. Aldosterone-, ET-1-, and Ang-II-induced Rhokinase activities were prevented by the Mibefradil and Efonidipine but not by Nifedipine. These results indicate that Mibefradil and Efonidipine attenuated Aldosterone-, ET-1-, and Ang-II-induced IL-18 expressions at the level between ET-1 or Ang-II receptor and Rho-kinase. Inhibition of IL-18 expression induced by Aldosterone, ET-1 or Ang-II might be one of the