Abstract
We previously reported on the use of enzymatic analysis to impair fatty acid metabolism followed by reduced myocardial energy content, leading to severe heart failure in adriamycin (ADR)-treated rats. The aim of this study is to investigate whether impaired myocardial energy metabolism can also be detected by other methods; i.e. measuring mitochondrial complex I activity and myocardial 125I-15-(p-iodophenyl)-3-(R,S)- methylpentadecanoic acid (BMIPP) accumulation in ADR-treated rats. Eight-week-old male Sprague-Dawley rats received 6 intraperitoneal injections of ADR (total 15 mg/kg: group ADR) or saline (control group) over 2 weeks. Left ventricular (LV) ejection fraction was assessed using echocardiography at 3- and 6-weeks after ADR injection (3 weeks and 6 weeks, respectively). Myocardial fatty acid utilization was assessed at 3 weeks and 6 weeks. The myocardial counts of BMIPP were measured after intravenous BMIPP (370 kBq) injection, and 125I counts were measured to calculate the uptake ratio. The enzymatic activity of complex I was assessed by monitoring the oxidation of nicotinamide-adenine-dinucleotide-disodium-salt (NADH). In rats treated with ADR, significant decrease in LV ejection fraction was observed only at 6 weeks compared to control (72.5 vs. 84.5%, p < 0.01rpar;. LV ejection fraction at 3 weeks was identical between group ADR and control (81.8 vs. 84.4%). However, at 3 weeks, complex I activity was already reduced significantly in group ADR as compared to control group (p = 0.03), but the reduction in BMIPP accumulation was not (p = 0.15). Our data indicated that reduced complex I activity in a phenomenon occurred in early phase of ADR-induced cardiomyopathy, and it might play an important role in the progression of ADR-induced heart failure.
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Shan K, Lincoff AM, Young JB: Anthracycline-induced cardiotoxicity. Ann Intern Med 125: 47-58, 1996
Bristow MR, Billingham ME, Mason JW, Daniels JR: Clinical spectrum of anthracycline antibiotic cardiotoxicity. Cancer Treat Rep 62: 873-879, 1978
Suzuki J, Yanagisawa A, Shigeyama T, Tsubota J, Yasumura T, Shimoyama K, Ishikawa K: Early detection of anthracycline-induced cardiotoxicity by radionuclide angiocardiography. Angiology 50: 37-45, 1999
Wakasugi S, Fischman AJ, Babich JW, Callahan RJ, Elmaleh DR, Wilkinson R, Strauss HW: Myocardial substrate utilization and left ventricular function in adriamycin cardiomyopathy. J Nucl Med 34: 1529-1535, 1993
Kawasaki N, Lee JD, Shimizu H, Ishii Y, Ueda T: Cardiac energy metabolism at several stages of adriamycin-induced heart failure in rats. Int J Cardiol 55: 217-225, 1996
Doroshow JH: Effect of anthracycline antibiotics on oxygen radical formation in rat heart. Cancer Res 43: 460-472, 1983
Ide T, Tsutsui H, Kinugawa S, Utsumi H, Kang D, Hattori N, Uchida K, Arimura K, Egashira K, Takeshita A: Mitochondrial electron transport complex I is a potential source of oxygen free radicals in the failing myocardium. Circ Res 85: 357-363, 1999
Tong J, Ganguly PK, Singal PK: Myocardial adrenergic changes at two stages of heart failure due to adriamycin treatment in rats. Am J Physiol 260: H909-H916, 1991
Li T, Signal PK: Adriamycin-induced early changes in myocardial antioxidant enzymes and their modulation by probucol. Circulation 102: 2105-2110, 2000
Ono T, Kohya T, Tsukamoto E, Mochizuki T, Itoh K, Itoh Y, Tomita F, Tamaki N, Kitabatake A: Improvement in fatty acid utilization in relation to a change in left ventricular hypertrophy in spontaneously hypertensive rats. Jpn Circ J 64: 117-120, 2000
Tsujimura E, Kusuoka H, Fukuchi K, Hasegawa S, Yutani K, Hori M, Hirono S, Izumi T, Nishimura T: Changes in perfusion and fatty acid metabolism of rat heart with autoimmune myocarditis. Ann Nucl Med 14: 361-367, 2000
Palmer JW, Tandler B, Hoppel CL: Biochemical properties of subsarcolemmal and interfibrillar mitochondria isolated from rat cardiac muscle. J Biol Chem 252: 8731-8739, 1977
Williams N, Amzel LM, Pedersen PL: Proton ATPase of rat liver mitochondria: A rapid procedure for purification of a stable, reconstitutively active F1 preparation using a modified chloroform method. Anal Biochem 140: 581-588, 1984
Jablonski E, DeLuca M: Purification and properties of the NADH and NADPH specific FMN oxidoreductases from beneckea harveyi. Biochemistry 16: 2932-2936, 1977
Taniuchi H, Fujibayashi Y, Yonekura Y, Konishi J, Yokoyama A: Hyperfixation of Copper-62-PTSM in rat brain after transient global ischemia. J Nucl Med 38: 1130-1134, 1997
Bristow MR, Mason JW, Billingham ME, Daniels JR: Dose-effect and structure-function relationships in doxorubicin cardiomyopathy. Am Heart J 102: 709-718, 1981
Kawasaki N, Lee JD, Shimizu H, Ueda T: Long-term 1-carnitine treatment prolongs the survival in rats with adriamycin-induced heart failure. J Card Fail 2: 293-299, 1996
Saito K, Takeda K, Okamoto S, Okamoto R, Makino K, Tameda Y, Nomura Y, Maeda H, Ichihara T, Nakano T: Detection of doxorubicin cardiotoxicity by using iodine-123 BMIPP early dynamic SPECT: Quantitative evaluation of early abnormality of fatty acid metabolism with the Rutland method. J Nucl Cardiol 7: 553-561, 2000
Ogata M: Myocardial uptake of 125I-BMIPP in rats treated with adriamycin. Kaku Igaku 26: 69-76, 1989
Fujibayashi Y, Yonekura Y, Takemura Y, Wada K, Matsumoto K, Tamaki N, Yamamoto K, Konishi J, Yokoyama A: Myocardial accumulation of iodinated beta-methyl-branched fatty acid analogue, iodine-125-15-(p-iodophenyl)-3-(R,S) methylpentadecanoic acid (BMIPP), in relation to ATP concentration. J Nucl Med 31: 1818-1822, 1990
Nohara R, Okuda K, Ogino M, Hosokawa R, Tamaki N, Konishi J, Fujibayashi Y, Yonekura Y, Fujita M, Sasayama S: Evaluation of myocardial viability with iodine-123-BMIPP in a canine model. J Nucl Med 37: 1403-1407, 1996
Serrano J, Palmeira CM, Kuehl DW, Wallace KB: Cardioselective and cumulative oxidation of mitochondrial DNA following subchronic doxorubicin administration. Biochim Biophys Acta 1411: 201-205, 1999
Takeda N: Cardiomyopathies and mitochondrial DNA mutations. Mol Cell Biochem 176: 287-290, 1997
Adachi K, Fujiura Y, Mayumi F, Nozuhara A, Sugiu Y, Sakanashi T, Hdiaka T, Toshima H: A deletion of mitochondrial DNA in murine doxorubicin induced cardiotoxicity. Biochem Biophys Res Commun 195: 945-951, 1993
Yen HC, Oberley TD, Gairola CG, Szweda LI, Clair DK: Manganese superoxide dismutase protects mitochondrial complex I against adriamycin-induced cardiomyopathy in transgenic mice. Arch Biochem Biophys 362: 59-66, 1999
Rajagopalan S, Politi PM, Sinha BK, Myers CE: Adriamycin-induced free radical formation in the perfused rat heart: Implications for cardiotoxicity. Cancer Res 48: 4766-4769, 1988
Li T, Danelisen I, Singal PK: Early changes in myocardial antioxidant enzymes in rats treated with adriamycin. Mol Cell Biochem 232: 19-26, 2002
Wakasugi S, Inoue M, Tazawa S: Assessment of adrenergic neuron function altered with progression of heart failure. J Nucl Med 36: 2069-2074, 1995
Suzuki T, Hayashi D, Yamazaki T, Mizuno T, Kanda Y, Komura I, Kurabayashi M, Yamaoki K, Mitani K, Hirai H, Nagai R, Yazaki Y: Elevated B-type natriuretic peptide levels after anthracycline administration. Am Heart J 136: 362-363, 1998
Mitsuke Y, Lee J.D, Shimizu H, Uzui H, Iwasaki H, Ueda T: Nitric oxide synthase activity in peripheral polymorphonuclear leukocytes in patients with chronic congestive heart failure. Am J Cardiol 87: 183-187, 2001
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Ohkura, K., Lee, JD., Shimizu, H. et al. Mitochondrials complex I activity is reduced in latent adriamycin-induced cardiomyopathy of rat. Mol Cell Biochem 248, 203–208 (2003). https://doi.org/10.1023/A:1024161024231
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DOI: https://doi.org/10.1023/A:1024161024231