Regulation of Cardiomyocyte Apoptotic Signaling by Insulin-like Growth Factor I

From the Departments of Medicine and Biological Chemistry, Division of Endocrinology, Diabetes, and Metabolism, University of California, Irvine.

Correspondence to Ping H. Wang, MD, University of California, Department of Medicine, Medical Science I, Room C240, Irvine, CA 92697-4086.

Abstract—Apoptosis is regulated by specific intracellular signaling pathways. The development of cardiomyopathy involves the apoptosis of cardiomyocytes; however, the details of their apoptotic signaling are not yet known. Insulin-like growth factor I (IGF I) is an important survival growth factor for myocardium and other tissues, but the effects of IGF I on apoptotic signaling remain largely unknown. To study apoptotic signaling pathways in cardiomyocytes and to understand IGF I actions on the apoptotic signaling of cardiac muscle cells, we have defined the effects of IGF I on Bcl-2, Bax, caspase 3, DNA fragmentation, and cell survival in primary cardiomyocytes. Compared with Bax levels, the levels of Bcl-2 were found to be quite low in these cells. Serum withdrawal and doxorubicin reduced cell viability, increased fragmentation of DNA, increased cellular contents of Bax, and activated caspase 3. IGF I enhanced cell viability, suppressed DNA fragmentation, attenuated Bax induction, and suppressed caspase 3 activation. The levels of Bcl-2–associated Bax were increased after serum withdrawal and incubation with doxorubicin and were reduced by IGF I. Thus, cardiomyocyte apoptosis induced by serum withdrawal and doxorubicin likely results, in part, from the induction of Bax and activation of caspase 3, but IGF I may inhibit cardiomyocyte apoptosis by attenuating Bax induction and caspase 3 activation. These findings provide new insight into the mechanisms of cardiomyocytes apoptosis and may help elucidate how IGF I modulates apoptotic signaling in cardiac muscle.

Key Words: apoptosis • insulin-like growth factor I • cardiac muscle • caspase 3 • Bax

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				J. Shiraishi, T. Tatsumi, N. Keira, K. Akashi, A. Mano, S. Yamanaka, S. Matoba, J. Asayama, T. Yaoi, S. Fushiki, et al. Important role of energy-dependent mitochondrial pathways in cultured rat cardiac myocyte apoptosis Am J Physiol Heart Circ Physiol, October 1, 2001; 281(4): H1637 - H1647. [Abstract] [Full Text] [PDF]

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				R. Beery, M. Haimsohn, N. Wertheim, R. Hemi, U. Nir, A. Karasik, H. Kanety, and A. Geier Activation of the Insulin-Like Growth Factor 1 Signaling Pathway by the Antiapoptotic Agents Aurintricarboxylic Acid and Evans Blue Endocrinology, July 1, 2001; 142(7): 3098 - 3107. [Abstract] [Full Text] [PDF]

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				K. Yamashita, J. Kajstura, D. J. Discher, B. J. Wasserlauf, N. H. Bishopric, P. Anversa, and K. A. Webster Reperfusion-Activated Akt Kinase Prevents Apoptosis in Transgenic Mouse Hearts Overexpressing Insulin-Like Growth Factor-1 Circ. Res., March 30, 2001; 88(6): 609 - 614. [Abstract] [Full Text] [PDF]

				S. Adachi, H. Ito, M. Tamamori-Adachi, Y. Ono, T. Nozato, S. Abe, M.-a. Ikeda, F. Marumo, and M. Hiroe Cyclin A/cdk2 Activation Is Involved in Hypoxia-Induced Apoptosis in Cardiomyocytes Circ. Res., March 2, 2001; 88(4): 408 - 414. [Abstract] [Full Text] [PDF]

				T. Yamamura, H. Otani, Y. Nakao, R. Hattori, M. Osako, and H. Imamura IGF-I differentially regulates Bcl-xL and Bax and confers myocardial protection in the rat heart Am J Physiol Heart Circ Physiol, March 1, 2001; 280(3): H1191 - H1200. [Abstract] [Full Text] [PDF]

				S. Negoro, H. Oh, E. Tone, K. Kunisada, Y. Fujio, K. Walsh, T. Kishimoto, and K. Yamauchi-Takihara Glycoprotein 130 Regulates Cardiac Myocyte Survival in Doxorubicin-Induced Apoptosis Through Phosphatidylinositol 3-Kinase/Akt Phosphorylation and Bcl-xL/Caspase-3 Interaction Circulation, January 30, 2001; 103(4): 555 - 561. [Abstract] [Full Text] [PDF]

				Y. Wen, J. Gu, Y. Liu, P. H. Wang, Y. Sun, and J. L. Nadler Overexpression of 12-Lipoxygenase Causes Cardiac Fibroblast Cell Growth Circ. Res., January 19, 2001; 88(1): 70 - 76. [Abstract] [Full Text] [PDF]

				R. Aikawa, M. Nawano, Y. Gu, H. Katagiri, T. Asano, W. Zhu, R. Nagai, and I. Komuro Insulin Prevents Cardiomyocytes From Oxidative Stress-Induced Apoptosis Through Activation of PI3 Kinase/Akt Circulation, December 5, 2000; 102(23): 2873 - 2879. [Abstract] [Full Text] [PDF]

				J. He, Y. Xiao, C. A. Casiano, and L. Zhang Role of Mitochondrial Cytochrome c in Cocaine-Induced Apoptosis in Coronary Artery Endothelial Cells J. Pharmacol. Exp. Ther., December 1, 2000; 295(3): 896 - 903. [Abstract] [Full Text]

				T. E. McDonald, M. N. Grinman, C. M. Carthy, and K. R. Walley Endotoxin infusion in rats induces apoptotic and survival pathways in hearts Am J Physiol Heart Circ Physiol, November 1, 2000; 279(5): H2053 - H2061. [Abstract] [Full Text] [PDF]

				C Berry and A.L Clark Catabolism in chronic heart failure Eur. Heart J., April 1, 2000; 21(7): 521 - 532. [PDF]

				A. Haunstetter and S. Izumo Toward Antiapoptosis as a New Treatment Modality Circ. Res., March 3, 2000; 86(4): 371 - 376. [Full Text] [PDF]

				S. R. Adderley and D. J. Fitzgerald Glycoprotein IIb/IIIa Antagonists Induce Apoptosis in Rat Cardiomyocytes by Caspase-3 Activation J. Biol. Chem., February 25, 2000; 275(8): 5760 - 5766. [Abstract] [Full Text] [PDF]

				L. J. De Windt, H. W. Lim, T. Taigen, D. Wencker, G. Condorelli, G. W. Dorn II, R. N. Kitsis, and J. D. Molkentin Calcineurin-Mediated Hypertrophy Protects Cardiomyocytes From Apoptosis In Vitro and In Vivo : An Apoptosis-Independent Model of Dilated Heart Failure Circ. Res., February 18, 2000; 86(3): 255 - 263. [Abstract] [Full Text] [PDF]

				Y. Fujio, T. Nguyen, D. Wencker, R. N. Kitsis, and K. Walsh Akt Promotes Survival of Cardiomyocytes In Vitro and Protects Against Ischemia-Reperfusion Injury in Mouse Heart Circulation, February 15, 2000; 101(6): 660 - 667. [Abstract] [Full Text] [PDF]

				G. Z. Feuerstein and P. R. Young Apoptosis in cardiac diseases: stress- and mitogen-activated signaling pathways Cardiovasc Res, February 1, 2000; 45(3): 560 - 569. [Abstract] [Full Text] [PDF]

				H. Yaoita, K. Ogawa, K. Maehara, and Y. Maruyama Apoptosis in relevant clinical situations: contribution of apoptosis in myocardial infarction Cardiovasc Res, February 1, 2000; 45(3): 630 - 641. [Abstract] [Full Text] [PDF]

				A. Haunstetter and S. Izumo Future perspectives and potential implications of cardiac myocyte apoptosis Cardiovasc Res, February 1, 2000; 45(3): 795 - 801. [Abstract] [Full Text] [PDF]

				Y. Xiao, J. He, R. D. Gilbert, and L. Zhang Cocaine Induces Apoptosis in Fetal Myocardial Cells through a Mitochondria-Dependent Pathway J. Pharmacol. Exp. Ther., January 1, 2000; 292(1): 8 - 14. [Abstract] [Full Text]

				T. Matsui, L. Li, F. del Monte, Y. Fukui, T. F. Franke, R. J. Hajjar, and A. Rosenzweig Adenoviral Gene Transfer of Activated Phosphatidylinositol 3'-Kinase and Akt Inhibits Apoptosis of Hypoxic Cardiomyocytes In Vitro Circulation, December 7, 1999; 100(23): 2373 - 2379. [Abstract] [Full Text] [PDF]

				M. C. DELAUGHTER, G. E. TAFFET, M. L. FIOROTTO, M. L. ENTMAN, and R. J. SCHWARTZ Local insulin-like growth factor I expression induces physiologic, then pathologic, cardiac hypertrophy in transgenic mice FASEB J, November 1, 1999; 13(14): 1923 - 1929. [Abstract] [Full Text]

				M. Brink, J. Chrast, S. R. Price, W. E. Mitch, and P. Delafontaine Angiotensin II Stimulates Gene Expression of Cardiac Insulin-Like Growth Factor I and Its Receptor Through Effects on Blood Pressure and Food Intake Hypertension, November 1, 1999; 34(5): 1053 - 1059. [Abstract] [Full Text] [PDF]

				W.-L. Lee, J.-W. Chen, C.-T. Ting, T. Ishiwata, S.-J. Lin, M. Korc, and P. H. Wang Insulin-Like Growth Factor I Improves Cardiovascular Function and Suppresses Apoptosis of Cardiomyocytes in Dilated Cardiomyopathy Endocrinology, October 1, 1999; 140(10): 4831 - 4840. [Abstract] [Full Text]

				N. ANDRIEU-ABADIE, J.-P. JAFFRÉZOU, S. HATEM, G. LAURENT, T. LEVADE, and J.-J. MERCADIER L-carnitine prevents doxorubicin-induced apoptosis of cardiac myocytes: role of inhibition of ceramide generation FASEB J, September 1, 1999; 13(12): 1501 - 1510. [Abstract] [Full Text]

				E. Delpy, S. N Hatem, N. Andrieu, C. de Vaumas, M. Henaff, C. Rucker-Martin, J.-P. Jaffrezou, G. Laurent, T. Levade, and J.-J. Mercadier Doxorubicin induces slow ceramide accumulation and late apoptosis in cultured adult rat ventricular myocytes Cardiovasc Res, August 1, 1999; 43(2): 398 - 407. [Abstract] [Full Text] [PDF]

				R. von Harsdorf, L. Hauck, F. Mehrhof, U. Wegenka, M. C. Cardoso, and R. Dietz E2F-1 Overexpression in Cardiomyocytes Induces Downregulation of p21CIP1 and p27KIP1 and Release of Active Cyclin-Dependent Kinases in the Presence of Insulin-Like Growth Factor I Circ. Res., July 23, 1999; 85(2): 128 - 136. [Abstract] [Full Text] [PDF]

				W. Wu, W.-L. Lee, Y. Y. Wu, D. Chen, T.-J. Liu, A. Jang, P. M. Sharma, and P. H. Wang Expression of Constitutively Active Phosphatidylinositol 3-Kinase Inhibits Activation of Caspase 3 and Apoptosis of Cardiac Muscle Cells J. Biol. Chem., December 15, 2000; 275(51): 40113 - 40119. [Abstract] [Full Text] [PDF]

				D. Camper-Kirby, S. Welch, A. Walker, I. Shiraishi, K. D. R. Setchell, E. Schaefer, J. Kajstura, P. Anversa, and M. A. Sussman Myocardial Akt Activation and Gender : Increased Nuclear Activity in Females Versus Males Circ. Res., May 25, 2001; 88(10): 1020 - 1027. [Abstract] [Full Text] [PDF]

				T.-j. Liu, H.-c. Lai, W. Wu, S. Chinn, and P. H. Wang Developing a Strategy to Define the Effects of Insulin-Like Growth Factor-1 on Gene Expression Profile in Cardiomyocytes Circ. Res., June 22, 2001; 88(12): 1231 - 1238. [Abstract] [Full Text] [PDF]