Summary
Diabetes mellitus is the most common disease in Westernized countries in large part because of the rising prevalence of obesity and physical inactivity. In addition, diabetes mellitus is an important risk factor for both heart failure and ischemic heart disease. As insulin resistance is known as an important pathophysiological feature in the cardiac diseases, understanding the mechanisms responsible for altered metabolism and insulin signaling in the diabetic heart may help identify novel targets in these conditions. Phosphatidylinositol (PI)-3 kinase (PI3K) and Akt are key signaling molecules in insulin and insulin-like growth factor-1 (IGF-1), which induce multiple biological effects in the heart such as cell survival and hypertrophy. Here, we have shown several fundamental techniques to study the role of PI3K and Akt in heart diseases.
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References
Kessler, A., Uphues, I., Ouwens, D.M., Till, M., and Eckel, J. (2001) Diversification of cardiac insulin signaling involves the p85 alpha/beta subunits of phosphatidylinositol 3-kinase. Am. J. Physiol. Endocrinol. Metab. 280, E65–74.
Poornima, I.G., Parikh, P., and Shannon, R.P. (2006) Diabetic cardiomyopathy: the search for a unifying hypothesis. Circ. Res. 98, 596–605.
Shioi, T., Kang, P.M., Douglas, P.S., Hampe, J., Yballe, C.M., Lawitts, J., Cantley, L.C., and Izumo, S. (2000). The conserved phosphoinositide 3-kinase pathway determines heart size in mice. EMBO J. 19, 2537–2548.
Shioi, T., McMullen, J.R., Kang, P.M., Douglas, P.S., Obata, T., Franke, T.F., Cantley, L.C., and Izumo, S. (2002) Akt/Protein kinase B promotes organ growth in transgenic mice. Mol. Cell. Biol. 22, 2799–2809.
Matsui, T., Li, L., Wu, J.C., Cook, S.A., Nagoshi, T., Picard, M.H., Liao, R., and Rosenzweig, A. (2002) Phenotypic spectrum caused by transgenic overexpression of activated Akt in the heart. J. Biol. Chem. 277, 22896–22901.
Condorelli, G., Drusco, A., Stassi, G., Bellacosa, A., Roncarati, R., Iaccarino, G., Russo, M.A., Gu, Y., Dalton, N., Chung, C., et al. (2002) Akt induces enhanced myocardial contractility and cell size in vivo in transgenic mice. Proc. Natl. Acad. Sci. U. S. A. 99, 12333–12338.
Matsui, T., Li, L., del Monte, F., Fukui, Y., Franke, T.F., Hajjar, R.J., and Rosenzweig, A. (1999) Adenoviral gene transfer of activated phosphatidylinositol 3′-kinase and Akt inhibits apoptosis of hypoxic cardiomyocytes in vitro. Circulation 100, 2373–2379.
Fujio, Y., Nguyen, T., Wencker, D., Kitsis, R.N., and Walsh, K. (2000) Akt promotes survival of cardiomyocytes in vitro and protects against ischemia-reperfusion injury in mouse heart. Circulation 101, 660–667.
Matsui, T., Tao, J., del Monte, F., Lee, K.H., Li, L., Picard, M., Force, T.L., Franke, T.F., Hajjar, R.J., and Rosenzweig, A. (2001) Akt activation preserves cardiac function and prevents injury after transient cardiac ischemia in vivo. Circulation 104, 330–335.
Yoon, Y.S., Lee, N., and Scadova, H. (2005) Myocardial regeneration with bone-marrow-derived stem cells. Biol. Cell 97, 253–263.
Rosenzweig, A. (2006) Cardiac cell therapy–mixed results from mixed cells. N. Engl. J. Med. 355, 1274–1277.
Narula, J., Haider, N., Virmani, R., DiSalvo, T.G., Kolodgie, F.D., Hajjar, R.J., Schmidt, U., Semigran, M.J., Dec, G.W., and Khaw, B.A. (1996) Apoptosis in myocytes in end-stage heart failure. N. Engl. J. Med. 335, 1182–1189.
Mallat, Z., Tedgui, A., Fontaliran, F., Frank, R., Durigon, M., and Fontaine, G. (1996) Evidence of apoptosis in arrhythmogenic right ventricular dysplasia. N. Engl. J. Med. 335, 1190–1196.
Vazquez-Jimenez, J.F., Qing, M., Hermanns, B., Klosterhalfen, B., Woltje, M., Chakupurakal, R., Schumacher, K., Messmer, B.J., von Bernuth, G., and Seghaye, M.C. (2001) Moderate hypothermia during cardiopulmonary bypass reduces myocardial cell damage and myocardial cell death related to cardiac surgery. J. Am. Coll. Cardiol. 38, 1216–1223.
Narula, J., Pandey, P., Arbustini, E., Haider, N., Narula, N., Kolodgie, F.D., Dal Bello, B., Semigran, M.J., Bielsa-Masdeu, A., Dec, G.W., et al. 1999. Apoptosis in heart failure: release of cytochrome c from mitochondria and activation of caspase-3 in human cardiomyopathy. Proc. Natl. Acad. Sci. U. S. A. 96, 8144–8149.
Abbate, A., Bussani, R., Biondi-Zoccai, G.G., Rossiello, R., Silvestri, F., Baldi, F., Biasucci, L.M., and Baldi, A. (2002) Persistent infarct-related artery occlusion is associated with an increased myocardial apoptosis at postmortem examination in humans late after an acute myocardial infarction. Circulation 106, 1051–1054.
Frustaci, A., Kajstura, J., Chimenti, C., Jakoniuk, I., Leri, A., PINTOMaseri, A., Nadal-Ginard, B., and Anversa, P. (2000) Myocardial cell death in human diabetes. Circ. Res. 87, 1123–1132.
Nagoshi, T., Matsui, T., Aoyama, T., Leri, A., Anversa, P., Li, L., Ogawa, W., del Monte, F., Gwathmey, J.K., Grazette, L., et al. (2005) PI3K rescues the detrimental effects of chronic Akt activation in the heart during ischemia/reperfusion injury. J. Clin. Invest. 115, 2128–2138.
Shiojima, I., Sato, K., Izumiya, Y., Schiekofer, S., Ito, M., Liao, R., Colucci, W.S., and Walsh, K. (2005) Disruption of coordinated cardiac hypertrophy and angiogenesis contributes to the transition to heart failure. J. Clin. Invest. 115, 2108–2118.
Matsui, T., Nagoshi, T., Hong, E.G., Luptak, I., Hartil, K., Li, L., Gorovits, N., Charron, M.J., Kim, J.K., Tian, R., et al. (2006) Effects of chronic Akt activation on glucose uptake in the heart. Am. J. Physiol. Endocrinol. Metab. 290, E789–797.
Fruman, D.A., Meyers, R.E., and Cantley, L.C. (1998) Phosphoinositide kinases. Annu. Rev. Biochem. 67, 481–507.
Kobayashi, M., Nagata, S., Kita, Y., Nakatsu, N., Ihara, S., Kaibuchi, K., Kuroda, S., Ui, M., Iba, H., Konishi, H., et al. (1997) Expression of a constitutively active phosphatidylinositol 3-kinase induces process formation in rat PC12 cells. Use of Cre/loxP recombination system. J. Biol. Chem. 272, 16089–16092.
Acknowledgments
This work was supported in part by NIH HL04250 to T. Matsui and NIH R01 HL66895 and American Diabetes Association Research Award 7-04-RA-23 to A. J. Davidoff. The authors thank Dr. Kenta Hara for his helpful advice.
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Matsui, T., Davidoff, A.J. (2007). Assessment of PI-3 Kinase and Akt in Ischemic Heart Diseases in Diabetes. In: Sreejayan, N., Ren, J. (eds) Vascular Biology Protocols. Methods in Molecular Medicine™, vol 139. Humana Press. https://doi.org/10.1007/978-1-59745-571-8_22
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DOI: https://doi.org/10.1007/978-1-59745-571-8_22
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