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15. Abstract

Author

Snider, Douglas D., Finucane, Brendan T., Clarke, Donna, Loiselle, J., Doak, G., Anderson, B., Wood, Dan, Shysh, Sandy, Perrault, Michel-Antoine, Chouinard, Philippe, Fugère, François, Girard, François, Ruel, Monique, Hall, Wendy C. E., Hrazdil, Jiri, Jolly, Donald T., Galbraith, John C., Greacen, Maria C., Clanachan, Alexander S., Wijeysundera, Duminda N., Beattie, W. Scott, Chochinov, Michelle, Halpern, Stephen, McKeen, Dolores M., Nunn, Robert T., Barrett, Brendan S., Finley, G. Allen, Buffett-Jerrott, Susan, Stewart, Sherry, Millington, Donna, Karkouti, Keyvan, Rampersaud, Yoga R., McCluskey, Stuart A., Evans, Lucia, Ghannam, Mohammed M., Mahomed, Nizar N., Singh, Sudha, Morley-Forster, Patricia, Shamsah, Mohammed, Thomson, Ian R., Brown, Aaron D., Freedman, Jeffrey I., Hudson, Robert J., Hong, Murray, Hall, Sean, Milne, Brian, Wang, Louie, Loomis, Chris, Gilron, Ian, Tod, Debbie, Bell, Allan, Orr, Elizabeth, Dobson, Gary, Karamanoglu, Mustafa, Tyberg, John V., Chung, Frances, Imarengiaye, Charles, Rocchi, Angela, Forte, Lindy, Van Den Kerkhof, Elizabeth G., Goldstein, David H., Rimmer, Mike, Lee, Hoi Kwan, Charest, Isabelle, Martin, René, Plante, François, Shaikh, Shaheen, Yung, Damian, Bernstein, Mark, Imasogie, Ngozi, Wong, David, Luk, Ken, Yogendran, Suntheralingam, Prabhu, Atul, Hendy, Ayman, McGuire, Glenn, Wong, Jean, Daley, M. Denise, Norman, Peter H., Srejic, Una, Dougherty, Thomas, Hogervorst, Sarah, Hemmerling, Thomas M., Schmidt, Joachim, Beaulieu, Pierre, Jacobi, Klaus E., Lennox, Pamela H., Mayson, Kelly V., Arai, Toshimi, Saito, Kaori, Yamashita, Masao, Gauthier, Alain, Boudreault, Daniel, Girard, Dominique C., Wang, Louie T. S., Sikich, Nancy, Petroz, Guy, Lerman, Jerrold, Hare, Gregory M. T., Baker, Andrew J., Hum, Kathryn M., Kim, Steve Y., Barr, Aiala, Mazer, C. David, Yemen, Terrance A., Howlett, Thomas, Baker, Andrew, Phan, Nicholas, Persaud, N., Zhao, Min, Liu, Elaine, Fehlings, Michael, Withington, Davinia E., AlAyed, T., Davis, G. Michael, Ansley, David M., Dhaliwal, B. S., Xia, Zhengyuan, Ho, Anthony M. -H., Lee, Anna, Ling, Elizabeth, Daly, Alan, Teoh, Kevin, Warkentin, Theodore E., Godin, David V., Chang, Thomas K. H., Fortier, Joanne D., Basile, Fadi, Prieto, Ignacio, Mazer, David, Duke, Peter, Finegan, Barry, Cheng, Davy, Hall, Richard, Lim, B., Shannon, J., Ho, C. M., Tsai, S. K., Srebrnjak, Margaret, Walsh, Vivien, Joseph, Geena, Gomez, Teresa Valois, Fuenmayor, Carmen Rivero, Bach, Paul S., Kamani, Allaudin, Douglas, Joanne, Esler, Mark, Gunka, Vit, Angle, Pamela, Tang, Sam, Thompson, Dorothy, Kronberg, Jean, Morgan, Anwar, Leicht, Craig H., Velickovic, Ivan A., Raphael, David T., Benbassat, Maxim, Arnaudov, Dimiter, Bohorquez, Alex, Nasseri, Bita, Doyle, D. John, Kolman, Jacelyn, Keith, Ian, Morgan, Pamela J., Cleave-Hogg, Doreen, Eveleigh, Susan, Tarshis, Jordan, Davies, Sharon, Doyle, John, Loughlin, Heather Lee, O’Connor, J. Patrick, Dolman, John F., Mikelberg, Fred S., Dulovic, Gordana, Feagan, Brian G., Wong, Cindy J., Kirkley, Alexandra, Johnston, D. W. C., Smith, Frank C., Whitsitt, Paul, Shanl, William Li Pi, Backman, Steven B., Barkun, Jeffrey, Metrakos, Peter, Tchervenkov, John, Salpeter, Mary Jane, Jamnicky, Leah, Jewett, Michael, Arellano, Ramiro, Muirhead, Brian, Rashiq, Saifundin, Shah, Meera, Wilkinson, Vikki, Woolsey, Samantha J., Finegan, Barry A., Fiorilli, Carol, Parlow, Joel L., Avery, Nicole D., Dhaliwal, B. S., Djaiani, George N., Muhkerji, Jayanta, Karski, Jacek M., Carroll, Jo A., McCluskey, Stuart, Harris, Linda, Paton, Jan, Kanetos, Emmanuel, Williams, William G., Kerkhof, Elizabeth G. Van Den, Milne, Brian, Beattie, W. Scott, Hurtado, Cristina, Finegan, Barry A., Gandhi, Manoj, Clanachan, Sandy, Shin, Woo Jong, Winegar, Bruce, D., Shim, Jae Hang, Jeon, Woo Jae, Kim, Kyung Hun, Wang, Bing, Archer, David P., Samanani, Naaznin, Roth, Sheldon H., Coimbra, Claudia, Choinière, Manon, Babin, Denis, Donati, Francois, Lennox, Pamela H., Henderson, Cynthia L., Friesen, John H. P., Jacka, Michael, Cheng, Alan, McAlister, Finlay, Leak, Jessie A., Bui, Tao, Nguyen, Dy, Kowalski, Alicia, Popat, Keruyi, Kuerer, Henry, Serowka, Paul, Turner, Kim, Milne, Brian, Ashbury, Ted, Wang, Tianlong, El-Kebir, Driss, Hubert, Bernard, Veldhuizen, Ruud A. W., Gauvin, Dominique, Blaise, Gilbert, Yang, Fan, and Amicone, Patricia

Published
2002
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19. Abstracts

Author

Hurtado, Cristina, Bradley, John, Burns, Andrew R., Bradley, John, Karkouti, Keyvan, Hurtado, Cristina, Burns, Andrew R., Bradley, John, Anderson, Rob, Abrahamson, Simon D., Mazer, C. David, Hung, O. R., Comeau, L., Fisher, Joseph A., Tessler, Janet, Rucker, Joshua, Mathicu, Alix, Murray-Foster, Sara, Tz-Chong Chou, Chi-Yuan Li, Tsuda, Takako, Tabuchi, Akihiko, Sasano, Hiroshi, Kiriyama, Masanobu, Okada, Akinori, Hayano, Junichiro, Takeuchi, Akinori, Katsuya, Hirotada, Tousignant, Claude P., Mazer, C. David, Tousignant, Claude P., Mazer, C. David, Ling, Elizabeth, Arellano, Ramiro, Dowd, N., Karski, J., Cheng, D., Carroll-Munro, J., Rose, D. K., Mazer, C. O., Cohen, M. M., Wigglesworth, D., McKay, William P. S., Teskey, Robert J., Militzer, Julio, Kember, Guy, Blanchet, Travis, Gregson, Peter H., Howells, Steven R., Robblee, James A., Breen, Terrance W., Dierenfield, Laura, McNeil, Tacie, Breen, Terrance W., McNeil, Tacie, Dierenfield, Laura, Nicholson, Donna J., Kowalski, Stephen E., Hamilton, G. Andrew, Meyers, Michael P., Serrette, Carl, Duke, Peter C., Custeau, Ingrid, Martin, Rend, Larabée, Sonia, Pirlet, Martine, Pilote, Madeleine, Tetrault, Jean-Pierre, Tsui, Ban C. H., Gupta, Sunil, Finucane, Brendan, Weisbrod, Mitchell J., Chan, Vincent W. S., Kaszas, Z., Dragomir, C., Cohen, M. R., Gandhi, M., Clanachan, A. S., Finegan, B. A., Isaac, Lisa, Splinter, William M., Hall, L. A., Gould, H. M., Rhine, E. J., Bergeron, Lyne, Girard, Michel, Drolet, Pierre, Truong, Hong Hanh Le, Boucher, Carl, Vézina, Daniel, Lessard, Martin R., Gourdeau, Marie, Trépanier, Claude A., Yang, Theresa, Breen, Terrance W., Macarthur, Alison, Chouinard, P., Fugère, F., Ruel, M., Tarkkila, Pekka, Silvasti, Marja, Tuominen, Marjatta, Svartling, Nils, Rosenberg, Per H., Bond, David M., Rudan, John F., Adams, Michael A., Tsang, Brian K., Keahey, Wanda, Gagliese, Lucia, Jackson, Marla, Ritvo, Paul, Wowk, Adarose, Sandler, Alan N., Katz, Joel, Laffey, J. G., Boylan, J. F., Badner, Neal H., Komar, Wendy E., Bond, David M., Cherry, R. A., Spadafora, S. M., Butler, R. J., McHardy, Fiona, Fortier, Joanne, Chung, Frances, Marshall, Scott, Krishnathas, Ananthan, Wong, Jean, Chung, Frances, Ritchie, Ewan, McHardy, Fiona, Marshall, Scott, Fortier, Joanne, Meikle, Andrew, Avery, Nicole, van Vlymen, Janet, Parlow, Joel L., Sinclair, David, Chung, Frances, Mezei, Gabor, Jin, Fengling, Chung, Frances, Norris, Andrew, Ganeshram, Tharini, MacLeod, Bernard A., Azmudéh, Aliréza, Franciosi, Luigi G., Ries, Craig R., Schwarz, Stephan K. W., McKay, William PS, Gregson, Peter H., McKay, Benjamin W. S., Blanchet, Travis, Meuret, Pascal, Bonhomme, Vincent, Plourde, Gilles, Fiset, Pierre, Backman, Stevens B., Vesely, Alex, Takeuchi, Akinori, Sommer, Leeor, Rucker, Joshua, Greenwald, Joel, Lavine, Elana, Iscoe, Steve, Volgyesi, George, Fedorko, Ludwik, Fisher, Joseph, Lobato, Emilio B., Sulek, Cheri A., Davies, Laurie K., Gearen, Peter F., Bellemare, François, Donati, François, Couture, Jacques, Joo, Hwan S., Rose, D. K., Kapoor, Sunil, Shayan, Shahriar, Karkouti, Keyvan, LeDez, Kenneth M., Au, Jim, Tucker, John H., Redmond, Edwin B., Gadag, V., Penney, Catherine, Hare, Gregory M. T., Lee, Timothy D. G., Hirsch, Gregory M., Yang, Fan, Troncy, Eric, Blaise, Gilbert, Naito, Yoshiyuki, Arisawa, Shoji, Ide, Masahiro, Nakano, Susumu, Yamazaki, Kazuo, Kawamura, Takae, Nara, Noriko, Wakusawa, Reiji, Inada, Katsuya, Hudson, Robert J., Singh, Karanbir, Harding, Gary A., Henderson, Blair T., Thomson, Ian R., Harding, Gary A., Hudson, Robert J., Thomson, Ian R., Thomson, Ian R., Singh, Karanbir, Hudson, Robert J., Wherrett, Christopher G., Miller, Donald R., Giachino, Alan A., Turek, Michelle A., Rody, Kelly, Vaghadia, H., Chan, V., Ganapathy, S., Lui, A., McKenna, J., Zimmer, K., Schwarz, Stephan K. W., MacLeod, Bernard A., Ries, Craig R., Franciosi, Luigi G., Regan, William D., Davidson, Ross G., Nevin, Krista, Escobedo, Sergio, Mitmaker, E., Tessler, M. J., Kardash, K., Kleiman, S. J., Rossignol, M., Kahn, L., Baxter, F., Dauphin, A., Goldsmith, C., Jackson, P., McChesney, J., Miller, J., Takeuchi, L., Young, E., Klubien, Kristine, Bandi, Edith, Carli, Franco, Dattilo, Kathleen, Tong, Doris, Bhandari, Mohit, Carli, Franco, Klubien, Kristine, Mazza, Louise, Wykes, Linda, Sommer, L. Z., Rucker, J., Veseley, A., Levene, E., Greenwald, Y., Volgyesi, G., Fedorko, L., Iscoe, S., Fisher, J. A., Tian, Guo-Feng, Baker, Andrew J., Reinders, F. X., Baker, A. J., Moulton, R. J., Brown, J. I. M., Schlichter, L., Troncy, Eric, Van Tulder, Laurence, Carignan, Stéphane, Prénovault, Julie, Collet, Jean-Paul, Shapiro, Stan, Guimond, Jean-Gilles, Blait, Louis, Ducruet, Thierry, Francœur, Martin, Charbonneau, Marc, Cousineau, Guy, Blaise, Gilbert, Wong, Daniel R., McCall, Michele, Walsh, Fergus, Kurian, Regina, Keith, Mary, Sole, Michael J., Jeejeebhoy, Kursheed N., Mazer, C. David, Whitten, E., Norman, P. H., Aucar, J. A., Coveler, L. A., Solgonick, Rodney M., Bastien, Y., Mazer, Bruce, Lihara, Koji, Orser, Beverley A., Tymianski, Michael, Finucane, Brendan T., Zaman, Nuzhat, Kashkari, Ibrahim, Tawfik, Soheir, Tarn, Yun K., Slinger, Peter D., McRae, Karen, Winton, Timothy, Sandier, Alan N., Zamora, J. E., Salpeter, Mary Jane, Bai, Donglin, MacDonald, John F., Orser, Beverley A., Mayson, Kelly, Gofton, Ed, Chambers, Keith, Belo, Susan E., Kay, J. Colin, Mazer, C. David, Hall, Sean R. R., Wang, Louie, Milne, Brian, Loomis, Chris, Tsang, Brian K., He, Zhi, Wougchanapai, Wichai, Ho, Ing K., Eichhorn, John H., Tsang, Brian K., Ma, Tangeng, Wongchanapai, Wichai, He, Zhi, Ho, Ing K., Eicnhorn, John H., Tsang, Brian K., Wongchanapai, Wichai, He, Zhi, Ho, Ing K., Eichhorn, John H., Murphy, Damian B., Murphy, M. B., Bonhomme, Vincent, Meuret, Pascal, Backman, Steven B., Plourde, Gilles, Fiset, Pierre, Stein, Reuben D., Backman, Steven B., Collier, Brian, Polosa, Canio, Li, Chi-Yuan, Chou, Tz-Chong, Wang, Jia-Yi, Fuller, John, Butler, Ronald, Spadafora, Salvatore, Donen, Neil, Brownell, Laurence, Donen, Neil, Brownell, Laurence, Shysh, Sandy, Carter, Keith, Eagle, Chris, Devito, Isabella, Halpern, Stephen, Devitt, J. Hugh, Yee, Doreen A., deLacy, John L., Oxorn, Donald C., Morris, Gary F., Yip, Raymond W., Gregoret-Quinn, M. G., Seal, R. F., Smith, LJ., Jones, A. B., Tang, C., Clanachan, A. S., Gallant, B. J., Nadwidny, L. A., Goresky, Gerald V., Cowtan, Tara, Bridge, Hilary S., Montgomery, Carolyne J., Kennedy, Ross A., Merrick, Pamela M., Yamashita, M., Wada, K., LeMay, Sylvie, Hardy, Jean-François, Morgan, Pamela, Halpern, Steven, Evers, Jana, Ronaldson, P., Rose, D. K., Dexter, F., Cohen, M. M., Wigglesworth, D., Writer, Desmond, Muir, Holly, Shukla, Romesh, Nunn, Rob, Scovil, John, Pridham, Jeremy, Rosaeg, Ola, Sandier, Allan, Morley-Foster, Patricia, Lucy, Simon, Crone, Lesley-Ann, Zimmer, Karen, Wilson, Deborah J., Heid, Robert, Douglas, M. Joanne, Rurak, Dan W., Fabrizi, Anna, Crochetière, Chantal T., Roy, Louise, Villeneuve, Edith, Lortie, Louise, Katsiris, Sandra, Leighton, Barbara, Halpern, Stephen, Wilson, Donna, Kronberg, Jean, Swica, Leszek, Midgley, Janet, Nunn, Robert, Muir, Holly, Shukla, Romesh, Smith, Bruce, Rooney, Michael E., Campbell, David C., Riben, Celina M., Crone, Lesley-Ann, Yip, Ray W., Halpern, Stephen, Halpern, Stephen, MacDonell, Jo, Levine, Tracey, and Wilson, Donna

Published
1998
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21. The mechanism of Intralipid®-mediated cardioprotection complex IV inhibition by the active metabolite, palmitoylcarnitine, generates reactive oxygen species and activates reperfusion injury salvage kinases.

Author

Phing-How Lou, Eliana Lucchinetti, Liyan Zhang, Andreas Affolter, Marcus C Schaub, Manoj Gandhi, Martin Hersberger, Blair E Warren, Hélène Lemieux, Hany F Sobhi, Alexander S Clanachan, and Michael Zaugg

Subjects
Medicine, Science
Abstract

Intralipid® administration at reperfusion elicits protection against myocardial ischemia-reperfusion injury. However, the underlying mechanisms are not fully understood.Sprague-Dawley rat hearts were exposed to 15 min of ischemia and 30 min of reperfusion in the absence or presence of Intralipid® 1% administered at the onset of reperfusion. In separate experiments, the reactive oxygen species (ROS) scavenger N-(2-mercaptopropionyl)-glycine was added either alone or with Intralipid®. Left ventricular work and activation of Akt, STAT3, and ERK1/2 were used to evaluate cardioprotection. ROS production was assessed by measuring the loss of aconitase activity and the release of hydrogen peroxide using Amplex Red. Electron transport chain complex activities and proton leak were measured by high-resolution respirometry in permeabilized cardiac fibers. Titration experiments using the fatty acid intermediates of Intralipid® palmitoyl-, oleoyl- and linoleoylcarnitine served to determine concentration-dependent inhibition of complex IV activity and mitochondrial ROS release.Intralipid® enhanced postischemic recovery and activated Akt and Erk1/2, effects that were abolished by the ROS scavenger N-(2-mercaptopropionyl)glycine. Palmitoylcarnitine and linoleoylcarnitine, but not oleoylcarnitine concentration-dependently inhibited complex IV. Only palmitoylcarnitine reached high tissue concentrations during early reperfusion and generated significant ROS by complex IV inhibition. Palmitoylcarnitine (1 µM), administered at reperfusion, also fully mimicked Intralipid®-mediated protection in an N-(2-mercaptopropionyl)-glycine -dependent manner.Our data describe a new mechanism of postconditioning cardioprotection by the clinically available fat emulsion, Intralipid®. Protection is elicited by the fatty acid intermediate palmitoylcarnitine, and involves inhibition of complex IV, an increase in ROS production and activation of the RISK pathway.

Published
2014
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22. Loss of Intralipid®- but not sevoflurane-mediated cardioprotection in early type-2 diabetic hearts of fructose-fed rats: importance of ROS signaling.

Author

Phing-How Lou, Eliana Lucchinetti, Liyan Zhang, Andreas Affolter, Manoj Gandhi, Martin Hersberger, Blair E Warren, Hélène Lemieux, Hany F Sobhi, Alexander S Clanachan, and Michael Zaugg

Subjects
Medicine, Science
Abstract

Insulin resistance and early type-2 diabetes are highly prevalent. However, it is unknown whether Intralipid® and sevoflurane protect the early diabetic heart against ischemia-reperfusion injury.Early type-2 diabetic hearts from Sprague-Dawley rats fed for 6 weeks with fructose were exposed to 15 min of ischemia and 30 min of reperfusion. Intralipid® (1%) was administered at the onset of reperfusion. Peri-ischemic sevoflurane (2 vol.-%) served as alternative protection strategy. Recovery of left ventricular function was recorded and the activation of Akt and ERK 1/2 was monitored. Mitochondrial function was assessed by high-resolution respirometry and mitochondrial ROS production was measured by Amplex Red and aconitase activity assays. Acylcarnitine tissue content was measured and concentration-response curves of complex IV inhibition by palmitoylcarnitine were obtained.Intralipid® did not exert protection in early diabetic hearts, while sevoflurane improved functional recovery. Sevoflurane protection was abolished by concomitant administration of the ROS scavenger N-2-mercaptopropionyl glycine. Sevoflurane, but not Intralipid® produced protective ROS during reperfusion, which activated Akt. Intralipid® failed to inhibit respiratory complex IV, while sevoflurane inhibited complex I. Early diabetic hearts exhibited reduced carnitine-palmitoyl-transferase-1 activity, but palmitoylcarnitine could not rescue protection and enhance postischemic functional recovery. Cardiac mitochondria from early diabetic rats exhibited an increased content of subunit IV-2 of respiratory complex IV and of uncoupling protein-3.Early type-2 diabetic hearts lose complex IV-mediated protection by Intralipid® potentially due to a switch in complex IV subunit expression and increased mitochondrial uncoupling, but are amenable to complex I-mediated sevoflurane protection.

Published
2014
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24. Suppression of 5'-AMP-activated protein kinase activity does not impair recovery of contractile function during reperfusion of ischemic hearts

Author

Folmes, Clifford D.L., Wagg, Cory S., Shen, Mei, Clanachan, Alexander S., Tian, Rong, and Lopaschuk, Gary D.

Subjects
Protein kinases -- Properties, Biological oxidation (Metabolism) -- Observations, Fatty acids -- Properties, Ischemia -- Diagnosis, Biological sciences
Abstract

Activation of 5'-AMP-activated protein kinase (AMPK) may benefit the heart during ischemia-reperfusion by increasing energy production. While AMPK stimulates glycolysis, mitochondrial oxidative metabolism is the major source of ATP production during reperfusion of ischemic hearts. Stimulating AMPK increases mitochondrial fatty acid oxidation, but this is usually accompanied by a decrease in glucose oxidation, which can impair the functional recovery of ischemic hearts. To examine the relationship between AMPK and cardiac energy substrate metabolism, we subjected isolated working mouse hearts expressing a dominant negative (DN) [[alpha].sub.2]-subunit of AMPK (AMPK-[[alpha].sub.2] DN) to 20 min of global no-flow ischemia and 40 min of reperfusion with Krebs-Henseleit solution containing 5 mM [U-[sup.14]C]glucose, 0.4 mM [9, 10-[sup.3]H]palmitate, and 100 [micro]U/ml insulin. AMPK-[[alpha].sub.2] DN hearts had reduced AMPK activity at the end of reperfusion (82 [+ or -] vs. 141 [+ or -] 7 pmol x [mg.sup.-1] x [min.sup.-1]) with no changes in high-energy phosphates. Despite this, AMPK-[[alpha].sub.2] DN hearts had improved recovery of function during reperfusion (14.9 [+ or -] 0.8 vs. 9.4 [+ or -] 1.4 beats x [min.sup.-1] x mmHg x [10.sup.-3]). During reperfusion, fatty acid oxidation provided 44.0 [+ or -] 2.8% of total acetyl-CoA in AMPK-[[alpha].sub.2] DN hearts compared with 55.0 [+ or -] 3.2% in control hearts. Since insulin can inhibit both AMPK activation and fatty acid oxidation, we also examined functional recovery in the absence of insulin. Functional recovery was similar in both groups despite a decrease in AMPK activity and a decreased reliance on fatty acid oxidation during reperfusion (66.4 [+ or -] 9.4% vs. 85.3 [+ or -] 4.3%). These data demonstrate that the suppression of cardiac AMPK activity does not produce an energetically compromised phenotype and does not impair, but may in fact improve, the recovery of function after ischemia. ischemia-reperfusion; fatty acid oxidation; glycolysis; glucose oxidation

Published
2009

25. Role of glucose metabolism in the recovery of postischemic LV mechanical function: effects of insulin and other metabolic modulators

Author

Gandhi, Manoj, Finegan, Barry A., and Clanachan, Alexander S.

Subjects
Glucose metabolism -- Influence, Reperfusion injury -- Physiological aspects, Heart -- Properties, Biological sciences
Abstract

The role of proton ([H.sup.+]) production from glucose metabolism in the recovery of myocardial function during postischemic reperfusion and its alteration by insulin and other metabolic modulators were examined. Rat hearts were perfused in vitro with Krebs-Henseleit solution containing palmitate (1.2 retool/l) and glucose (11 retool/l) under nonischemic conditions or during reperfusion following no-flow ischemia. Perfusate contained normal insulin (n-Ins, 50 mU/l), zero insulin (0-1ns), or supplemental insulin (s-Ins, 1,000 mU/l) or other metabolic modulators [dichloroacetate (DCA) at 3 retool/l, oxfenicine at 1 retool/l, and [N.sup.6]-cyclohexyladenosine (CHA) at 0.5 [micro]mol/1]. Relative to n-Ins, 0-Ins depressed rates of glycolysis and glucose oxidation in nonischemic hearts and impaired recovery of postischemic function. Relative to n-lns, s-Ins did not affect aerobic glucose metabolism and did not improve recovery when present during reperfusion. When present during ischemia and reperfusion, s-Ins impaired recovery. Combinations of metabolic modulators with s-Ins stimulated glucose oxidation ~2.5-fold in nonischemic hearts and reduced [H.sup.+] production. DCA and CHA, in combination with s-Ins, improved recovery of function, but addition of oxfenicine to this combination provided no further benefit. Although DCA and CHA were each partially protective in hearts perfused with n-Ins, optimal protection was achieved with DCA + CHA; recovery of function was inversely proportional to [H.sup.+] production during reperfusion. Although supplemental insulin is not beneficial, elimination of [H.sup.+] production from glucose metabolism by simultaneous inhibition of glycolysis and stimulation of glucose oxidation optimizes recovery of postischemic mechanical function. proton production; ischemia-reperfusion; contractile function; rat hearts

Published
2008

26. Ischemia-induced activation of AMPK does not increase glucose uptake in glycogen-replete isolated working rat hearts

Author

Omar, Mohamed A., Fraser, Heather, and Clanachan, Alexander S.

Subjects
Myocardial ischemia -- Physiological aspects, Glycogen -- Physiological aspects, Cyclic adenylic acid -- Physiological aspects, Protein kinases -- Physiological aspects, Glucose metabolism -- Evaluation, Glucose metabolism -- Health aspects, Biological sciences
Abstract

Alterations in myocardial glucose metabolism are a key determinant of ischemia-induced depression of left ventricular mechanical function. Since myocardial glycogen is an important source of endogenous glucose, we compared the effects of ischemia on glucose uptake and utilization in isolated working rat hearts in which glycogen content was either replete (G replete, 114 [micro]mol/g dry wt) or partially depleted (G depleted, 71 [micro]mol/g dry wt). The effects of low-flow ischemia (LFI, 0.5 ml/min) on glucose uptake, glycogen turnover (glycogenolysis and glycogen synthesis), glycolysis, adenosine 5'-monophosphate-activated protein kinase (AMPK) activity, and GLUT4 translocation were measured. Relative to preischemic values, LFI caused a time-dependent reduction in glycogen content in both G-replete and G-depleted groups due to an acceleration of glycogenolysis (by 12-fold and 6-fold, respectively). In G-replete hearts, LFI (15 min) decreased glucose uptake (by 59%) and did not affect GLUT4 translocation. In G-depleted hearts, LFI also decreased initially glucose uptake (by 90%) and glycogen synthesis, but after 15 min, when glycogenolysis slowed due to exhaustion of glycogen content, glucose uptake increased (by 31%) in association with an increase in GLUT4 translocation. After 60 min of LFI, glucose uptake, glycogenolysis, and glycolysis recovered to near-preischemic values in both groups. LFI increased AMPK activity in a time-dependent manner in both groups (by 6-fold and 4-fold, respectively). Thus, when glycogen stores are replete before ischemia, ischemia-induced AMPK activation is not sufficient to increase glucose uptake. Under these conditions, an acceleration of glycogen degradation provides sufficient endogenous substrate for glycolysis during ischemia. low-flow ischemia; glucose uptake; glycogen metabolism; glucose metabolism; adenosine-5'-monophosphate-activated protein kinase

Published
2008

27. Diabetic Rat Hearts Show More Favorable Metabolic Adaptation to Omegaven Containing High Amounts of n3 Fatty Acids Than Intralipid Containing n6 Fatty Acids

Author

Michael Zaugg, Alexander S. Clanachan, Eliana Lucchinetti, Phing-How Lou, Martin Hersberger, and University of Zurich

Subjects
Male, medicine.medical_specialty, Diabetic Cardiomyopathies, Dietary Sugars, medicine.medical_treatment, 610 Medicine & health, Fructose, Omegaven, Rats, Sprague-Dawley, 03 medical and health sciences, 0302 clinical medicine, Insulin resistance, Fish Oils, 030202 anesthesiology, Internal medicine, Medicine, Animals, Glycolysis, Myocytes, Cardiac, Glycogen synthase, Phospholipids, Triglycerides, chemistry.chemical_classification, biology, business.industry, Insulin, Albumin, Fatty acid, medicine.disease, Soybean Oil, Insulin receptor, Disease Models, Animal, Endocrinology, Anesthesiology and Pain Medicine, chemistry, 10036 Medical Clinic, biology.protein, Emulsions, Insulin Resistance, business, Energy Metabolism, Oxidation-Reduction, 030217 neurology & neurosurgery
Abstract

While Omegaven, an omega-3 (n3) fatty acid-based lipid emulsion, fosters insulin signaling in healthy hearts, it is unknown whether beneficial metabolic effects occur in insulin-resistant diabetic hearts.Diabetic hearts from fructose-fed Sprague-Dawley rats were perfused in the working mode for 90 minutes in the presence of 11 mM glucose and 1.2 mM palmitate bound to albumin, the first 30 minutes without insulin followed by 60 minutes with insulin (50 mU/L). Hearts were randomly allocated to Intralipid (25 and 100 µM), Omegaven (25 and 100 µM), or no emulsion (insulin alone) for 60 minutes. Glycolysis, glycogen synthesis, and glucose oxidation were measured with the radioactive tracers [5-H]glucose and [U-C]glucose. Central carbon metabolites, acyl-coenzyme A species (acyl-CoAs), ketoacids, purines, phosphocreatine, acylcarnitines, and acyl composition of phospholipids were measured with mass spectrometry.Diabetic hearts showed no response to insulin with regard to glycolytic flux, consistent with insulin resistance. Addition of either lipid emulsion did not alter this response but unexpectedly increased glucose oxidation (ratio of treatment/baseline, ie, fold change): no insulin 1.3 (0.3) [mean (standard deviation)], insulin alone 1.4 (0.4), insulin + 25 µM Intralipid 1.8 (0.5), insulin + 100 µM Intralipid 2.2 (0.4), P.001; no insulin 1.3 (0.3), insulin alone 1.4 (0.4), insulin + 25 µM Omegaven 2.3 (0.5) insulin + 100 µM Omegaven 1.9 (0.4), P.001. Intralipid treatment led to accumulation of acylcarnitines as a result of the released linoleic acid (C18:2-n6) and enhanced its integration into phospholipids, consistent with incomplete or impaired β-oxidation necessitating a compensatory increase in glucose oxidation. Accumulation of acylcarnitines was also associated with a higher nicotinamide adenine dinucleotide reduced/oxidized (NADH/NAD) ratio, which inhibited pyruvate dehydrogenase (PDH), and resulted in excess lactate production. In contrast, Omegaven-treated hearts showed no acylcarnitine accumulation, low malonyl-CoA concentrations consistent with activated β-oxidation, and elevated PDH activity and glucose oxidation, together indicative of a higher metabolic rate possibly by substrate cycling.Omegaven is the preferred lipid emulsion for insulin-resistant diabetic hearts.

Published
2020

28. Inhibition of p38 MAPK and AMPK restores adenosine-induced cardioprotection in hearts stressed by antecedent ischemia by altering glucose utilization

Author

Jaswal, Jagdip S., Gandhi, Manoj, Finegan, Barry A., Dyck, Jason R.B., and Clanachan, Alexander S.

Subjects
Protein kinases -- Properties, Glucose metabolism -- Evaluation, Ischemia -- Physiological aspects, Heart -- Physiological aspects, Biological sciences
Abstract

p38 mitugen-activated protein kinase (MAPK) and 5'-AMP-activated protein kinase (AMPK) are activated by metabolic stresses and are implicated in the regulation of glucose utilization and ischemia-reperfusion (IR) injury. This study tested the hypothesis that inhibition of p38 MAPK restores the cardioprotective effects of adenosine in stressed hearts by preventing activation of AMPK and the uncoupling of glycolysis from glucose oxidation. Working rat hearts were perfused with Krebs solution (1.2 mM palmitate, 11 mM [[sup.3]H/[sup.14]C]glucose, and 100 mU/l insulin). Hearts were stressed by transient antecedent IR (2 X 10 rain I/5 min R) before severe IR (30 min I/30 min R). Hearts were treated with vehicle, p38 MAPK inhibitor (SB-202190, 10 [micro]M), adenosine (500 [micro]M), or their combination before severe IR. After severe IR, the phosphorylation (arbitrary density units) of p38 MAPK and AMPK, rates of glucose metabolism ([micro]mol*g dry [wt.sup.-1]*[min.sup.-1), and recovery of left ventricular (LV) work (Joules) were similar in vehicle-, SB-202190- and adenosine-treated hearts. Treatment with SB202190 + adenosine versus adenosine alone decreased p38 MAPK (0.03 [+ or -] 0.01, n = 3 vs. 0.48 [+ or -] 0.10, n = 3, P < 0.05) and AMPK (0.00 [+ or -] 0.00, n = 3 vs. 0.26 [+ or -] 0.08, n = 3 P < 0.05) phosphorylation. This was accompanied by attenuated rates of glycolysis (1.51 [+ or -] 0.40, n = 7 vs. 3.95 [+ or -] 0.65, n = 7, P < 0.05) and [H.sup.+] production (2.12 [+ or -] 0.76, n = 7 vs. 6.96 [+ or -] 1.48, n = 7, P < 0.05), and increased glycogen synthesis (1.91 [+ or -] 0.25, n = 6 vs. 0.27 [+ or -] 0.28, n = 6, P < 0.05) and improved recovery of LV work (0.81 [+ or -] 0.08, n = 7 vs. 0.30 [+ or -] 0.15, n = 8, P < 0.05). These data indicate that inhibition of p38 MAPK abolishes subsequent phosphorylation of AMPK and improves the coupling of glucose metabolism, thereby restoring adenosine-induced cardioprotection. p38 mitogen-activated protein kinase; 5'-adenosine monophosphateactivated protein kinase; glucose metabolism

Published
2007

29. p38 mitogen-activated protein kinase mediates adenosine-induced alterations in myocardial glucose utilization via 5'-AMP-activated protein kinase

Author

Jaswal, Jagdip S., Gandhi, Manoj, Finegan, Barry A., Dyck, Jason R.B., and Clanachan, Alexander S.

Subjects
Adenosine -- Physiological aspects, Adenosine -- Research, Protein kinases -- Research, Glycogen -- Synthesis, Glycogen -- Research, Biological sciences
Abstract

Adenosineinduced acceleration of glycolysis in hearts stressed by transient ischemia is accompanied by suppression of glycogen synthesis and by increases in activity of adenosine 5'-monophosphate-activated protein kinase (AMPK). Because p38 mitogen-activated protein kinase (MAPK) may regulate glucose metabolism and may be activated downstream of AMPK, this study determined the effects of the p38 MAPK inhibitors SB202190 and SB203580 on adenosine-induced alterations in glucose utilization and AMPK activity. Studies were performed in working rat hearts perfused aerobically following stressing by transient ischemia (2 x 10-min ischemia followed by 5-min reperfusion). Phosphorylation of AMPK and p38 MAPK each were increased fourfold by adenosine, and these effects were inhibited by either SB202190 or SB203580. Neither of these inhibitors directly affected AMPK activity. Attenuation of the adenosine-induced increase in AMPK and p38 MAPK phosphorylation by SB202190 and SB203580 occurred independently of any change in tissue ATP-to-AMP ratio and did not alter glucose uptake, but it was accompanied by an increase in glycogen synthesis and glycogen content and by inhibition of glycolysis and proton production. There was a significant inverse correlation between the rate of glycogen synthesis and AMPK activity and between AMPK activity and glycogen content. These data demonstrate that AMPK is likely downstream of p38 MAPK in mediating the effects of adenosine on glucose utilization in hearts stressed by transient ischemia. The ability of p38 MAPK inhibitors to relieve the inhibition of glycogen synthesis and to inhibit glycolysis and proton production suggests that these agents may restore adenosine -induced cardioprotection in stressed hearts. adenosine; adenosine 5'-monophosphate-activated protein kinase; glycogen metabolism

Published
2007

30. Differential Effects of Anesthetics and Opioid Receptor Activation on Cardioprotection Elicited by Reactive Oxygen Species–Mediated Postconditioning in Sprague-Dawley Rat Hearts

Author

Alexander S. Clanachan, Eliana Lucchinetti, Phing-How Lou, Michael Zaugg, and Manoj Gandhi

Subjects
Male, medicine.drug_class, Remifentanil, Ischemia, Myocardial Reperfusion Injury, 030204 cardiovascular system & hematology, Pharmacology, Sevoflurane, Rats, Sprague-Dawley, 03 medical and health sciences, 0302 clinical medicine, 030202 anesthesiology, Opioid receptor, Animals, Medicine, Ischemic Postconditioning, Propofol, chemistry.chemical_classification, Cardioprotection, Reactive oxygen species, business.industry, Heart, Isolated Heart Preparation, medicine.disease, Rats, Cardiovascular physiology, Analgesics, Opioid, Anesthesiology and Pain Medicine, chemistry, Anesthetics, Inhalation, Receptors, Opioid, Reactive Oxygen Species, business, Anesthetics, Intravenous, medicine.drug
Abstract

BACKGROUND Despite an array of cardioprotective interventions identified in preclinical models of ischemia-reperfusion (IR) injury, successful clinical translation has not been achieved. This study investigated whether drugs routinely used in clinical anesthesia influence cardioprotective effectiveness by reducing effects of reactive oxygen species (ROS), upstream triggers of cardioprotective signaling. Effects of propofol, sevoflurane, or remifentanil were compared on postischemic functional recovery induced by ROS-mediated postconditioning with Intralipid. METHODS Recovery of left ventricular (LV) work, an index of IR injury, was measured in isolated Sprague-Dawley rat hearts subjected to global ischemia (20 minutes) and reperfusion (30 minutes). Hearts were either untreated or were treated with postconditioning with Intralipid (1%, throughout reperfusion). Propofol (10 μM), sevoflurane (2 vol%), remifentanil (3 nM), or combinations thereof were administered peri-ischemically (before and during IR). The effects of anesthetics on ROS production were measured in LV cardiac fibers by Amplex Red assay under phosphorylating and nonphosphorylating conditions. RESULTS Recovery of LV work (expressed as percentage of the preischemic value ± standard deviation) in untreated hearts was poor (20% ± 7%) and was improved by Intralipid postconditioning (58% ± 8%, P = .001). In the absence of Intralipid postconditioning, recovery of LV work was enhanced by propofol (28% ± 9%, P = .049), sevoflurane (49% ± 5%, P < .001), and remifentanil (51% ± 6%, P < .001). The benefit of Intralipid postconditioning was abolished by propofol (33% ± 10%, P < .001), but enhanced by sevoflurane (80% ± 7%, P < .001) or remifentanil (80% ± 9%, P < .001). ROS signaling in LV fibers was abolished by propofol, but unaffected by sevoflurane or remifentanil. We conclude that propofol abolishes ROS-mediated Intralipid postconditioning by acting as a ROS scavenger. Sevoflurane and remifentanil are protective per se and provide additive cardioprotection to ROS-mediated cardioprotection. CONCLUSIONS These divergent effects of routinely used drugs in clinical anesthesia may influence the translatability of cardioprotective therapies such as Intralipid postconditioning.

Published
2018
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32. Effects of adenosine on myocardial glucose and palmitate metabolism after transient ischemia: role of 5'-AMP-activated protein kinase

Author

Jaswal, Jagdip S., Gandhi, Manoj, Finegan, Barry A., Dyck, Jason R.B., and Clanachan, Alexander S.

Subjects
Protein kinases -- Research, Cerebral ischemia -- Risk factors, Cerebral ischemia -- Physiological aspects, Cerebral ischemia -- Health aspects, Glucose metabolism -- Research, Biological sciences
Abstract

Loss of cardioprotection by adenosine in hearts stressed by transient ischemia may be due to its effects on glucose metabolism. In the absence of transient ischemia, adenosine inhibits glycolysis, whereas it accelerates glycolysis after transient ischemia. Inasmuch as 5'-AMP-activated protein kinase (AMPK) is implicated as a regulator of glucose and fatty acid utilization, this study determined whether a differential alteration of AMPK activity contributes to acceleration of glycolysis by adenosine in hearts stressed by transient ischemia. Studies were performed in working rat hearts perfused aerobically under normal conditions or after transient ischemia (two 10-min periods of ischemia followed by 5 min of reperfusion). LV work was not affected by adenosine. AMPK phosphorylation was not affected by transient ischemia; however, phosphorylation and activity were increased nine-and threefold, respectively, by adenosine in stressed hearts. Phosphorylation of acetyl-CoA carboxylase and rates of palmitate oxidation were unaltered. Glycolysis and calculated proton production were increased 1.8-and 1.7-fold, respectively, in hearts with elevated AMPK activity. Elevated AMPK activity was associated with inhibition of glycogen synthesis and unchanged rates of glucose uptake and glycogenolysis. Phentolamine, an [alpha]-adrenoceptor antagonist, which prevents adenosine-induced activation of glycolysis in stressed hearts, prevented AMPK phosphorylation. These data demonstrate that adenosine-induced activation of AMPK after transient ischemia is not sufficient to alter palmitate oxidation or glucose uptake. Rather, activation of AMPK alters partitioning of glucose away from glycogen synthesis; the increase in glycolysis may in part contribute to loss of adenosine-induced cardioprotection in hearts subjected to transient ischemia. glucose metabolism; glucose uptake; glycogen

Published
2006

39. Phosphorylation of cardiac protein kinase B is regulated by palmitate

Author

Soltys, Carrie-Lynn M., Buchholz, Lori, Gandhi, Manoj, Clanachan, Alexander S., Walsh, Kenneth, and Dyck, Jason R.B.

Subjects
Glucose metabolism -- Physiological aspects, Heart cells -- Physiological aspects, Protein kinases -- Physiological aspects, Phosphorylation -- Physiological aspects, Sphingolipids -- Physiological aspects, Biological sciences
Abstract

In this study isolated perfused working rat hearts were used to investigate the role of palmitate-regulated protein kinase B (PKB) phosphorylation on glucose metabolism. Rat hearts were perfused aerobically in working mode with 11 mM glucose and either 100 [micro]U/ml insulin or 100 [micro]U/ml insulin and 1.2 mM palmitate. PKB activity and phosphorylation state were reduced in the presence of 1.2 mM palmitate, which correlates with a decrease in glycolysis (47%), glucose oxidation (84%), and glucose uptake (43%). In contrast to skeletal muscle, neither p38 nor ERK underwent changes in their phosphorylation states in response to insulin or insulin and palmitate. Moreover, pharmacological restoration of glucose oxidation rates in hearts perfused with 1.2 mM palmitate demonstrated no increase in PKB phosphorylation state. In cultured mouse cardiac muscle HL-1 cells, insulin markedly increased PKB phosphorylation, which was blunted by pre- and cotreatment with 1.2 mM palmitate. However, neither palmitate nor [C.sub.2]-ceramide treatment of insulin-stimulated cells was able to accelerate PKB dephosphorylation beyond that observed following the removal of insulin alone. Taken together, these experiments show the control of PKB phosphorylation by palmitate is independent of ceramide and suggest that this signaling event may be an important regulator of myocardial glucose uptake and oxidation. insulin; glucose; ceramide; Akt, metabolism

Published
2002

44. Hearts lacking plasma membrane KATP channels display changes in basal aerobic metabolic substrate preference and AMPK activity

Author

Jason R.B. Dyck, Scott A. Campbell, Peter E. Light, Beth E. Hunter, Manoj Gandhi, Nermeen Youssef, Amy J. Barr, Alexander S. Clanachan, and Vernon W. Dolinsky

Subjects
0301 basic medicine, medicine.medical_specialty, Physiology, Substrate (chemistry), Biology, Cell biology, 03 medical and health sciences, Basal (phylogenetics), 030104 developmental biology, Endocrinology, Membrane, AMP-activated protein kinase, Katp channels, Physiology (medical), Internal medicine, biology.protein, medicine, Glycolysis, Cardiology and Cardiovascular Medicine, Protein kinase A, Beta oxidation
Abstract

Cardiac ATP-sensitive K+ (KATP) channels couple changes in cellular metabolism to membrane excitability and are activated during metabolic stress, although under basal aerobic conditions, KATP channels are thought to be predominately closed. Despite intense research into the roles of KATP channels during metabolic stress, their contribution to aerobic basal cardiac metabolism has not been previously investigated. Hearts from Kir6.2+/+ and Kir6.2−/− mice were perfused in working mode, and rates of glycolysis, fatty acid oxidation, and glucose oxidation were measured. Changes in activation/expression of proteins regulating metabolism were probed by Western blot analysis. Despite cardiac mechanical function and metabolic efficiency being similar in both groups, hearts from Kir6.2−/− mice displayed an approximately twofold increase in fatty acid oxidation and a 0.45-fold reduction in glycolytic rates but similar glucose oxidation rates compared with hearts from Kir6.2+/+ mice. Kir6.2−/− hearts also possessed elevated levels of activated AMP-activated protein kinase (AMPK), higher glycogen content, and reduced mitochondrial density. Moreover, activation of AMPK by isoproterenol or diazoxide was significantly blunted in Kir6.2−/− hearts. These data indicate that KATP channel ablation alters aerobic basal cardiac metabolism. The observed increase in fatty acid oxidation and decreased glycolysis before any metabolic insult may contribute to the poor recovery observed in Kir6.2−/− hearts in response to exercise or ischemia-reperfusion injury. Therefore, KATP channels may play an important role in the regulation of cardiac metabolism through AMPK signaling. NEW & NOTEWORTHY In this study, we show that genetic ablation of plasma membrane ATP-sensitive K+ channels results in pronounced changes in cardiac metabolic substrate preference and AMP-activated protein kinase activity. These results suggest that ATP-sensitive K+ channels may play a novel role in regulating metabolism in addition to their well-documented effects on ionic homeostasis during periods of stress.

Published
2017
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46. Lipid Emulsion Containing High Amounts of n3 Fatty Acids (Omegaven) as Opposed to n6 Fatty Acids (Intralipid) Preserves Insulin Signaling and Glucose Uptake in Perfused Rat Hearts

Author

Martin Hersberger, Eliana Lucchinetti, Michael Zaugg, Alexander S. Clanachan, Phing-How Lou, and University of Zurich

Subjects
Fat Emulsions, Intravenous, food.ingredient, Phosphofructokinase-2, Phosphofructokinase-1, Glucose uptake, 610 Medicine & health, Carbohydrate metabolism, Soybean oil, Rats, Sprague-Dawley, Omegaven, Fish Oils, food, Carnitine, Animals, Insulin, Myocyte, Medicine, Myocytes, Cardiac, Protein Phosphatase 2, Phosphorylation, Phospholipids, Triglycerides, biology, business.industry, NF-kappa B, Isolated Heart Preparation, Fish oil, Soybean Oil, Insulin receptor, Glucose, Anesthesiology and Pain Medicine, Biochemistry, 10036 Medical Clinic, biology.protein, Emulsions, 2703 Anesthesiology and Pain Medicine, Energy Metabolism, business, Oxidation-Reduction, Proto-Oncogene Proteins c-akt, Signal Transduction
Abstract

It is currently unknown whether acute exposure to n3 fatty acid-containing fish oil-based lipid emulsion Omegaven as opposed to the n6 fatty acid-containing soybean oil-based lipid emulsion Intralipid is more favorable in terms of insulin signaling and glucose uptake in the intact beating heart.Sprague-Dawley rat hearts were perfused in the working mode for 90 minutes in the presence of 11 mM glucose and 1.2 mM palmitate bound to albumin, the first 30 minutes without insulin followed by 60 minutes with insulin (50 mU/L). Hearts were randomly allocated to 100 µM Intralipid, 100 µM Omegaven, or no emulsion (insulin treatment alone) for 60 minutes. Glycolysis and glycogen synthesis were measured with the radioactive tracer [5-H]glucose, and glucose uptake was calculated. Phosphorylation of protein phosphatase 2A (PP2A), protein kinase Akt, and phosphofructokinase (PFK)-2 was measured by immunoblotting. Glycolytic metabolites were determined by enzymatic assays. Mass spectrometry was used to establish acylcarnitine profiles. Nuclear factor κB (NFκB) nuclear translocation served as reactive oxygen species (ROS) biosensor.Insulin-mediated glucose uptake was decreased by Intralipid (4.9 ± 0.4 vs 3.7 ± 0.3 μmol/gram dry heart weight [gdw]·min; P = .047) due to both reduced glycolysis and glycogen synthesis. In contrast, Omegaven treatment did not affect insulin-mediated glycolysis or glycogen synthesis and thus preserved glucose uptake (5.1 ± 0.3 vs 4.9 ± 0.4 μmol/gdw·min; P = .94). While Intralipid did not affect PP2A phosphorylation status, Omegaven resulted in significantly enhanced tyrosine phosphorylation and inhibition of PP2A. This was accompanied by increased selective threonine phosphorylation of Akt and the downstream target PFK-2 at S483. PFK-1 activity was increased when compared with Intralipid as measured by the ratio of fructose 1,6-bisphosphate to fructose 6-phosphate (Omegaven 0.60 ± 0.11 versus Intralipid 0.47 ± 0.09; P = .023), consistent with increased formation of fructose 2,6-bisphosphate by PFK2, its main allosteric activator. Omegaven lead to accumulation of acylcarnitines and fostered a prooxidant response as evidenced by NFκB nuclear translocation and activation.Omegaven as opposed to Intralipid preserves glucose uptake via the PP2A-Akt-PFK pathway in intact beating hearts. n3 fatty acids decelerate β-oxidation causing accumulation of acylcarnitine species and a prooxidant response, which likely inhibits redox-sensitive PP2A and thus preserves insulin signaling and glucose uptake.

Published
2020

47. Abstracts

Author

Kavanagh, Brian P., Ngo, Cuong, Raymer, Karen, Yang, Homer, Alhashemi, Jamal A., Lui, Anne C. P., Reid, Dennis, Cicutti, Nicholas, Krepski, Barbra, Wood, Gordon, Heyland, Daren K., Badner, Neal H., Murkin, John M., Mohr, Jim, McKenzie, F. Neil, van der Starre, Peter J. A., van Rooyen-Butijn, W. T., Wilson-Yang, Kristine, Teoh, Kevin, Lee, R. M. K. W., Hossain, Imtiaz, Cheng, Davy, Karski, Jacek, Asokumar, Buvanendran, Sandier, Alan, St-Amand, Marc A., Murkin, John M., Menkis, Alan H., Downey, Donal B., Nantau, William, Adams, Sandy, Dowd, Noreen, Cheng, Davy, Wong, David, Carroll-Munro, Jo, Trachuk, Clare, Cregg, N., Cheng, D. C. H., Williams, W. G., Karski, J. M., Siu, S., Webb, G., Cheng, Davy C. H., Wong, David T., Kustra, Rafal, Karski, Jacek, Tibshirani, Robert J., Côté, Dany L., Lacey, David E., LeDez, Kenneth M., Smith, Julia A., Crosby, Edward T., Orkin, Fredrick K., Fisher, A., Volgyesi, G., Silverman, J., Edelstein, S., Rucker, J., Sommer, L., Dunington, S., Roy, L., Crochetière, C., Arsenault, M. -Y., Villeneuve, E., Lortie, L., Grange, Caroline S., Douglas, M. Joanne, Adams, Timothy J., Merrick, Pamela M., Lucas, S. Brian, Morgan, Pamela J., Halpern, Stephen, Lo, Jason, Giesinger, Carolyn L., Halpern, Stephen H., Breen, Terrance W., Vishnubala, Srigowri, Shetty, Geeta R., De Kock, M., Lagmiche, A., Scholtes, J. L., Grodecki, Wlodzimierz, Duffy, Peter J., Hull, Kathryn A., Hawboldt, Geoffrey S., Clark, Alexander J., Smith, J. Bruce, Norman, Richard W., Beattie, W. Scott, Sandier, A., Jewett, M., Valiquette, L., Katz, J., Fradet, Y., Redelmeier, D., Sampson, H., Cole, Jeff, Chedore, Todd, Snedden, Walter, Green, Robert G., Sosis, Mitchel B., Robles, Philip I., Lazar, Edward R., Jolly, Donald T., Tarn, Yun K., Tawfik, Soheir R., Clanachan, Alexander S., Milne, Avaleigh, Beamish, Travis, Cuillerier, D. J., Sharpe, M. D., Lee, J. K., Basta, M., Krahn, A. D., Klein, G. J., Yee, R., Vakharia, Narendra, Francis, Heather, Scheepers, Louis, Vaghadia, Himat, Carrier, Joanne, Martin, René, Pirlet, Marline, Claprood, Yves, Tétrault, Jean-Pierre, Wong, T. D., Ryner, L., Kozlowski, P., Scarth, G., Warrian, R. K., Lefevre, G., Thiessen, D., Girling, L., Doiron, L., McCudden, C., Saunders, J., Mutch, W. A. C., Duffy, Peter J., Langevin, Stéphan, Lessard, Martin R., Trépanier, Claude A., Hare, Gregory M. T., Ngan, Johnson C. S., Viskari, Dan, Berrill, A., Jodoin, Christian, Couture, Jacques, Bellemare, François, Farmer, Stephen, Muir, Holly, Money, Phyllis, Milne, Brian, Parlow, Joel, Raymond, Jennifer, Williams, Julie M., Craen, Rosemary A., Novick, Teresa, Komar, Wendy, Frenette, Luc, Cox, Jerry, Lockhart, B., McArdle, P., Eckhoff, D., Bynon, S., Dobkowski, Wojciech B., Grant, David R., Wall, William J., Chedrawy, Edgar G., Hall, Richard I., Nedelcu, Vivian, Parlow, Joel, Viale, Jean-Paul, Bégou, Gérard, Sagnard, Pierre, Hughson, Richard, Quintin, Luc, Troncy, Éric, Collet, Jean-Paul, Shapiro, Stan, Guimond, Jean-Gilles, Blair, Louis, Ducruet, Thiérry, Francœur, Martin, Charbonneau, Marc, Blaise, Gilbert, Snedden, W., Bernadska, E., Manson, H. I., Kutt, Juditli L., Mezon, Beruie Y., Nishida, Osamu, Arellano, Ramiro, Boylen, Patty, DeMajo, Wilfred, Archer, David P., Roth, Sheldon H., Raman, Sitaram, Manninen, Pirjo, Boyle, Kevin, Cenic, Aleksa, Lee, Ting-Yim, Gelb, Adrian W., Reinders, F. X., Brown, J. I. M., Baker, A. J., Moulton, R. J., Schlichtert, L., Schwarz, Stephan K. W., Puil, Ernest, Finegan, Barry A., Finucane, Brendan T., Kurrek, Matt M., Devitt, J. Hugh, Morgan, Pamela J., Cleave-Hogg, Doreen, Bradley, John, Byrick, Robert, Spadafora, Salvatore M., Fuller, John G., Gelula, Mark H., Mayson, Kelly, Forster, Bruce, Byrick, R. J., McKnight, D. J., Kurrek, M., Kolton, M., Cleave-Hogg, D., Haughton, J., Halpern, S., Kronberg, J., Shysh, Sandy, Eagle, Chris, Dagnone, A. Joel, Parlow, Joel L., Blaise, G., Yang, F., Nguyen, H., Troncy, E., Czaika, G., Wachowski, Ireneusz, Basta, M., Krahn, A. D., Yee, R., Deladrière, Hervé, Cambier, Chantal, Pendeville, Philippe, Hung, O. R., Coonan, E., Whynot, S. C., Mezei, M., Coonan, E., Whynot, S. C., Ho, Anthony M. -H., Luchsinger, Ingrid S., Ling, Elizabeth, Mashava, Doreen, Chinyanga, Herbert M., Cohen, Marsha M., Shaw, Melissa, Robblee J. A., Labow R. S., Rubens F. D., Diemunsch, A. M., Gervais, R., Rose, D. K., Cohen, M. M., O’Brien-Pallas, L., Copplestone, C., Rose, D. K., Karkouti, K., Sykora, K., Cheung, Shirley L. W., Booker, Peter D., Franks, Roger, Pozzi, Marco, Guard, Beverley, Sikich, Nancy, Lerman, Jerrold, Levine, Mark, Swan, Hilton, Cox, Peter, Montgomery, Carolyne, Dunn, Gillian, Bourne, Russell, Kinahan, Anna, McCormack, James, Dunn, Gillian S., Reimer, Eleanor J., Sanderson, Peter, Sanderson, Peter M., Montgomery, Carolyne J., Betts, Terri A., Orlay, Guy R., Wong, David H., Cohen, Marsha, Al-Kaisy, A. A., Chan, V., Peng, P., Perlas, A., Miniad, A., Cushing, Edward V., Mills, Keith R., El-Beheiry, Hossam, Jahromi, Shokrollah S., Weaver, John, Morris, Mary, Carien, Peter L., Cowan, Robert McTaggart, Manninen, Pirjo, Richards, Jonathan, Robblee, J. A., Labow, R. S., Rubens, F. D., Menkis, Alan H., Adams, Sandy, Henderson, Blair T., Hudson, Robert J., Thomson, Ian R., Moon, Michael, Peterson, Mark D., Rosenbloom, Morley, Davison, Patrick J., Ali, Mohamed, Ali, Naheed S., Searle, Norman R., Thomson, Ian, Roy, Micheline, Gagnon, Line, Lye, A., Walsh, F., Middleton, W., Wong, D., Langer, A., Errett, L., Mazer, C. D., Karski, Jacek, Tibshirani, Robert J., Williamson, Karin M., Smith, Graham, Gnanendran, Kandiah P., Bignell, S. J., Jones, S., Sleigh, J., Arnell, M., Schultz, Jan-Ake I., Fear, David W., Ganapathy, S., Moote, C., Wassermann, R., Watson, J., Armstrong, K., Calikyan, Aznif Ozsolak, Yilmaz, Oya, Kose, Yildiz, Peng, Philip, Chan, Vincent, Chung, Frances, Claxton, Andrew R., Krishnathas, Ananthan, Mezei, Gabor, Badner, Neal H., Paul, Terri L., Doyle, Jacqueline A., Mehta, Mahesh, DeLima, Luiz G. R., Silva, Lucia E. O., May, Warren L., Maliakkal, Roy J., Mehta, Mahesh, Kolesar, Richard, Arellano, Ramiro, Rafuse, Sara, Fletcher, Mary, Dunn, Geoffrey, Curran, Michael, Bragg, Paul, Chamberlain, Wayne, Crossan, MaryLou, Ganapathy, S., Sandhu, H., Spadafora, S., Mian, R., Evans, B., Hurst, L., and Katsiris, S.

Published
1997
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48. Assessment of glycogen turnover in aerobic, ischemic, and reperfused working rat hearts

Author

Fraser, Heather, Lopaschuk, Gary D., and Clanachan, Alexander S.

Subjects
Glycogen metabolism -- Research, Heart -- Physiological aspects, Biological sciences
Abstract

Glucose labeled with hydrogen and carbon isotopes was used to measure glycogen turnover in isolated rat hearts during periods of aerobic metabolism, low-flow ischemia and reperfusion. It is important to take into account the simultaneous measurement of glycogen synthesis and degradation to accurately assess the rate of glycogen turnover. This method detects glycogen in the rat myocardium during aerobic, ischemic and reperfused conditions.

Published
1998

49. Acute effects of triiodothyronine on glucose and fatty acid metabolism during reperfusion of ischemic rat hearts

Author

Liu, Que, Clanachan, Alexander S., and Lopaschuk, Gary D.

Subjects
Glucose metabolism -- Research, Triiodothyronine -- Physiological aspects, Fatty acid metabolism -- Research, Ischemia -- Physiological aspects, Heart muscle -- Research, Biological sciences
Abstract

Experiments were performed to examine the ability of triiodothyronine (t3) treatment to improve the mechanical function and cardiac efficiency during reperfusion of ischemic rat hearts by modulation of glucose metabolism. Isolated working rat hearts were subjected to no-flow ischemia and aerobic reperfusion after being perfused with high levels of fatty acids. Results showed that T3 enhanced the recovery of mechanical function and cardiac performance in the post-ischemic rat heart when H+ production from glucose metabolism was lowered.

Published
1998

50. Intrinsic ANG II type 1 receptor stimulation contributes to recovery of postischemic mechanical function

Author

Ford, William R., Clanachan, Alexander S., Lopaschuk, Gary D., Schulz, Richard, and Jugdutt, Bodh I.

Subjects
Angiotensin -- Receptors, Ischemia -- Physiological aspects, Glucose metabolism -- Physiological aspects, Biological sciences
Abstract

The effects of selective intrinsic angiotensin II (ANG II) type 1 receptor (AT1-R) blockage with losartan on proton production from glucose metabolism and recovery of function in isolated working rat hearts perfused with Krebs-Henseleit buffer with palmitate, glucose and insulin, were studied. Results showed that the presence of endogenous ANG II played a role in the recovery under control conditions. Also, the losartan-induced inhibition of mechanical recovery was mediated through myocardial AT1-R antagonism and is reversed by displacement of losartan from its receptor by ANG II.

Published
1998

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