429 results on '"Hausenloy, DJ"'
Search Results
2. Targeting DJ-1 for cardioprotection
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Hernandez Resendiz, S, primary, Lu, S, additional, Prakash, A, additional, Crespo-Avilan, GE, additional, and Hausenloy, DJ, additional
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- 2022
- Full Text
- View/download PDF
3. Hydralazine protects the heart against acute ischaemia/reperfusion injury by inhibiting Drp1-mediated mitochondrial fission
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Kalkhoran, SB, Kriston-Vizi, J, Hernandez-Resendiz, S, Crespo-Avilan, GE, Rosdah, AA, Lees, JG, Simoes Da Costa, JR, Ling, NXY, Holien, JK, Samangouei, P, Chinda, K, Yap, EP, Riquelme, JA, Ketteler, R, Yellon, DM, Lim, SY, Hausenloy, DJ, Kalkhoran, SB, Kriston-Vizi, J, Hernandez-Resendiz, S, Crespo-Avilan, GE, Rosdah, AA, Lees, JG, Simoes Da Costa, JR, Ling, NXY, Holien, JK, Samangouei, P, Chinda, K, Yap, EP, Riquelme, JA, Ketteler, R, Yellon, DM, Lim, SY, and Hausenloy, DJ
- Abstract
AIMS: Genetic and pharmacological inhibition of mitochondrial fission induced by acute myocardial ischaemia/reperfusion injury (IRI) has been shown to reduce myocardial infarct size. The clinically used anti-hypertensive and heart failure medication, hydralazine, is known to have anti-oxidant and anti-apoptotic effects. Here, we investigated whether hydralazine confers acute cardioprotection by inhibiting Drp1-mediated mitochondrial fission. METHODS AND RESULTS: Pre-treatment with hydralazine was shown to inhibit both mitochondrial fission and mitochondrial membrane depolarisation induced by oxidative stress in HeLa cells. In mouse embryonic fibroblasts (MEFs), pre-treatment with hydralazine attenuated mitochondrial fission and cell death induced by oxidative stress, but this effect was absent in MEFs deficient in the mitochondrial fission protein, Drp1. Molecular docking and surface plasmon resonance studies demonstrated binding of hydralazine to the GTPase domain of the mitochondrial fission protein, Drp1 (KD 8.6±1.0 µM), and inhibition of Drp1 GTPase activity in a dose-dependent manner. In isolated adult murine cardiomyocytes subjected to simulated IRI, hydralazine inhibited mitochondrial fission, preserved mitochondrial fusion events, and reduced cardiomyocyte death (hydralazine 24.7±2.5% vs. control 34.1±1.5%, P=0.0012). In ex vivo perfused murine hearts subjected to acute IRI, pre-treatment with hydralazine reduced myocardial infarct size (as % left ventricle: hydralazine 29.6±6.5% vs. vehicle control 54.1±4.9%, P=0.0083), and in the murine heart subjected to in vivo IRI, the administration of hydralazine at reperfusion, decreased myocardial infarct size (as % area-at-risk: hydralazine 28.9±3.0% vs. vehicle control 58.2±3.8%, P<0.001). CONCLUSION: We show that, in addition to its antioxidant and anti-apoptotic effects, hydralazine, confers acute cardioprotection by inhibiting IRI-induced mitochondrial fission, raising the possibility of repurposing hydralazine
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- 2022
4. P645T2-mapping cardiac MRI for in vivo quantification of myocardial area-at-risk
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Dongworth, RK, Campbell-Washburn, AE, Roberts, T, Yellon, DM, Lythgoe, MF, and Hausenloy, DJ
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- 2014
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5. P445The differential effects of Sirtuin-3 in cardio-protection
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Hall, A R, Dongworth, RK, Kumar, S, Burke, N, Yellon, DM, and Hausenloy, DJ
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- 2014
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6. P166Extracellular RNA in cardiac ischemia/reperfusion injury: prevention of heart failure and cell damage by RNase1
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Cabrera-Fuentes, H A, Ruiz-Meana, M, Kostin, S, Lecour, S, Hausenloy, DJ, Garcia-Dorado, DJ, Schluter, KD, and Preissner, KT
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- 2014
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7. P143Targeting the mitochondrial fission proteins, MiD49 and MiD51, as a therapeutic strategy for cardioprotection
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Samangouei, P, Elder, JM, Burke, N, Hall, A, and Hausenloy, DJ
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- 2014
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8. The effect of cyclosporin-A on peri-operative myocardial injury in adult patients undergoing coronary artery bypass graft surgery: a randomised controlled clinical trial
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Hausenloy, DJ, Kunst, G, Boston-Griffiths, E, Kolvekar, S, Chaubey, S, John, L, Desai, J, and Yellon, DM
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- 2014
- Full Text
- View/download PDF
9. Magnetic Resonance Perfusion or Fractional Flow Reserve in Coronary Disease
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Nagel, E, Greenwood, JP, McCann, GP, Bettencourt, N, Shah, AM, Hussain, ST, Perera, D, Plein, S, Bucciarelli-Ducci, C, Paul, M, Westwood, MA, Marber, M, Richter, W-S, Puntmann, VO, Schwenke, C, Schulz-Menger, J, Das, R, Wong, J, Hausenloy, DJ, Steen, H, Berry, C, and MR-INFORM Investigators
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Adult ,Male ,medicine.medical_specialty ,medicine.medical_treatment ,Fractional flow reserve ,Coronary Artery Disease ,030204 cardiovascular system & hematology ,Coronary disease ,Revascularization ,Coronary Angiography ,Magnetic resonance angiography ,Angina ,Magnetic resonance perfusion ,Coronary artery disease ,03 medical and health sciences ,0302 clinical medicine ,Risk Factors ,Internal medicine ,medicine ,Humans ,030212 general & internal medicine ,Angina, Stable ,Aged ,medicine.diagnostic_test ,business.industry ,Angina, Stable/complications ,Magnetic resonance imaging ,General Medicine ,Middle Aged ,medicine.disease ,Fractional Flow Reserve, Myocardial ,Cardiology ,Female ,business ,Magnetic Resonance Angiography ,Coronary Artery Disease/diagnostic imaging - Abstract
BACKGROUND: In patients with stable angina, two strategies are often used to guide revascularization: one involves myocardial-perfusion cardiovascular magnetic resonance imaging (MRI), and the other involves invasive angiography and measurement of fractional flow reserve (FFR). Whether a cardiovascular MRI-based strategy is noninferior to an FFR-based strategy with respect to major adverse cardiac events has not been established.METHODS: We performed an unblinded, multicenter, clinical-effectiveness trial by randomly assigning 918 patients with typical angina and either two or more cardiovascular risk factors or a positive exercise treadmill test to a cardiovascular MRI-based strategy or an FFR-based strategy. Revascularization was recommended for patients in the cardiovascular-MRI group with ischemia in at least 6% of the myocardium or in the FFR group with an FFR of 0.8 or less. The composite primary outcome was death, nonfatal myocardial infarction, or target-vessel revascularization within 1 year. The noninferiority margin was a risk difference of 6 percentage points.RESULTS: A total of 184 of 454 patients (40.5%) in the cardiovascular-MRI group and 213 of 464 patients (45.9%) in the FFR group met criteria to recommend revascularization (P = 0.11). Fewer patients in the cardiovascular-MRI group than in the FFR group underwent index revascularization (162 [35.7%] vs. 209 [45.0%], P = 0.005). The primary outcome occurred in 15 of 421 patients (3.6%) in the cardiovascular-MRI group and 16 of 430 patients (3.7%) in the FFR group (risk difference, -0.2 percentage points; 95% confidence interval, -2.7 to 2.4), findings that met the noninferiority threshold. The percentage of patients free from angina at 12 months did not differ significantly between the two groups (49.2% in the cardiovascular-MRI group and 43.8% in the FFR group, P = 0.21).CONCLUSIONS: Among patients with stable angina and risk factors for coronary artery disease, myocardial-perfusion cardiovascular MRI was associated with a lower incidence of coronary revascularization than FFR and was noninferior to FFR with respect to major adverse cardiac events. (Funded by the Guy's and St. Thomas' Biomedical Research Centre of the National Institute for Health Research and others; MR-INFORM ClinicalTrials.gov number, NCT01236807.).
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- 2019
10. Mineralocorticoid receptor antagonist pre-treatment and early post-treatment to minimize reperfusion injury after ST-elevation myocardial infarction: The MINIMIZE STEMI trial
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Bulluck, H, Fröhlich, GM, Nicholas, JM, Mohdnazri, S, Gamma, R, Davies, J, Sirker, A, Mathur, A, Blackman, D, Garg, P, Moon, JC, Greenwood, JP, and Hausenloy, DJ
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cardiovascular system ,cardiovascular diseases - Abstract
BACKGROUND: Mineralocorticoid receptor antagonist (MRA) therapy has been shown to prevent adverse left ventricular (LV) remodeling in ST-segment elevation myocardial infarction (STEMI) patients with heart failure. Whether initiating MRA therapy prior to primary percutaneous coronary intervention (PPCI) accrues additional benefit of reducing myocardial infarct size and preventing adverse LV remodeling is not known. We aimed to investigate whether MRA therapy initiated prior to reperfusion reduces myocardial infarct (MI) size and prevents adverse LV remodeling in STEMI patients. METHODS: STEMI patients presenting within 12 hours and with a proximal coronary artery occlusion with Thrombolysis In Myocardial Infarction flow grade 0 were consented and randomized to either an intravenous bolus of potassium canrenoate, followed by oral spironolactone for 3 months or matching placebo. The primary endpoint was MI size by cardiovascular magnetic resonance at 3 months. RESULTS: Sixty-seven patients completed the study. There was no significant difference in the final MI size at 3 months between the 2 groups (placebo: 17 ± 11%, MRA: 16 ± 10%, P = .574). There was also no difference in acute MI size (26 ± 16% versus 23 ± 14%, P = .425) or myocardial salvage (26 ± 12% versus 24 ± 8%, P = .456). At follow-up, there was a trend towards an improvement in LVEF (placebo: 49 ± 8%, MRA: 54 ± 11%, P = .053), and the MRA group had significantly greater percentage decrease in LVEDV (mean difference: -12.2 (95% CI -20.3 to -4.4)%, P = .003) and LVESV (mean difference: -18.2 (95% CI -30.1 to -6.3)%, P = .003). CONCLUSION: This pilot study showed no benefit of MRA therapy in reducing MI size in STEMI patients when initiated prior to reperfusion, but there was an improvement in LV remodeling at 3 months. Adequately powered studies are warranted to confirm these findings.
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- 2019
11. Mitochondrial respiratory states and rate
- Author
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Gnaiger, E., Aasander Frostner, E., Abdul Karim, N., Abumrad, NA., Acuna-Castroviejo, D., Adiele, RC., Ahn, B., Ali, SS., Alton, L., Alves, MG., Amati, F., Amoedo, ND., Andreadou, I., Arago, M., Aral, C., Arandarcikaite, O., Armand, AS., Arnould, T., Avram, VF., Bailey, DM., Bajpeyi, S., Bajzikova, M., Bakker, BM., Barlow, J., Bastos Sant'Anna Silva, AC., Batterson, P., Battino, M., Bazil, J., Beard, DA., Bednarczyk, P., Bello, F., Ben-Shachar, D., Bergdahl, A., Berge, RK., Bergmeister, L., Bernardi, P., Berridge, MV., Bettinazzi, S., Bishop, D., Blier, PU., Blindheim, DF., Boardman, NT., Boetker, HE., Borchard, S., Boros, M., Borsheim, E., Borutaite, V., Botella, J., Bouillaud, F., Bouitbir, J., Boushel, RC., Bovard, J., Breton, S., Brown, DA., Brown, GC., Brown, RA., Brozinick, JT., Buettner, GR., Burtscher, J., Calabria, E., Calbet, JA., Calzia, E., Cannon, DT., Cano Sanchez, M., Canto, AC., Cardoso, LHD., Carvalho, E., Casado Pinna, M., Cassar, S., Cassina, AM., Castelo, MP., Castro, L., Cavalcanti-de-Albuquerque, JP., Cervinkova, Z., Chabi, B., Chakrabarti, L., Chakrabarti, S., Chaurasia, B., Chen, Q., Chicco, AJ., Chinopoulos, C., Chowdhury, SK., Cizmarova, B., Clementi, E., Coen, PM., Cohen, BH., Coker, RH., Collin, A., Crisostomo, L., Dahdah, N., Dalgaard, LT., Dambrova, M., Danhelovska, T., Darveau, CA., Das, AM., Dash, RK., Davidova, E., Davis, MS., De Goede, P., De Palma, C., Dembinska-Kiec, A., Detraux, D., Devaux, Y., Di Marcello, M., Dias, TR., Distefano, G., Doermann, N., Doerrier, C., Dong, L., Donnelly, C., Drahota, Z., Duarte, FV., Dubouchaud, H., Duchen, MR., Dumas, JF., Durham, WJ., Dymkowska, D., Dyrstad, SE., Dyson, A., Dzialowski, EM., Eaton, S., Ehinger, J., Elmer, E., Endlicher, R., Engin, AB., Escames, G., Ezrova, Z., Falk, MJ., Fell, DA., Ferdinandy, P., Ferko, M., Ferreira, JCB., Ferreira, R., Ferri, A., Fessel, JP., Filipovska, A., Fisar, Z., Fischer, C., Fischer, M., Fisher, G., Fisher, JJ., Ford, E., Fornaro, M., Galina, A., Galkin, A., Gallee, L., Galli, GL., Gama Perez, P., Gan, Z., Ganetzky, R., Garcia-Rivas, G., Garcia-Roves, PM., Garcia-Souza, LF., Garipi, E., Garlid, KD., Garrabou, G., Garten, A., Gastaldelli, A., Gayen, J., Genders, AJ., Genova, ML., Giovarelli, M., Goncalo Teixeira da Silva, R., Goncalves, DF., Gonzalez-Armenta, JL., Gonzalez-Freire, M., Gonzalo, H., Goodpaster, BH., Gorr, TA., Gourlay, CW., Granata, C., Grefte, S., Guarch, ME., Gueguen, N., Gumeni, S., Haas, CB., Haavik, J., Haendeler, J., Haider, M., Hamann, A., Han, J., Han, WH., Hancock, CR., Hand, SC., Handl, J., Hargreaves, IP., Harper, ME., Harrison, DK., Hassan, H., Hausenloy, DJ., Heales, SJR., Heiestad, C., Hellgren, KT., Hepple, RT., Hernansanz-Agustin, P., Hewakapuge, S., Hickey, AJ., Ho, DH., Hoehn, KL., Hoel, F., Holland, OJ., Holloway, GP., Hoppel, CL., Hoppel, F., Houstek, J., Huete-Ortega, M., Hyrossova, P., Iglesias-Gonzalez, J., Irving, BA., Isola, R., Iyer, S., Jackson, CB., Jadiya, P., Jana, PF., Jang, DH., Jang, YC., Janowska, J., Jansen, K., Jansen-Duerr, P., Jansone, B., Jarmuszkiewicz, W., Jaskiewicz, A., Jedlicka, J., Jespersen, NR., Jha, RK., Jurczak, MJ., Jurk, D., Kaambre, T., Kaczor, JJ., Kainulainen, H., Kampa, RP., Kandel, SM., Kane, DA., Kapferer, W., Kappler, L., Karabatsiakis, A., Karavaeva, I., Karkucinska-Wieckowska, A., Kaur, S., Keijer, J., Keller, MA., Keppner, G., Khamoui, AV., Kidere, D., Kilbaugh, T., Kim, HK., Kim, JKS., Klepinin, A., Klepinina, L., Klingenspor, M., Klocker, H., Komlodi, T., Koopman, WJH., Kopitar-Jerala, N., Kowaltowski, AJ., Kozlov, AV., Krajcova, A., Krako Jakovljevic, N., Kristal, BS., Krycer, JR., Kuang, J., Kucera, O., Kuka, J., Kwak, HB., Kwast, K., Laasmaa, M., Labieniec-Watala, M., Lagarrigue, S., Lai, N., Land, JM., Lane, N., Laner, V., Lanza, IR., Laranjinha, J., Larsen, TS., Lavery, GG., Lazou, A., Lee, HK., Leeuwenburgh, C., Lehti, M., Lemieux, H., Lenaz, G., Lerfall, J., Li, PA., Li Puma, L., Liepins, E., Liu, J., Lopez, LC., Lucchinetti, E., Ma, T., Macedo, MP., Maciej, S., MacMillan-Crow, LA., Majtnerova, P., Makarova, E., Makrecka-Kuka, M., Malik, AN., Markova, M., Martin, DS., Martins, AD., Martins, JD., Maseko, TE., Maull, F., Mazat, JP., McKenna, HT., McKenzie, M., Menze, MA., Merz, T., Meszaros, AT., Methner, A., Michalak, S., Moellering, DR., Moisoi, N., Molina, AJA., Montaigne, D., Moore, AL., Moreau, K., Moreira, BP., Moreno-Sanchez, R., Mracek, T., Muccini, AM., Munro, D., Muntane, J., Muntean, DM., Murray, AJ., Musiol, E., Nabben, M., Nair, KS., Nehlin, JO., Nemec, M., Neufer, PD., Neuzil, J., Neviere, R., Newsom, SA., Nozickova, K., O'Brien, KA., O'Gorman, D., Olgar, Y., Oliveira, B., Oliveira, MF., Oliveira, MT., Oliveira, PF., Oliveira, PJ., Orynbayeva, Z., Osiewacz, HD., Pak, YK., Pallotta, ML., Palmeira, CM., Parajuli, N., Passos, JF., Passrugger, M., Patel, HH., Pavlova, N., Pecina, P., Pedersen, TM., Pereira da Silva Grilo da Silva, F., Pereira, SP., Perez Valencia, JA., Perks, KL., Pesta, D., Petit, PX., Pettersen, IKN., Pichaud, N., Pichler, I., Piel, S., Pietka, TA., Pino, MF., Pirkmajer, S., Plangger, M., Porter, C., Porter, RK., Procaccio, V., Prochownik, EV., Prola, A., Pulinilkunnil, T., Puskarich, MA., Puurand, M., Radenkovic, F., Ramzan, R., Rattan, SIS., Reboredo, P., Renner-Sattler, K., Rial, E., Robinson, MM., Roden, M., Rodriguez, E., Rodriguez-Enriquez, S., Roesland, GV., Rohlena, J., Rolo, AP., Ropelle, ER., Rossignol, R., Rossiter, HB., Rubelj, I., Rybacka-Mossakowska, J., Saada, A., Safaei, Z., Saharnaz, S., Salin, K., Salvadego, D., Sandi, C., Saner, N., Sanz, A., Sazanov, LA., Scatena, R., Schartner, M., Scheibye-Knudsen, M., Schilling, JM., Schlattner, U., Schoenfeld, P., Schots, PC., Schulz, R., Schwarzer, C., Scott, GR., Selman, C., Shabalina, IG., Sharma, P., Sharma, V., Shevchuk, I., Shirazi, R., Shiroma, JG., Siewiera, K., Silber, AM., Silva, AM., Sims, CA., Singer, D., Singh, BK., Skolik, R., Smenes, BT., Smith, J., Soares, FAA., Sobotka, O., Sokolova, I., Sonkar, VK., Sowton, AP., Sparagna, GC., Sparks, LM., Spinazzi, M., Stankova, P., Starr, J., Stary, C., Stelfa, G., Stepto, NK., Stiban, J., Stier, A., Stocker, R., Storder, J., Sumbalova, Z., Suomalainen, A., Suravajhala, P., Svalbe, B., Swerdlow, RH., Swiniuch, D., Szabo, I., Szewczyk, A., Szibor, M., Tanaka, M., Tandler, B., Tarnopolsky, MA., Tausan, D., Tavernarakis, N., Tepp, K., Thakkar, H., Thapa, M., Thyfault, JP., Tomar, D., Ton, R., Torp, MK., Towheed, A., Tretter, L., Trewin, AJ., Trifunovic, A., Trivigno, C., Tronstad, KJ., Trougakos, IP., Truu, L., Tuncay, E., Turan, B., Tyrrell, DJ., Urban, T., Valentine, JM., Van Bergen, NJ., Van Hove, J., Varricchio, F., Vella, J., Vendelin, M., Vercesi, AE., Victor, VM., Vieira Ligo Teixeira, C., Vidimce, J., Viel, C., Vieyra, A., Vilks, K., Villena, JA., Vincent, V., Vinogradov, AD., Viscomi, C., Vitorino, RMP., Vogt, S., Volani, C., Volska, K., Votion, DM., Vujacic-Mirski, K., Wagner, BA., Ward, ML., Warnsmann, V., Wasserman, DH., Watala, C., Wei, YH., Whitfield, J., Wickert, A., Wieckowski, MR., Wiesner, RJ., Williams, CM., Winwood-Smith, H., Wohlgemuth, SE., Wohlwend, M., Wolff, JN., Wrutniak-Cabello, C., Wuest, RCI., Yokota, T., Zablocki, K., Zanon, A., Zanou, N., Zaugg, K., Zaugg, M., Zdrazilova, L., Zhang, Y., Zhang, YZ., Zikova, A., Zischka, H., Zorzano, A., and Zvejniece, L.
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Mitochondrial respiratory control, coupling control, mitochondrial preparations, protonmotive force, uncoupling, oxidative phosphorylation, OXPHOS, efficiency, electron transfer, ET ,proton leak, LEAK, residual oxygen consumption, ROX, State 2, State 3, State 4, normalization, flow, flux, O2 - Abstract
As the knowledge base and importance of mitochondrial physiology to human health expands, the necessity for harmonizing the terminologyconcerning mitochondrial respiratory states and rates has become increasingly apparent. Thechemiosmotic theoryestablishes the mechanism of energy transformationandcoupling in oxidative phosphorylation. Theunifying concept of the protonmotive force providestheframeworkfordeveloping a consistent theoretical foundation ofmitochondrial physiology and bioenergetics.We followguidelines of the International Union of Pure and Applied Chemistry(IUPAC)onterminology inphysical chemistry, extended by considerationsofopen systems and thermodynamicsof irreversible processes.Theconcept-driven constructive terminology incorporates the meaning of each quantity and alignsconcepts and symbols withthe nomenclature of classicalbioenergetics. We endeavour to provide a balanced view ofmitochondrial respiratory control and a critical discussion on reporting data of mitochondrial respiration in terms of metabolic flows and fluxes.Uniform standards for evaluation of respiratory states and rates will ultimatelycontribute to reproducibility between laboratories and thussupport the development of databases of mitochondrial respiratory function in species, tissues, and cells.Clarity of concept and consistency of nomenclature facilitate effective transdisciplinary communication, education, and ultimately further discovery.
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- 2019
12. Mitochondrial fission protein Drp1 inhibition promotes cardiac mesodermal differentiation of human pluripotent stem cells
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Hoque, A, Sivakumaran, P, Bond, ST, Ling, NXY, Kong, AM, Scott, JW, Bandara, N, Hernández, D, Liu, GS, Wong, RCB, Ryan, MT, Hausenloy, DJ, Kemp, BE, Oakhill, JS, Drew, BG, Pébay, A, Lim, SY, Hoque, A, Sivakumaran, P, Bond, ST, Ling, NXY, Kong, AM, Scott, JW, Bandara, N, Hernández, D, Liu, GS, Wong, RCB, Ryan, MT, Hausenloy, DJ, Kemp, BE, Oakhill, JS, Drew, BG, Pébay, A, and Lim, SY
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- 2018
13. Mitochondrial fission protein Drp1 inhibition promotes cardiac mesodermal differentiation of human pluripotent stem cells
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Hogue, A, Sivakumaran, P, Bond, ST, Ling, NXY, Kong, AM, Scott, JW, Bandara, N, Hernandez, D, Liu, G-S, Wong, RCB, Ryan, MT, Hausenloy, DJ, Kemp, BE, Oakhill, JS, Drew, BG, Pebay, A, Lim, SY, Hogue, A, Sivakumaran, P, Bond, ST, Ling, NXY, Kong, AM, Scott, JW, Bandara, N, Hernandez, D, Liu, G-S, Wong, RCB, Ryan, MT, Hausenloy, DJ, Kemp, BE, Oakhill, JS, Drew, BG, Pebay, A, and Lim, SY
- Abstract
Human induced pluripotent stem cells (iPSCs) are a valuable tool for studying the cardiac developmental process in vitro, and cardiomyocytes derived from iPSCs are a putative cell source for personalized medicine. Changes in mitochondrial morphology have been shown to occur during cellular reprogramming and pluripotent stem cell differentiation. However, the relationships between mitochondrial dynamics and cardiac mesoderm commitment of iPSCs remain unclear. Here we demonstrate that changes in mitochondrial morphology from a small granular fragmented phenotype in pluripotent stem cells to a filamentous reticular elongated network in differentiated cardiomyocytes are required for cardiac mesodermal differentiation. Genetic and pharmacological inhibition of the mitochondrial fission protein, Drp1, by either small interfering RNA or Mdivi-1, respectively, increased cardiac mesoderm gene expression in iPSCs. Treatment of iPSCs with Mdivi-1 during embryoid body formation significantly increased the percentage of beating embryoid bodies and expression of cardiac-specific genes. Furthermore, Drp1 gene silencing was accompanied by increased mitochondrial respiration and decreased aerobic glycolysis. Our findings demonstrate that shifting the balance of mitochondrial morphology toward fusion by inhibition of Drp1 promoted cardiac differentiation of human iPSCs with a metabolic shift from glycolysis towards oxidative phosphorylation. These findings suggest that Drp1 may represent a new molecular target for future development of strategies to promote the differentiation of human iPSCs into cardiac lineages for patient-specific cardiac regenerative medicine.
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- 2018
14. Quantifying the area-at-risk of myocardial infarction in-vivo using arterial spin labeling cardiac magnetic resonance
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Dongworth, RK, Campbell-Washburn, AE, Cabrera-Fuentes, HA, Bulluck, H, Roberts, T, Price, AN, Hernandez-Resendiz, S, Ordidge, RJ, Thomas, DL, Yellon, DM, Lythgoe, MF, Hausenloy, DJ, Dongworth, RK, Campbell-Washburn, AE, Cabrera-Fuentes, HA, Bulluck, H, Roberts, T, Price, AN, Hernandez-Resendiz, S, Ordidge, RJ, Thomas, DL, Yellon, DM, Lythgoe, MF, and Hausenloy, DJ
- Abstract
T2-weighted cardiovascular magnetic resonance (T2-CMR) of myocardial edema can quantify the area-at-risk (AAR) following acute myocardial infarction (AMI), and has been used to assess myocardial salvage by new cardioprotective therapies. However, some of these therapies may reduce edema, leading to an underestimation of the AAR by T2-CMR. Here, we investigated arterial spin labeling (ASL) perfusion CMR as a novel approach to quantify the AAR following AMI. Adult B6sv129-mice were subjected to in vivo left coronary artery ligation for 30 minutes followed by 72 hours reperfusion. T2-mapping was used to quantify the edema-based AAR (% of left ventricle) following ischemic preconditioning (IPC) or cyclosporin-A (CsA) treatment. In control animals, the AAR by T2-mapping corresponded to that delineated by histology. As expected, both IPC and CsA reduced MI size. However, IPC, but not CsA, also reduced myocardial edema leading to an underestimation of the AAR by T2-mapping. In contrast, regions of reduced myocardial perfusion delineated by cardiac ASL were able to delineate the AAR when compared to both T2-mapping and histology in control animals, and were not affected by either IPC or CsA. Therefore, ASL perfusion CMR may be an alternative method for quantifying the AAR following AMI, which unlike T2-mapping, is not affected by IPC.
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- 2017
15. ESC Joint Working Groups on Cardiovascular Surgery and the Cellular Biology of the Heart Position Paper: Peri-operative myocardial injury and infarction in patients undergoing coronary artery bypass graft surgery
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Thielmann, M, Sharma, V, Al-Attar, N, Bulluck, H, Bisleri, G, Bunge, Jeroen, Czerny, M, Ferdinandy, P, Frey, UH, Heusch, G, Holfeld, J, Kleinbongard, P, Kunst, G, Lang, I, Lentini, S, Madonna, R, Meybohm, P, Muneretto, C, Obadia, JF, Perrino, C, Prunier, F, Sluijter, JPG, Van Laake, L, Sousa-Uva, M, Hausenloy, DJ, Thielmann, M, Sharma, V, Al-Attar, N, Bulluck, H, Bisleri, G, Bunge, Jeroen, Czerny, M, Ferdinandy, P, Frey, UH, Heusch, G, Holfeld, J, Kleinbongard, P, Kunst, G, Lang, I, Lentini, S, Madonna, R, Meybohm, P, Muneretto, C, Obadia, JF, Perrino, C, Prunier, F, Sluijter, JPG, Van Laake, L, Sousa-Uva, M, and Hausenloy, DJ
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- 2017
16. From basic mechanisms to clinical applications in heart protection, new players in cardiovascular diseases and cardiac theranostics: meeting report from the third international symposium on 'New frontiers in cardiovascular research'
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Cabrera-Fuentes, HA, Aragones, J, Bernhagen, J, Boening, A, Boisvert, WA, Botker, HE, Bulluck, H, Cook, S, Di Lisa, F, Engel, FB, Engelmann, B, Ferrazzi, F, Ferdinandy, P, Fong, A, Fleming, I, Gnaiger, E, Hernandez-Resendiz, S, Kalkhoran, SB, Kim, MH, Lecour, S, Liehn, EA, Marber, MS, Mayr, M, Miura, T, Ong, S-B, Peter, K, Sedding, D, Singh, MK, Suleiman, MS, Schnittler, HJ, Schulz, R, Shim, W, Tello, D, Vogel, C-W, Walker, M, Li, QOY, Yellon, DM, Hausenloy, DJ, Preissner, KT, Cabrera-Fuentes, HA, Aragones, J, Bernhagen, J, Boening, A, Boisvert, WA, Botker, HE, Bulluck, H, Cook, S, Di Lisa, F, Engel, FB, Engelmann, B, Ferrazzi, F, Ferdinandy, P, Fong, A, Fleming, I, Gnaiger, E, Hernandez-Resendiz, S, Kalkhoran, SB, Kim, MH, Lecour, S, Liehn, EA, Marber, MS, Mayr, M, Miura, T, Ong, S-B, Peter, K, Sedding, D, Singh, MK, Suleiman, MS, Schnittler, HJ, Schulz, R, Shim, W, Tello, D, Vogel, C-W, Walker, M, Li, QOY, Yellon, DM, Hausenloy, DJ, and Preissner, KT
- Abstract
In this meeting report, particularly addressing the topic of protection of the cardiovascular system from ischemia/reperfusion injury, highlights are presented that relate to conditioning strategies of the heart with respect to molecular mechanisms and outcome in patients' cohorts, the influence of co-morbidities and medications, as well as the contribution of innate immune reactions in cardioprotection. Moreover, developmental or systems biology approaches bear great potential in systematically uncovering unexpected components involved in ischemia-reperfusion injury or heart regeneration. Based on the characterization of particular platelet integrins, mitochondrial redox-linked proteins, or lipid-diol compounds in cardiovascular diseases, their targeting by newly developed theranostics and technologies opens new avenues for diagnosis and therapy of myocardial infarction to improve the patients' outcome.
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- 2016
17. T1 mapping for ECV measurement: is the bolus technique good enough? A 123 patient study with gold standard of histological validatation and EQ-CMR
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White, Sk, Fontana, M, Sado, Dm, Banypersad, Sm, Maestrini, Viviana, Piechnik, Sk, Robson, Md, Hausenloy, Dj, Sheikh, Am, Hawkins, P, and Moon, Jc
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- 2012
18. THE NOVEL MITOCHONDRIAL FISSION PROTEINS, MID49 AND MID51: NEW THERAPEUTIC TARGETS FOR CARDIOPROTECTION
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Elder, JM, primary, Samangouei, P, additional, Burke, N, additional, Hall, AR, additional, Osellame, LD, additional, Ryan, MT, additional, and Hausenloy, DJ, additional
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- 2014
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19. CARDIAC ARTERIAL SPIN LABELLING MRI AS A NOVEL APPROACH FOR IN VIVO QUANTIFICATION OF THE AREA-AT-RISK
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Dongworth, RK, primary, Campbell-Washburn, AE, additional, Roberts, T, additional, Yellon, DM, additional, Lythgoe, MF, additional, and Hausenloy, DJ, additional
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- 2014
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20. 3D ELECTRON MICROSCOPY TOMOGRAPHY TO ASSESS MITOCHONDRIAL MORPHOLOGY IN THE ADULT HEART
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Kalkhoran, S, primary, Hall, AR, additional, Cole, A, additional, White, I, additional, Yellon, DM, additional, and Hausenloy, DJ, additional
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- 2014
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21. Remote ischennic conditioning: from bench to bedside
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Lim, SY, Hausenloy, DJ, Lim, SY, and Hausenloy, DJ
- Abstract
Remote ischemic conditioning (RIC) is a therapeutic strategy for protecting organs or tissue against the detrimental effects of acute ischemia-reperfusion injury (IRI). It describes an endogenous phenomenon in which the application of one or more brief cycles of non-lethal ischemia and reperfusion to an organ or tissue protects a remote organ or tissue from a sustained episode of lethal IRI. Although RIC protection was first demonstrated to protect the heart against acute myocardial infarction, its beneficial effects are also seen in other organs (lung, liver, kidney, intestine, brain) and tissues (skeletal muscle) subjected to acute IRI. The recent discovery that RIC can be induced non-invasively by simply inflating and deflating a standard blood pressure cuff placed on the upper arm or leg, has facilitated its translation into the clinical setting, where it has been reported to be beneficial in a variety of cardiac scenarios. In this review article we provide an overview of RIC, the potential underlying mechanisms, and its potential as a novel therapeutic strategy for protecting the heart and other organs from acute IRI.
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- 2012
22. Rapid assessment of myocardial infarct size in rodents using multi-slice inversion recovery late gadolinium enhancement CMR at 9.4T
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Price, AN, Cheung, KK, Lim, SY, Yellon, DM, Hausenloy, DJ, Lythgoe, MF, Price, AN, Cheung, KK, Lim, SY, Yellon, DM, Hausenloy, DJ, and Lythgoe, MF
- Abstract
BACKGROUND: Myocardial infarction (MI) can be readily assessed using late gadolinium enhancement (LGE) cardiovascular magnetic resonance (CMR). Inversion recovery (IR) sequences provide the highest contrast between enhanced infarct areas and healthy myocardium. Applying such methods to small animals is challenging due to rapid respiratory and cardiac rates relative to T1 relaxation. METHODS: Here we present a fast and robust protocol for assessing LGE in small animals using a multi-slice IR gradient echo sequence for efficient assessment of LGE. An additional Look-Locker sequence was used to assess the optimum inversion point on an individual basis and to determine most appropriate gating points for both rat and mouse. The technique was applied to two preclinical scenarios: i) an acute (2 hour) reperfused model of MI in rats and ii) mice 2 days following non-reperfused MI. RESULTS: LGE images from all animals revealed clear areas of enhancement allowing for easy volume segmentation. Typical inversion times required to null healthy myocardium in rats were between 300-450 ms equivalent to 2-3 R-waves and ~330 ms in mice, typically 3 R-waves following inversion. Data from rats was also validated against triphenyltetrazolium chloride staining and revealed close agreement for infarct size. CONCLUSION: The LGE protocol presented provides a reliable method for acquiring images of high contrast and quality without excessive scan times, enabling higher throughput in experimental studies requiring reliable assessment of MI.
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- 2011
23. Mitochondrial cyclophilin-D as a potential therapeutic target for post-myocardial infarction heart failure
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Lim, SY, Hausenloy, DJ, Arjun, S, Price, AN, Davidson, SM, Lythgoe, MF, Yellon, DM, Lim, SY, Hausenloy, DJ, Arjun, S, Price, AN, Davidson, SM, Lythgoe, MF, and Yellon, DM
- Abstract
The pharmacological inhibition or genetic ablation of cyclophilin-D (CypD), a critical regulator of the mitochondrial permeability transition pore (mPTP), confers myocardial resistance to acute ischemia-reperfusion injury, but its role in post-myocardial infarction (MI) heart failure is unknown. The aim of this study was to determine whether mitochondrial CypD is also a therapeutic target for the treatment of post-MI heart failure. Wild-type (WT) and CypD(-/-) mice were subjected to either sham surgery or permanent ligation of the left main coronary artery to induce MI, and were assessed at either 2 or 28 days to determine the long-term effects of CypD ablation. After 2 days, myocardial infarct size was smaller and left ventricular (LV) function was better preserved in CypD(-/-) mice compared to WT mice. After 28 days, when compared to WT mice, in the CypD(-/-) mice, mortality was halved, myocardial infarct size was reduced, LV systolic function was better preserved, LV dilatation was attenuated and in the remote non-infarcted myocardium, there was less cardiomyocyte hypertrophy and interstitial fibrosis. Finally, ex vivo fibroblast proliferation was found to be reduced in CypD(-/-) cardiac fibroblasts, and in WT cardiac fibroblasts treated with the known CypD inhibitors, cyclosporin-A and sanglifehrin-A. Following an MI, mice lacking CypD have less mortality, smaller infarct size, better preserved LV systolic function and undergo less adverse LV remodelling. These findings suggest that the inhibition of mitochondrial CypD may be a novel therapeutic treatment strategy for post-MI heart failure.
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- 2011
24. Mitochondrial cyclophilin-D as a critical mediator of ischaemic preconditioning
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Hausenloy, DJ, Lim, SY, Ong, S-G, Davidson, SM, Yellon, DM, Hausenloy, DJ, Lim, SY, Ong, S-G, Davidson, SM, and Yellon, DM
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AIMS: It has been suggested that mitochondrial reactive oxygen species (ROS), Akt and Erk1/2 and more recently the mitochondrial permeability transition pore (mPTP) may act as mediators of ischaemic preconditioning (IPC), although the actual interplay between these mediators is unclear. The aim of the present study is to determine whether the cyclophilin-D (CYPD) component of the mPTP is required by IPC to generate mitochondrial ROS and subsequently activate Akt and Erk1/2. METHODS AND RESULTS: Mice lacking CYPD (CYPD-/-) and B6Sv129 wild-type (WT) mice were used throughout. We have demonstrated that under basal conditions, non-pathological mPTP opening occurs (indicated by the percent reduction in mitochondrial calcein fluorescence). This effect was greater in WT cardiomyocytes compared with CYPD-/- ones (53 ± 2% WT vs. 17 ± 3% CYPD-/-; P < 0.01) and was augmented by hypoxic preconditioning (HPC) (70 ± 9% WT vs. 56 ± 1% CYPD-/-; P < 0.01). HPC reduced cell death following simulated ischaemia-reperfusion injury in WT (23.2 ± 3.5% HPC vs. 43.7 ± 3.2% WT; P < 0.05) but not CYPD-/- cardiomyocytes (19.6 ± 1.4% HPC vs. 24.4 ± 2.6% control; P > 0.05). HPC generated mitochondrial ROS in WT (four-fold increase; P < 0.05) but not CYPD-/- cardiomyocytes. HPC induced significant Akt phosphorylation in WT cardiomyocytes (two-fold increase; P < 0.05), an effect which was abrogated by ciclosporin-A (a CYPD inhibitor) and N-2-mercaptopropionyl glycine (a ROS scavenger). Finally, in vivo IPC of adult murine hearts resulted in significant phosphorylation of Akt and Erk1/2 in WT but not CYPD-/- hearts. CONCLUSION: The CYPD component of the mPTP is required by IPC to generate mitochondrial ROS and phosphorylate Akt and Erk1/2, major steps in the IPC signalling pathway.
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- 2010
25. The novel adipocytokine visfatin exerts direct cardioprotective effects
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Lim, SY, Davidson, SM, Paramanathan, AJ, Smith, CCT, Yellon, DM, Hausenloy, DJ, Lim, SY, Davidson, SM, Paramanathan, AJ, Smith, CCT, Yellon, DM, and Hausenloy, DJ
- Abstract
Visfatin is an adipocytokine capable of mimicking the glucose-lowering effects of insulin and activating the pro-survival kinases phosphatidylinositol-3-OH kinase (PI3K)-protein kinase B (Akt) and mitogen-activated protein kinase kinase 1 and 2 (MEK1/2)-extracellular signal-regulated kinase 1 and 2 (Erk 1/2). Experimental studies have demonstrated that the activation of these kinases confers cardioprotection through the inhibition of the mitochondrial permeability transition pore (mPTP). Whether visfatin is capable of exerting direct cardioprotective effects through these mechanisms is unknown and is the subject of the current study. Anaesthetized C57BL/6 male mice were subjected to in situ 30 min. of regional myocardial ischaemia and 120 min. of reperfusion. The administration of an intravenous bolus of visfatin (5 x 10(-6) micromol) at the time of myocardial reperfusion reduced the myocardial infarct size from 46.1+/-4.1% in control hearts to 27.3+/-4.0% (n>or= 6/group, P<0.05), an effect that was blocked by the PI3K inhibitor, wortmannin, and the MEK1/2 inhibitor, U0126 (48.8+/-5.5% and 45.9+/-8.4%, respectively, versus 27.3+/-4.0% with visfatin; n>or= 6/group, P<0.05). In murine ventricular cardiomyocytes subjected to 30 min. of hypoxia followed by 30 min. of reoxygenation, visfatin (100 ng/ml), administered at the time of reoxygenation, reduced the cell death from 65.2+/-4.6% in control to 49.2+/-3.7%(n>200 cells/group, P<0.05), an effect that was abrogated by wortmannin and U0126 (68.1+/-5.2% and 59.7+/-6.2%, respectively; n>200 cells/group, P>0.05). Finally, the treatment of murine ventricular cardiomyocytes with visfatin (100 ng/ml) delayed the opening of the mPTP induced by oxidative stress from 81.2+/-4 sec. in control to 120+/-7 sec. (n>20 cells/group, P<0.05) in a PI3K- and MEK1/2-dependent manner. We report that the adipocytokine, visfatin, is capable of reducing myocardial injury when administered at the time of myocardial reperfusion in both the in si
- Published
- 2008
26. 225 T2-MAPPING CARDIAC MAGNETIC RESONANCE IMAGING FOR ASSESSING AREA-AT-RISK IN A MURINE MODEL OF MYOCARDIAL ISCHAEMIA-REPERFUSION INJURY
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Dongworth, R K, primary, Campbell-Washburn, A E, additional, Roberts, T, additional, Yellon, D M, additional, Lythgoe, M F, additional, and Hausenloy, DJ, additional
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- 2013
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27. Cyclosporin A and cardioprotection: from investigative tool to therapeutic agent
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Hausenloy, DJ, primary, Boston-Griffiths, EA, additional, and Yellon, DM, additional
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- 2012
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28. Targeting DJ-1 for cardioprotection.
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Resendiz, S Hernandez, Lu, S, Prakash, A, Crespo-Avilan, GE, and Hausenloy, DJ
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MYOCARDIAL reperfusion ,MYOCARDIAL infarction ,AMINO acid sequence ,SYSTOLIC blood pressure ,REPERFUSION injury - Abstract
Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): The National Medical Research Council (NMRC) Background Additional protection beyond timely reperfusion is still needed as more patients who have survived an acute myocardial infarction (AMI) developed heart failure (HF)1. DJ-1 was recently reported as a cytoprotective protein that preserves mitochondrial complex I activity and subsequently inhibits mitochondrial reactive species (ROS) production2. DJ-1 downregulation dramatically increases the susceptibility to cell death after myocardial infarction in mice. A substantial reduction in total DJ-1 protein levels in left ventricular tissue has been identified in patients at the end-stage of human HF3, suggesting that DJ-1 protects the myocardium against AMI cell death and is essential in the remodelling process post-infarct. Purpose: The translation of cardioprotection to clinical practice has been difficult, and it remains a challenge between the bench and the bedside. Nanotechnology has shown significant improvements in the settings of AMI. Given the protective effect observed with DJ-1, we designed ND-13, a new cell-permeable 13- fragment of the DJ-1 amino acid sequence. Then, we loaded it into nanoparticles (ND-13NPs) to achieve cardioprotective outcomes against IRI. Methods: We tested the efficacy and efficiency of our new ND-13NPs to reduce infarct size in the ex vivo heart perfused IRI model and the in vivo AMI-murine model. Results: Naked ND-13 (20µM) continuously perfused for the first 15 minutes of reperfusion significantly improved LV pressure and systolic function. Afterwards, we tested 60 mg/Kg of the naked peptide injected 5 minutes before reperfusion in the in vivo model. ND-13 reduced 35% of the infarct size (non-treated, 49 ± 6.4% vs. treated, 32 ± 5 %). Fluorescently loaded ND-13NPs were intravenously injected into infarcted mice to assess their distribution in cardiac tissue. The ND-13NPs were abundantly detected in the infarct border and minimally detected in the remote myocardium. 20mg/Kg of ND-13 loaded into NPs reduced 45% the infarct size compared with 60mg/Kg and 20mg/Kg of naked ND-13 (27 ± 6% vs. 32 ± 5% and 44 ± 8%, respectively). We demonstrated that NPs improved the delivery and efficacy of ND-13 in the ischemic heart following AMI. We observed a robust antioxidative effect when the infarcted heart was treated with ND-13NPs (90 ± 1.5% vs 39 ± 9%, respectively). The activation of the myocardial reperfusion injury salvage kinase (RISK) and the survivor activating factor enhancement (SAFE) pathway at reperfusion protects the mitochondria against IRI. Therefore, we addressed whether ND-13NPs impact mitochondrial function. Can ND-13 protect beyond a cardioprotective pathway, or has the threshold of protection already been achieved by activating a direct effect on mitochondria? Conclusion: Intravenously injected ND-13NPs selectively accumulated in the infarct area and protects the myocardium from IRI via the ROS-mitochondria effect. This new drug may potentially bridge the gaps between basic and clinical research. [ABSTRACT FROM AUTHOR]
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- 2022
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29. Remote ischemic conditioning: a clinical trial's update.
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Candilio L, Hausenloy DJ, Yellon DM, Candilio, Luciano, Hausenloy, Derek J, and Yellon, Derek M
- Abstract
Coronary artery disease (CAD) is the leading cause of death and disability worldwide, and early and successful restoration of myocardial reperfusion following an ischemic event is the most effective strategy to reduce final infarct size and improve clinical outcome. This process can, however, induce further myocardial damage, namely acute myocardial ischemia-reperfusion injury (IRI) and worsen clinical outcome. Therefore, novel therapeutic strategies are required to protect the myocardium against IRI in patients with CAD. In this regard, the endogenous cardioprotective phenomenon of "ischemic conditioning," in which the heart is put into a protected state by subjecting it to one or more brief nonlethal episodes of ischemia and reperfusion, has the potential to attenuate myocardial injury during acute IRI. Intriguingly, the heart can be protected in this manner by applying the "ischemic conditioning" stimulus to an organ or tissue remote from the heart (termed remote ischemic conditioning or RIC). Furthermore, the discovery that RIC can be noninvasively applied using a blood pressure cuff on the upper arm to induce brief episodes of nonlethal ischemia and reperfusion in the forearm has greatly facilitated the translation of RIC into the clinical arena. Several recently published proof-of-concept clinical studies have reported encouraging results with RIC, and large multicenter randomized clinical trials are now underway to investigate whether this simple noninvasive and virtually cost-free intervention has the potential to improve clinical outcomes in patients with CAD. In this review article, we provide an update of recently published and ongoing clinical trials in the field of RIC. [ABSTRACT FROM AUTHOR]
- Published
- 2011
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30. Inhibiting mitochondrial fission protects the heart against ischemia/reperfusion injury.
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Ong SB, Subrayan S, Lim SY, Yellon DM, Davidson SM, and Hausenloy DJ
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- 2010
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31. Enhancing cardiovascular disease risk reduction: raising high-density lipoprotein levels.
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Hausenloy DJ, Yellon DM, Hausenloy, Derek J, and Yellon, Derek M
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- 2009
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32. Targeting residual cardiovascular risk: raising high-density lipoprotein cholesterol levels.
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Hausenloy DJ, Yellon DM, Hausenloy, D J, and Yellon, D M
- Abstract
The last 20 years have witnessed dramatic reductions in cardiovascular risk using 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors ("statins") to lower levels of low-density lipoprotein cholesterol (LDL-C). Using this approach one can achieve a reduction in the risk of major cardiovascular events of 21% for every 1 mmol/l (39 mg/dl) decrease in LDL-C. However, despite intensive therapy with high dose "statins" to lower LDL-C levels below 2.6 mmol/l (100 mg/dl), the risk of a major cardiovascular event in patients with established coronary artery disease remains significant at a level approaching an annual risk of 9%, paving the way for new strategies for reducing the residual cardiovascular risk in this patient group. Early epidemiological studies have identified low levels of high-density lipoprotein cholesterol (HDL-C) (<1.0 mmol/l or 40 mg/dl), a common feature of type 2 diabetes mellitus and the metabolic syndrome, to be an independent determinant of increased cardiovascular risk. The beneficial effects of HDL-C on the cardiovascular system have been attributed to its ability to remove cellular cholesterol, as well as its anti-inflammatory, antioxidant and antithrombotic properties, which act in concert to improve endothelial function and inhibit atherosclerosis, thereby reducing cardiovascular risk. As such, raising HDL-C in patients with aggressively lowered LDL-C provides an additional strategy for addressing the residual cardiovascular risk present in these patients groups. Studies suggest that for every 0.03 mmol/l (1.0 mg/dl) increase in HDL-C, cardiovascular risk is reduced by 2-3%. Raising HDL-C can be achieved by both lifestyle changes and pharmacological means, the former of which include smoking cessation, aerobic exercise, weight loss and dietary manipulation. Therapeutic strategies have included niacin, fibrates, thiazolidinediones and bile acid sequestrants. Newly developed pharmacological agents include apolipoprotein A-I mimetics and the cholesteryl ester transfer protein (CETP) inhibitors, JTT-705 and torcetrapib, the latter of which has been recently withdrawn from clinical testing because of serious adverse effects. Emerging experimental studies investigating the complex pathways of HDL metabolism have identified several new targets for raising HDL-C with new pharmaceutical agents currently in development. For the time being, the long-acting formulations of nicotinic acid remain the most effective and best tolerated pharmacological strategy for raising HDL-C in patients already on statin therapy to control LDL-C. Therefore, raising HDL-C represents an important strategy for reducing residual cardiovascular risk in patients already optimally treated with statins, and should lead to further improvements in clinical outcomes in these patient groups. [ABSTRACT FROM AUTHOR]
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- 2008
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33. Myocardial reperfusion injury.
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Yellon DM and Hausenloy DJ
- Published
- 2007
34. Effect of remote ischaemic preconditioning on myocardial injury in patients undergoing coronary artery bypass graft surgery: a randomised controlled trial.
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Hausenloy DJ, Mwamure PK, Venugopal V, Harris J, Barnard M, Grundy E, Ashley E, Vichare S, Di Salvo C, Kolvekar S, Hayward M, Keogh B, MacAllister RJ, and Yellon DM
- Abstract
BACKGROUND: Whether remote ischaemic preconditioning, an intervention in which brief ischaemia of one tissue or organ protects remote organs from a sustained episode of ischaemia, is beneficial for patients undergoing coronary artery bypass graft surgery is unknown. We did a single-blinded randomised controlled study to establish whether remote ischaemic preconditioning reduces myocardial injury in these patients. METHODS: 57 adult patients undergoing elective coronary artery bypass graft surgery were randomly assigned to either a remote ischaemic preconditioning group (n=27) or to a control group (n=30) after induction of anaesthesia. Remote ischaemic preconditioning consisted of three 5-min cycles of right upper limb ischaemia, induced by an automated cuff-inflator placed on the upper arm and inflated to 200 mm Hg, with an intervening 5 min of reperfusion during which the cuff was deflated. Serum troponin-T concentration was measured before surgery and at 6, 12, 24, 48, and 72 h after surgery. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00397163. FINDINGS: Remote ischaemic preconditioning significantly reduced overall serum troponin-T release at 6, 12, 24, and 48 h after surgery. The total area under the curve was reduced by 43%, from 36.12 microg/L (SD 26.08) in the control group to 20.58 microg/L (9.58) in the remote ischaemic preconditioning group (mean difference 15.55 [SD 5.32]; 95% CI 4.88-26.21; p=0.005). INTERPRETATION: We have shown that adult patients undergoing elective coronary artery bypass graft surgery at a single tertiary centre could benefit from remote ischaemic preconditioning, using transient upper limb ischaemia. [ABSTRACT FROM AUTHOR]
- Published
- 2007
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35. Preconditioning the diabetic heart: the importance of Akt phosphorylation.
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Tsang A, Hausenloy DJ, Mocanu MM, Carr RD, Yellon DM, Tsang, Andrew, Hausenloy, Derek J, Mocanu, Mihaela M, Carr, Richard D, and Yellon, Derek M
- Abstract
Conflicting evidence exists whether diabetic myocardium can be protected by ischemic preconditioning (IPC). The phosphatidylinositol 3-kinase (PI3K)-Akt pathway is important in IPC. However, components of this cascade have been found to be defective in diabetes. We hypothesize that IPC in diabetic hearts depends on intact signaling through the PI3K-Akt pathway to reduce myocardial injury. Isolated perfused Wistar (normal) and Goto-Kakizaki (diabetic) rat hearts were subjected to 1) 35 min of regional ischemia and 120 min of reperfusion with infarct size determined; 2) preconditioning (IPC) using 5 min of global ischemia followed by 10 min of reperfusion performed one, two, or three times before prolonged ischemia; or 3) determination of Akt phosphorylation after stabilization or after one and three cycles of IPC. In Wistar rats, one, two, and three cycles of IPC reduced infarct size 44.7 +/- 3.8% (P < 0.05), 31.4 +/- 4.9% (P < 0.01), and 34.3 +/- 6.1% (P < 0.01), respectively, compared with controls (60.7 +/- 4.5%). However, in diabetic rats only three cycles of IPC significantly reduced infarction to 20.8 +/- 2.6% from 46.6 +/- 5.2% in controls (P < 0.01), commensurate with significant Akt phosphorylation after three cycles of IPC. To protect the diabetic myocardium, it appears necessary to increase the IPC stimulus to achieve the threshold for cardioprotection and a critical level of Akt phosphorylation to mediate myocardial protection. [ABSTRACT FROM AUTHOR]
- Published
- 2005
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36. T1 Mapping for Myocardial Extracellular Volume Measurement by CMR Bolus Only Versus Primed Infusion Technique
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White, SK, Sado, DM, Fontana, M, Banypersad, SM, Maestrini, V, Flett, AS, Piechnik, SK, Robson, MD, Hausenloy, DJ, Sheikh, AM, Hawkins, PN, and Moon, JC
- Subjects
bolus ,cardiac imaging techniques ,cardiac magnetic resonance ,dynamic ,ecv ,eq-cmr ,equilibrium ,extracellular space ,extracellular volume ,fibrosis ,infusion ,t1 mapping ,adult ,aged ,aged, 80 and over ,biopsy ,cardiomyopathy, hypertrophic ,contrast media ,extracellular matrix ,female ,gadolinium dtpa ,humans ,magnetic resonance imaging, cine ,male ,middle aged ,myocardium ,predictive value of tests ,reproducibility of results ,young adult ,radiology, nuclear medicine and imaging ,cardiology and cardiovascular medicine ,EQ-CMR ,ECV ,T1 mapping - Abstract
Objectives: The aim of this study was to determine the accuracy of the contrast "bolus only" T1 mapping cardiac magnetic resonance (CMR) technique for measuring myocardial extracellular volume fraction (ECV). Background: Myocardial ECV can be measured with T1 mapping before and after contrast agent if the contrast agent distribution between blood/myocardium is at equilibrium. Equilibrium distribution can be achieved with a primed contrast infusion (equilibrium contrast-CMR [EQ-CMR]) or might be approximated by the dynamic equilibration achieved by delayed post-bolus measurement. This bolus only approach is highly attractive, but currently limited data support its use. We compared the bolus only technique with 2 independent standards: collagen volume fraction (CVF) from myocardial biopsy in aortic stenosis (AS); and the infusion technique in 5 representative conditions. Methods: One hundred forty-seven subjects were studied: healthy volunteers (n = 50); hypertrophic cardiomyopathy (n = 25); severe AS (n = 22); amyloid (n = 20); and chronic myocardial infarction (n = 30). Bolus only (at 15 min) and infusion ECV measurements were performed and compared. In 18 subjects with severe AS the results were compared with histological CVF. Results: The ECV by both techniques correlated with histological CVF (n = 18, r2 = 0.69, p < 0.01 vs. r2 = 0.71, p < 0.01, p = 0.42 for comparison). Across health and disease, there was strong correlation between the techniques (r2 = 0.97). However, in diseases of high ECV (amyloid, hypertrophic cardiomyopathy late gadolinium enhancement, and infarction), Bland-Altman analysis indicates the bolus only technique has a consistent and increasing offset, giving a higher value for ECVs above 0.4 (mean difference ± limit of agreement for ECV 0.4 = 0.040 ± 0.075, p < 0.001). Conclusions: Bolus only, T1 mapping-derived ECV measurement is sufficient for ECV measurement across a range of cardiac diseases, and this approach is histologically validated in AS. However, when ECV is >0.4, the bolus only technique consistently measures ECV higher compared with infusion. © 2013 American College of Cardiology Foundation. © 2013 By Theamerican College of Cardiology Foundation.
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37. The evolving story of 'conditioning' to protect against acute myocardial ischaemia-reperfusion injury.
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Hausenloy DJ and Yellon DM
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- 2007
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38. A deep learning pipeline for automatic analysis of multi-scan cardiovascular magnetic resonance.
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Fadil, H., Totman, John J., Hausenloy, DJ, Ho, H-H., Joseph, P., Low, A.F-H., Richards, A.M., Chan, M.Y., Marchesseau, S., Fadil, H., Totman, John J., Hausenloy, DJ, Ho, H-H., Joseph, P., Low, A.F-H., Richards, A.M., Chan, M.Y., and Marchesseau, S.
- Abstract
BACKGROUND: Cardiovascular magnetic resonance (CMR) sequences are commonly used to obtain a complete description of the function and structure of the heart, provided that accurate measurements are extracted from images. New methods of extraction of information are being developed, among them, deep neural networks are powerful tools that showed the ability to perform fast and accurate segmentation. Iq1n order to reduce the time spent by reading physicians to process data and minimize intra- and inter-observer variability, we propose a fully automatic multi-scan CMR image analysis pipeline. METHODS: Sequence specific U-Net 2D models were trained to perform the segmentation of the left ventricle (LV), right ventricle (RV) and aorta in cine short-axis, late gadolinium enhancement (LGE), native T1 map, post-contrast T1, native T2 map and aortic flow sequences depending on the need. The models were trained and tested on a set of data manually segmented by experts using semi-automatic and manual tools. A set of parameters were computed from the resulting segmentations such as the left ventricular and right ventricular ejection fraction (EF), LGE scar percentage, the mean T1, T1 post, T2 values within the myocardium, and aortic flow. The Dice similarity coefficient, Hausdorff distance, mean surface distance, and Pearson correlation coefficient R were used to assess and compare the results of the U-Net based pipeline with intra-observer variability. Additionally, the pipeline was validated on two clinical studies. RESULTS: The sequence specific U-Net 2D models trained achieved fast (≤ 0.2 s/image on GPU) and precise segmentation over all the targeted region of interest with high Dice scores (= 0.91 for LV, = 0.92 for RV, = 0.93 for Aorta in average) comparable to intra-observer Dice scores (= 0.86 for LV, = 0.87 for RV, = 0.95 for aorta flow in average). The automatically and manually computed parameters were highly correlated (R = 0.91 in average) showing results superior t
39. Aprotinin -- still courting controversy.
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Hausenloy DJ, Pagano D, and Keogh B
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- 2008
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40. P143 Targeting the mitochondrial fission proteins, MiD49 and MiD51, as a therapeutic strategy for cardioprotection.
- Author
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Samangouei, P, Elder, JM, Burke, N, Hall, A, and Hausenloy, DJ
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TARGETED drug delivery ,MITOCHONDRIAL dynamics ,PROTEINS ,CARDIOVASCULAR system ,HEART disease related mortality ,REPERFUSION injury - Abstract
Background: Ischaemic heart disease is the major cause of morbidity and mortality worldwide. Novel therapeutic strategies are essential to protect the heart from acute ischaemia-reperfusion injury (IRI). It has been reported that inhibiting mitochondrial fission, protects the heart against cardiomyocyte death during acute IRI. We investigated the mitochondrial fission proteins, MiD49 and MiD51, as novel targets for cardioprotection,Methods and Results: Genetic ablation of both MiD49 and MiD51 in HL-1 cardiac cells (a murine atrial-derived cell line), using shRNAs had the following effects: (1) A significant increase in the proportion of cells expressing predominantly elongated mitochondria (81.5±2.9% MiD49+MiD51 knockdown vs. 49.4±4.9% vector control: n=120 cells/group; P<0.05); (2) It led to a delay in time taken to induce mitochondrial permeability transition pore (MPTP) opening (485±61 seconds MiD49+MiD51 knockdown vs. 233±20 seconds vector control: n=120 cells/group; P<0.05); (3) Cell death following simulated IRI was reduced (27.9±3.0% MiD49+MiD51 knockdown vs. 56.7±2.4% vector control: n=300 cells/group; P<0.05). Interestingly, the individual knockdown of either MiD49 or MiD51 alone had no effect on these parameters. Unexpectedly, the over-expression of either MiD49 or MiD51 had similar beneficial effects: (1) The formation of abnormally elongated (hyperfused) mitochondria with a peri-nuclear distribution; (2) It delayed the induction of MPTP opening (339±23 seconds MiD49 over-expression, 336±19 seconds MiD51 over-expression vs. 208±16 seconds vector control: n=120 cells/group; P<0.05); (3) It reduced cell death following simulated IRI (21.5±3.7% MiD49 over-expression, 20.0±3.7% MiD51 over-expression vs. 52.0±4.6% vector control: n=300; P<0.05). The explanation for this apparent beneficial effect with MiD49 or MiD51 over-expression, may be due to Drp1 sequestration to mitochondria, leading to unopposed abnormal mitochondrial elongation (hyperfusion).Conclusions: Here we show that combined knockdown of the newly discovered mitochondrial fission proteins, MiD49 and MiD51, induced mitochondrial elongation, delayed MPTP opening, and protected cells against simulated acute IRI, implicating MiD49 and MiD51 as novel targets for cardioprotection. Unexpectedly, the over-expression of these fission proteins induced a state of abnormal hyperfusion, delayed MPTP opening, and protected cells against simulated acute IRI. [ABSTRACT FROM AUTHOR]
- Published
- 2014
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41. P445 The differential effects of Sirtuin-3 in cardio-protection.
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Hall, A R, Dongworth, RK, Kumar, S, Burke, N, Yellon, DM, and Hausenloy, DJ
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CELL lines ,PHOSPHORYLATION ,LABORATORY mice ,GENETIC mutation ,HEART physiology ,REPERFUSION injury - Abstract
Background: A mitochondrial specific deacetylase, Sirtuin-3 has been reported to regulate oxidative phosphorylation, the activity of Cyclophilin D (a key component of the mitochondrial permeability transition pore, MPTP), and the ROS scavenger MnSOD. We hypothesised that Sirtuin-3 could be a potential therapeutic target for cardio-protection based its ability to prevent MPTP formation and inhibit ROS generation.Methods and Results: In HL-1 cells (a murine cardiac cell line), over-expression of Sirtuin-3 reduced cell death following simulated ischemia-reperfusion injury (assessed by propidium iodide staining). Futhermore, Sirtuin-3 over-expression reduced MPTP formation (assessed by ROS-induced mitochondrial depolarization), and induced mitochondrial fusion (assessed by 3 blinded investigators and the PEG fusion assay). The catalytically inactive mutant form of Sirtuin-3 failed to mediate any of these beneficial effects. To investigate the role of endogenous Sirtuin-3 in the adult heart, Sirtuin-3 (whole body) KO mice and WT littermates were subjected to in vivo cardiac ischemia (30 min) followed by 24 hrs reperfusion. myocardial infarct (MI) size was determined as a percentage of area at risk. Interestingly, no differences in MI size were observed between WT and KO mice under fed conditions. However, overnight fasting (to induce Sirtuin-3 expression and activity) resulted in a smaller MI size in the Sirtuin-3 KO when compared to WT mice.Conclusions: We report that the role of Sirtuin-3 in cardio-protection differs between the HL-1 cardiac cell line and the adult heart. In the HL-1 cell, Sirtuin-3 over-expression had beneficial effects against acute IRI, suggesting that activating Sirtuin-3 in this cell-line may be cardio-protective. In contrast, fasted mice deficient in Sirtuin-3 had smaller MI following IRI, suggesting that inhibiting Sirtuin-3 in the fasted adult heart may be cardio-protective. This finding may have clinical implications in patients who are fasted before surgery. [ABSTRACT FROM AUTHOR]
- Published
- 2014
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42. P166 Extracellular RNA in cardiac ischemia/reperfusion injury: prevention of heart failure and cell damage by RNase1.
- Author
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Cabrera-Fuentes, H A, Ruiz-Meana, M, Kostin, S, Lecour, S, Hausenloy, DJ, Garcia-Dorado, DJ, Schluter, KD, and Preissner, KT
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RNA ,REPERFUSION injury ,HEART failure ,RIBONUCLEASES ,MORTALITY ,MYOCARDIAL infarction - Abstract
Despite optimal therapy, the morbidity and mortality of patients presenting with an acute myocardial infarction (MI) remain significant. Extracellular RNA (eRNA), exposed after cell damage, serves as cofactor for coagulation proteases and cytokines thereby promoting their procoagulant and proinflammatory functions in vivo. Following myocardial ischemia/reperfusion (I/R) in mice or I/R induced in the isolated Langendorff heart, increased eRNA levels were found together with cell injury markers. Likewise, eRNA was released from cardiomyocytes under hypoxia and subsequently induced tumor-necrosis-factor-a (TNF-α) liberation by activation of TNF-α converting enzyme (TACE) and provoked cardiomyocyte death. Conversely, TNF-a promoted eRNA release especially under hypoxia, feeding a vicious cell damaging cycle during I/R. Administration of RNase1 or TAPI (TACE-inhibitor) prevented cell death and myocardial infarction. Likewise, RNase1 significantly reduced I/R-mediated energy exhaustion, opening of mitochondrial permeability transition pores (mPTP) as well as oxidative damage in cardiomyocytes. Together, RNase1 as well as inhibition of TACE provide novel therapeutic regimen to interfere with the adverse eRNA-TNF-a interplay and significantly reduce or prevent the pathological outcome of ischemic heart injury. [ABSTRACT FROM PUBLISHER]
- Published
- 2014
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43. P645 T2-mapping cardiac MRI for in vivo quantification of myocardial area-at-risk.
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Dongworth, RK, Campbell-Washburn, AE, Roberts, T, Yellon, DM, Lythgoe, MF, and Hausenloy, DJ
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CARDIAC magnetic resonance imaging ,GENE mapping ,REPERFUSION injury ,CARDIOTONIC agents ,MYOCARDIAL infarction ,LABORATORY mice - Abstract
Purpose: Novel therapeutic strategies are required to protect the heart against acute ischaemia-reperfusion injury (IRI). Assessing their cardioprotective efficacy requires measurement of infarct size (IS) and the "area-at-risk (AAR). T2-weighted cardiac magnetic resonance imaging (cMR) can delineate the AAR in vivo by detecting areas of oedema following IRI. However, clinical studies suggest that some cardioprotective interventions can reduce the extent of oedema measured by T2-weighted cMR, thereby affecting AAR measurement by this cMR method. We sought to investigate the validity of T2-mapping cMR for in vivo AAR quantification in hearts protected by ischaemic preconditioning (IPC).Methods: B6SV129 mice were subjected to in vivo acute IRI comprising LAD ligation for 30 minutes followed by 72 hours reperfusion. IPC-treated animals were subjected to a standard cardioprotective protocol of 5 minutes ischaemia and 5 minutes reperfusion prior to the main ischaemic insult. Following 3 days reperfusion, mice underwent cMR consisting of late-gadolinium enhancement and T2-mapping for assessment of infarct size and putative AAR, respectively. Immediately following cMR, hearts were excised and subjected to histological staining using triphenyl tetrazolium chloride and Evan's blue for infarct size and AAR, respectively. Assessment of cMR quantifications was performed by comparison with equivalent histological staining of left ventricular myocardial slices for infarct size (IS/LV%) and AAR (AAR/LV%).Results: cMR T2-maps of the myocardium in control and IPC-treated mice showed clearly defined regions of elevated T2-signal in spatially distinct regions of the myocardium. Comparison of T2-maps and histological staining for each slice demonstrated good agreement in the spatial localisation of AAR judged by T2-cMR and histology. Quantification of AAR from T2-maps showed no significant difference to AAR quantified by ‘gold-standard’ histological staining in control mice (AAR/LV% control: T2-cMR 60.4±2.4; versus histology 64.3±2.5: n=6, p>0.05). Importantly, T2-cMR significantly underestimated AAR in in IPC treated mice (AAR/LV% IPC: T2-cMR 46.0±13.2; versus histology 59.8±7.8: n=10, *p<0.05).Conclusions: Although the T2-mapping cMR protocol developed in here permits accurate quantification of myocardial area-at-risk in control mice following IRI; crucially, IPC significantly reduced the area of oedema and thus invalidated AAR measurement by T2-cMR in this model in the presence of IPC. Further investigation of the validity of T2-cMR for in vivo AAR assessment is now required for other therapeutic interventions. [ABSTRACT FROM AUTHOR]
- Published
- 2014
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44. Rapid assessment of myocardial infarct size in rodents using multi-slice inversion recovery late gadolinium enhancement CMR at 9.4T.
- Author
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Price AN, Cheung KK, Lim SY, Yellon DM, Hausenloy DJ, and Lythgoe MF
- Abstract
BACKGROUND: Myocardial infarction (MI) can be readily assessed using late gadolinium enhancement (LGE) cardiovascular magnetic resonance (CMR). Inversion recovery (IR) sequences provide the highest contrast between enhanced infarct areas and healthy myocardium. Applying such methods to small animals is challenging due to rapid respiratory and cardiac rates relative to T1 relaxation. METHODS: Here we present a fast and robust protocol for assessing LGE in small animals using a multi-slice IR gradient echo sequence for efficient assessment of LGE. An additional Look-Locker sequence was used to assess the optimum inversion point on an individual basis and to determine most appropriate gating points for both rat and mouse. The technique was applied to two preclinical scenarios: i) an acute (2 hour) reperfused model of MI in rats and ii) mice 2 days following non-reperfused MI. RESULTS: LGE images from all animals revealed clear areas of enhancement allowing for easy volume segmentation. Typical inversion times required to null healthy myocardium in rats were between 300-450 ms equivalent to 2-3 R-waves and ~330 ms in mice, typically 3 R-waves following inversion. Data from rats was also validated against triphenyltetrazolium chloride staining and revealed close agreement for infarct size. CONCLUSION: The LGE protocol presented provides a reliable method for acquiring images of high contrast and quality without excessive scan times, enabling higher throughput in experimental studies requiring reliable assessment of MI. [ABSTRACT FROM AUTHOR]
- Published
- 2011
45. Characterizing Nonculprit Lesions and Perivascular Adipose Tissue of Patients Following Acute Myocardial Infarction Using Coronary Computed Tomography Angiography: A Comparative Study.
- Author
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Wang X, Sia CH, Adamson PD, Greer CE, Huang W, Lee HK, Leng S, Loong YT, Raffiee NAS, Tan SY, Tan SH, Teo LLS, Wong SL, Yang X, Yew MS, Yong TH, Zhong L, Shaw LJ, Chan MYY, Hausenloy DJ, and Baskaran L
- Abstract
Background: The comparison of coronary computed tomography angiography plaques and perivascular adipose tissue (PVAT) between patients with acute myocardial infarction (AMI) posttreatment and patients with stable coronary artery disease is poorly understood. Our objective was to evaluate the differences in coronary computed tomography angiography-quantified plaque and PVAT characteristics in patients post-AMI and identify signs of residual inflammation., Methods and Results: We analyzed 205 patients (age, 59.77±9.24 years; 92.20% men) with AMI ≤1 month and matched them with 205 patients with stable coronary artery disease (age, 60.52±10.04 years; 90.24% men) based on age, sex, and cardiovascular risk factors. Coronary computed tomography angiography scans were assessed for nonculprit plaque and vessel characteristics, plaque volumes by composition, high-risk plaques, and PVAT mean attenuation. Both patient groups exhibited similar noncalcified plaque volumes (383.35±313.23 versus 378.63±426.25 mm
3 , P =0.899). However, multivariable analysis revealed that patients post-AMI had a greater patient-wise noncalcified plaque volume ratio (estimate, 0.089 [95% CI, 0.053-0.125], P <0.001), largely attributed to a higher fibrofatty and necrotic core volume ratio, along with higher peri-lesion PVAT mean attenuation (estimate, 3.968 [95% CI, 2.556-5.379], P <0.001). When adjusted for vessel length, patients post-AMI had more high-risk plaques (estimate, 0.417 [95% CI, 0.298-0.536], P <0.001) per patient., Conclusions: Patients post-AMI displayed heightened noncalcified plaque components, largely due to fibrofatty and necrotic core content, more high-risk plaques, and increased PVAT mean attenuation on a per-patient level, highlighting the necessity for refined risk assessment in patients with AMI after treatment.- Published
- 2024
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46. Acute Inhibition of Drp1 Mitigates Adverse Cardiac Remodelling following Chronic Reperfused Myocardial Infarction.
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Donner DG, Kong AM, Lees JG, Kiriazis H, Brown A, Tham YK, Holien JK, Shen HH, Hausenloy DJ, and Lim SY
- Published
- 2024
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47. The IMproving Preclinical Assessment of Cardioprotective Therapies (IMPACT): multicenter pig study on the effect of ischemic preconditioning.
- Author
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Kleinbongard P, Arriola CG, Badimon L, Crisostomo V, Giricz Z, Gyöngyösi M, Heusch G, Ibanez B, Kiss A, de Kleijn DPV, Podesser BK, Carracedo RR, Rodríguez-Sinovas A, Ruiz-Meana M, Sanchez Margallo FM, Vilahur G, Zamorano JL, Zaragoza C, Ferdinandy P, and Hausenloy DJ
- Abstract
Numerous cardioprotective interventions have been reported to reduce myocardial infarct size (IS) in pre-clinical studies. However, their translation for the benefit of patients with acute myocardial infarction (AMI) has been largely disappointing. One reason for the lack of translation is the lack of rigor and reproducibility in pre-clinical studies. To address this, we have established the European IMproving Preclinical Assessment of Cardioprotective Therapies (IMPACT) pig AMI network with centralized randomization and blinded core laboratory IS analysis and validated the network with ischemic preconditioning (IPC) as a positive control. Ten sites in the COST Innovators Grant (IG16225) network participated in the IMPACT network. Three sites were excluded from the final analysis through quality control of infarct images and use of pre-defined exclusion criteria. Using a centrally generated randomization list, pigs were allocated to myocardial ischemia/reperfusion (I/R, N = 5/site) or IPC + I/R (N = 5/site). The primary endpoint was IS [% area-at-risk (AAR)], as quantified by triphenyl-tetrazolium-chloride (TTC) staining in a centralized, blinded core laboratory (5 sites), or IS [% left-ventricular mass (LV)], as quantified by a centralized, blinded cardiac magnetic resonance (CMR) core laboratory (2 sites). In pooled analyses, IPC significantly reduced IS when compared to I/R (57 ± 14 versus 32 ± 19 [%AAR] N = 25 pigs/group; p < 0.001; 25 ± 13 versus 14 ± 8 [%LV]; N = 10 pigs/group; p = 0.021). In site-specific analyses, in 4 of the 5 sites, IS was significantly reduced by IPC when compared to I/R when quantified by TTC and in 1 of 2 sites when quantified by CMR. A pig AMI multicenter European network with centralized randomization and core blinded IS analysis was established and validated with the aim to improve the reproducibility of cardioprotective interventions in pre-clinical studies and the translation of cardioprotection for patient benefit., (© 2024. The Author(s).)
- Published
- 2024
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48. Interplay between the SAFE and the sphingolipid pathway for cardioprotection.
- Author
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Cour M, Pedretti S, Nduhirabandi F, Hacking D, Frias MA, Hausenloy DJ, and Lecour S
- Abstract
Aim: Activation of both the Survivor Activating Factor Enhancement (SAFE) pathway (including Tumor Necrosis Factor-alpha (TNF-α) and Signal Transducer and Activator of Transcription-3 (STAT-3)) and the sphingolipid signalling pathway (including sphingosine kinase-1 (SK1) and sphingosine-1 phosphate (S1P)) play a key role in promoting cardioprotection against ischemia-reperfusion injury (IRI). We investigated whether the activation of the SAFE pathway by exogenous S1P is dependent on the activation of SK1 for cardioprotection., Materials and Methods: Isolated cardiomyocytes from TNF-α knockout (KO) mice, cardiomyocyte-specific STAT-3 KO mice and their wild-type (WT) littermates were exposed to simulated ischemia in the presence of a trigger of the SAFE pathway (S1P) and SK1 inhibitor (SK1-I). Similarly, isolated perfused hearts from adult TNF-α KO, STAT-3 KO and WT mice were subjected to IRI with S1P and/or SK1-I. Cell viability, infarct size (IS) and SK1 activity were assessed., Key Findings: In isolated cardiomyocytes and in isolated hearts subjected to simulated ischemia/IRI, S1P pretreatment decreased cell death in WT mice, an effect that was abrogated in the presence of SK1-I. S1P failed to reduce cell death after simulated ischemia/IRI in both cardiomyocytes or hearts isolated from TNF-α KO and STAT-3 KO mice. Interestingly, S1P pretreatment increased SK1 activity in WT and STAT-3 KO mice, with no changes in TNF-α KO mice., Significance: Our data strongly suggest SK1 as a key component to activate STAT-3 downstream of TNF-α in the SAFE pathway, paving the way for the development of novel cardioprotective strategies that may target SK1 to modulate the SAFE pathway and increase cell survival following IRI., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)
- Published
- 2024
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49. Interleukin 11 therapy causes acute left ventricular dysfunction.
- Author
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Sweeney M, O'Fee K, Villanueva-Hayes C, Rahman E, Lee M, Tam CN, Pascual-Navarro E, Maatz H, Lindberg EL, Vanezis K, Ramachandra CJ, Andrew I, Jennings ER, Lim WW, Widjaja AA, Carling D, Hausenloy DJ, Hubner N, Barton PJR, and Cook SA
- Abstract
Aims: Interleukin 11 (IL11) was initially thought important for platelet production, which led to recombinant IL11 being developed as a drug to treat thrombocytopenia. IL11 was later found to be redundant for haematopoiesis and its use in patients is associated with unexplained and severe cardiac side effects. Here we aim to identify, for the first time, direct cardiomyocyte toxicities associated with IL11, which was previously believed cardioprotective., Methods and Results: We injected recombinant mouse lL11 (rmIL11) into mice and studied its molecular effects in the heart using immunoblotting, qRT-PCR, bulk RNA-seq, single nuclei RNA-seq (snRNA-seq) and ATAC-seq. The physiological impact of IL11 was assessed by echocardiography in vivo and using cardiomyocyte contractility assays in vitro. To determine the activity of IL11 specifically in cardiomyocytes we made two cardiomyocyte-specific Il11ra1 knockout (CMKO) mouse models using either AAV9-mediated and Tnnt2-restricted (vCMKO) or Myh6 (m6CMKO) Cre expression and an Il11ra1 floxed mouse strain. In pharmacologic studies, we studied the effects of JAK/STAT inhibition on rmIL11-induced cardiac toxicities. Injection of rmIL11 caused acute and dose-dependent impairment of left ventricular ejection fraction (saline: 62.4% ± 1.9; rmIL11: 32.6% ± 2.9, p<0.001, n=5). Following rmIL11 injection, myocardial STAT3 and JNK phosphorylation were increased and bulk RNA-seq revealed upregulation of pro-inflammatory pathways (TNFα, NFκB and JAK/STAT) and perturbed calcium handling. snRNA-seq showed rmIL11-induced expression of stress factors (Ankrd1, Ankrd23, Xirp2), activator protein-1 (AP-1) transcription factor genes and Nppb in the cardiomyocyte compartment. Following rmIL11 injection, ATAC-seq identified the Ankrd1 and Nppb genes and loci enriched for stress-responsive, AP-1 transcription factor binding sites. Cardiomyocyte-specific effects were examined in vCMKO and m6CMKO mice, which were both protected from rmIL11-induced left ventricular impairment and molecular pathobiologies. In mechanistic studies, inhibition of JAK/STAT signalling with either ruxolitinib or tofacitinib prevented rmIL11-induced cardiac dysfunction., Conclusions: Injection of IL11 directly activates IL11RA/JAK/STAT3 in cardiomyocytes to cause acute heart failure. Our data overturn the earlier assumption that IL11 is cardioprotective and explain the serious cardiac side effects associated with IL11 therapy., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)
- Published
- 2024
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50. Correction: Consumption of different types of meat and the risk of chronic limb-threatening ischemia: the Singapore Chinese Health Study.
- Author
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Fangting Ying A, Talaei M, Hausenloy DJ, and Koh WP
- Published
- 2024
- Full Text
- View/download PDF
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