Reduced reactive O2 species formation and preserved mitochondrial NADH and [Ca2+] levels during short-term 17 °C ischemia in intact hearts

Riess, Matthias L.; Camara, Amadou K.S.; Kevin, Leo G.; An, Jianzhong; Stowe, David F.

doi:10.1016/j.cardiores.2003.09.016

Cited by 109 publications

(144 citation statements)

References 53 publications

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“…The current results showing that cooling decreases cardiomyocyte ROS generation at reperfusion are consistent with prior studies of surgical cooling. Reiss et al (28) found evidence that hypothermia can suppress ROS generation at reperfusion following ischemia in whole hearts. Our findings here extend this work in two important ways.…”

Section: Discussionmentioning

confidence: 99%

Therapeutic hypothermia cardioprotection via Akt- and nitric oxide-mediated attenuation of mitochondrial oxidants

Shao¹,

Sharp²,

Wojcik

et al. 2010

American Journal of Physiology-Heart and Circulatory Physiology

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TL. Therapeutic hypothermia cardioprotection via Akt-and nitric oxide-mediated attenuation of mitochondrial oxidants. Am J Physiol Heart Circ Physiol 298: H2164-H2173, 2010. First published April 9, 2010 doi:10.1152/ajpheart.00994.2009.-Therapeutic hypothermia (TH) is a promising cardioprotective treatment for cardiac arrest and acute myocardial infarction, but its cytoprotective mechanisms remain unknown. In this study, we developed a murine cardiomyocyte model of ischemia-reperfusion injury to better determine the mechanisms of TH cardioprotection. We hypothesized that TH manipulates Akt, a survival kinase that mediates mitochondrial protection by modulating reactive oxygen species (ROS) and nitric oxide (NO) generation. Cardiomyocytes, isolated from 1-to 2-day-old C57BL6/J mice, were exposed to 90 min simulated ischemia and 3 h reperfusion. For TH, cells were cooled to 32°C during the last 20 min of ischemia and the first hour of reperfusion. Cell viability was evaluated by propidium iodide and lactate dehydrogenase release. ROS production was measured by 6-carboxy-2=,7=-dichlorodihydrofluorescein diacetate and mitochondrial membrane potential (⌬⌿m) by 5,5=,6,6=-tetrachloro-1,1=,3,3=-tetraethylbenzimidazoly-carbocyanine iodide (JC-1). Phospho (p)-Akt (Thr308), p-Akt (Ser473), and phosphorylated heat shock protein 27 (p-HSP27) (Ser82) were analyzed by Western blot analysis. TH attenuated reperfusion ROS generation, increased NO, maintained ⌬⌿m, and decreased cell death [19.3 Ϯ 3.3% (n ϭ 11) vs. 44.7 Ϯ 2.7% (n ϭ 10), P Ͻ 0.001]. TH also increased p-Akt during ischemia before reperfusion. TH protection and attenuation of ROS were blocked by the inhibition of Akt and NO synthase but not by a cGMP inhibitor. HSP27, a regulator of Akt, also exhibited increased phosphorylation (Ser82) during ischemia with TH. We conclude that TH cardioprotection is mediated by enhanced Akt/HSP27 phosphorylation and enhanced NO generation, resulting in the attenuation of ROS generation and the maintenance of ⌬⌿m following ischemia-reperfusion.ischemia-reperfusion; reactive oxygen species; cardiomyocyte DESPITE INITIAL resuscitation, many cardiac arrest patients die within hours after the return of spontaneous circulation (ROSC) (12). This ischemia-reperfusion (I/R) injury is likely related to significant increases in tissue oxidant stress seen within minutes of cardiopulmonary resuscitation (CPR) and ROSC (19). Recently, it has been demonstrated that significant levels of oxidant stress in the heart following cardiac arrest originate from the mitochondria within minutes of reperfusion (11). In isolated cardiomyocytes, simulated I/R induces mitochondrial reactive oxygen species (ROS) generation, contractile dysfunction, mitochondrial release of cytochrome c, caspase activation, opening of the mitochondrial permeability transition pore, and ultimately cardiomyocyte death (4, 29, 40).To date, therapeutic hypothermia (TH) is the only treatment currently known to improve survival in the clinical postcardiac arrest setting (27). Such cool...

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Section: Discussionmentioning

confidence: 99%

Therapeutic hypothermia cardioprotection via Akt- and nitric oxide-mediated attenuation of mitochondrial oxidants

Shao¹,

Sharp²,

Wojcik

et al. 2010

American Journal of Physiology-Heart and Circulatory Physiology

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“…An (15), all F signals were corrected for the corresponding temperature-and I/R-induced changes in auto F (NADH and FAD) obtained in previous experiments (1,2). The indo 1 transient is nonlinearly proportional to m [Ca 2ϩ ], which was calculated according to the following equation (39,40,48)…”

Section: Methodsmentioning

confidence: 99%

“…In previous experiments, S460 was measured as 2.29, Rmin as 0.57, and Rmax as 6.22 at the chosen photomultiplier settings (39,40). Kd was calculated as 249 nm at 37°C (48) and was corrected for changes in temperature (42).…”

Section: Methodsmentioning

confidence: 99%

“…The strategy behind hypothermic protection against ischemia, i.e., better tissue perfusion, and improved metabolic and mechanical function on reperfusion, is the reduced mitochondrial respiration and oxidative phosphorylation during ischemia that results in better mitochondrial respiration and regeneration of ATP on reperfusion. For example, we demonstrated that NADH, m [Ca 2ϩ ], and reactive O 2 species (ROS) levels were less altered during and after 30 min of ischemia at 17°C vs. 37°C (39). We reported that the more severe the hypothermia, the later is the onset of deleterious changes in mitochondrial function (1,2,16,22,31).…”

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confidence: 99%

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ROS scavenging before 27°C ischemia protects hearts and reduces mitochondrial ROS, Ca²⁺ overload, and changes in redox state

Camara¹,

Aldakkak²,

Heisner³

et al. 2007

American Journal of Physiology-Cell Physiology

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In this study, we determined 1) whether ROS scavenging only during cold perfusion before global ischemia improves mitochondrial and myocardial function, and 2) which ROS leads to compromised cardiac function during ischemia and reperfusion (I/R) injury. Using fluorescence spectrophotometry, we monitored redox balance (NADH and FAD), O 2•Ϫ levels and mitochondrial Ca 2ϩ (m[Ca 2ϩ ]) at the left ventricular wall in 120 guinea pig isolated hearts divided into control (Con), MnTBAP (a superoxide dismutase 2 mimetic), MnTBAP (M) ϩ catalase (C) ϩ glutathione (G) (MCG), CϩG (CG), and N G -nitro-L-arginine methyl ester (L-NAME; a nitric oxide synthase inhibitor) groups. After an initial period of warm perfusion, hearts were treated with drugs before and after at 27°C. Drugs were washed out before 2 h at 27°C ischemia and 2 h at 37°C reperfusion. We found that on reperfusion the MnTBAP group had the worst functional recovery and largest infarction with the highest m [Ca 2ϩ ], most oxidized redox state and increased ROS levels. The MCG group had the best recovery, the smallest infarction, the lowest ROS level, the lowest m [Ca 2ϩ ], and the most reduced redox state. CG and L-NAME groups gave results intermediate to those of the MnTBAP and MCG groups. Our results indicate that the scavenging of cold-induced O 2•Ϫ species to less toxic downstream products additionally protects during and after cold I/R by preserving mitochondrial function. Because MnTBAP treatment showed the worst functional return along with poor preservation of mitochondrial bioenergetics, accumulation of H 2 O 2 and/or hydroxyl radicals during cold perfusion may be involved in compromised function during subsequent cold I/R injury. hypothermic ischemia; mitochondrial Ca 2ϩ ; reactive oxygen species HYPOTHERMIA of the arrested, ischemic heart improves its function on reperfusion compared with the normothermic arrested ischemic heart. The strategy behind hypothermic protection against ischemia, i.e., better tissue perfusion, and improved metabolic and mechanical function on reperfusion, is the reduced mitochondrial respiration and oxidative phosphorylation during ischemia that results in better mitochondrial respiration and regeneration of ATP on reperfusion. For example, we demonstrated that NADH, m [Ca 2ϩ ], and reactive O 2 species (ROS) levels were less altered during and after 30 min of ischemia at 17°C vs. 37°C (39). We reported that the more severe the hypothermia, the later is the onset of deleterious changes in mitochondrial function (1,2,16,22,31).Although hypothermia is very protective against ischemia, hypothermic perfusion, e.g., before subsequent cardiac ischemia, may cause injury due to altered cellular ion homeostasis resulting from impaired membrane ion pumps and exchangers and/or to reduced activity of enzymes responsible for mitochondrial respiration, scavenging of ROS, and contractile activity. A well-known effect of hypothermia is hypercontracture with elevated cytosolic [Ca 2ϩ ] (42). Another is a decreasing temperature-depende...

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“…Free radicals such as superoxide anion (O 2 -º), per hydroxyl radical (HO 2 º), hydroxyl radical (ºOH) are produced during normal cellular metabolism and Reactive oxygen species (ROS) are generated during electron transport chain, mainly in the mitochondria [1]. ROS is believed to play a significant role in the progression of various diseases like cancer, cataract, atherosclerosis, diabetes and neurodegenaration.…”

Section: Introductionmentioning

confidence: 99%

Significantly high levels of estrogen and MDA together induce tumor progression in Oral squamous cell carcinoma

Nath¹,

Anand²,

Anshu³

et al. 2014

IOSRJESTFT

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Reduced reactive O2 species formation and preserved mitochondrial NADH and [Ca2+] levels during short-term 17 °C ischemia in intact hearts

Cited by 109 publications

References 53 publications

Therapeutic hypothermia cardioprotection via Akt- and nitric oxide-mediated attenuation of mitochondrial oxidants

Therapeutic hypothermia cardioprotection via Akt- and nitric oxide-mediated attenuation of mitochondrial oxidants

ROS scavenging before 27°C ischemia protects hearts and reduces mitochondrial ROS, Ca²⁺ overload, and changes in redox state

Significantly high levels of estrogen and MDA together induce tumor progression in Oral squamous cell carcinoma

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Reduced reactive O2 species formation and preserved mitochondrial NADH and [Ca2+] levels during short-term 17 °C ischemia in intact hearts

Cited by 109 publications

References 53 publications

Therapeutic hypothermia cardioprotection via Akt- and nitric oxide-mediated attenuation of mitochondrial oxidants

Therapeutic hypothermia cardioprotection via Akt- and nitric oxide-mediated attenuation of mitochondrial oxidants

ROS scavenging before 27°C ischemia protects hearts and reduces mitochondrial ROS, Ca2+ overload, and changes in redox state

Significantly high levels of estrogen and MDA together induce tumor progression in Oral squamous cell carcinoma

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ROS scavenging before 27°C ischemia protects hearts and reduces mitochondrial ROS, Ca²⁺ overload, and changes in redox state