OXIDATIVE STRESS AND RELATED RESPONSES ARE INDUCED DURING EX-SITU HEART PERFUSION AND MAY CONTRIBUTE TO THE FUNCTIONAL DECLINE OF THE EX-SITU-PERFUSED HEART

2019 ◽  
Vol 35 (10) ◽  
pp. S106
Author(s):  
S. Hatami ◽  
X. Qi ◽  
C. White ◽  
M. Buchko ◽  
S. Bozso ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Functional Decline ◽  
Ex Situ ◽  
Perfused Heart ◽  
Heart Perfusion

INFLAMMATION, OXIDATIVE STRESS AND FUNCTIONAL DECLINE OF THE HEART DURING EX SITU HEART PERFUSION: ARE LEUKOCYTES THE ULTIMATE VILLAINS?

2020 ◽  
Vol 36 (10) ◽  
pp. S69
Author(s):  
S. Hatami ◽  
X. Qi ◽  
S. Bozso ◽  
M. Khan ◽  
B. Tkachuk ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Functional Decline ◽  
Ex Situ ◽  
Heart Perfusion

scholarly journals A Novel Rat Model of Cardiac Donation After Circulatory Death Combined With Normothermic ex situ Heart Perfusion

2021 ◽  
Vol 8 ◽  
Author(s):  
Jiale Li ◽  
Chuqing Xue ◽  
Xiao Ling ◽  
Yu Xie ◽  
Desai Pavan ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Inflammatory Response ◽  
Rat Model ◽  
Energy State ◽  
Ex Situ ◽  
Cell Swelling ◽  
Donation After Circulatory Death ◽  
Histopathological Changes ◽  
Heart Perfusion ◽  
Circulatory Death

Background: In heart transplantation, the adoption of hearts from donation after circulatory death (DCD) is considered to be a promising approach to expanding the donor pool. Normothermic ex situ heart perfusion (ESHP) is emerging as a novel preservation strategy for DCD hearts. Therefore, pre-clinical animal models of ESHP are essential to address some key issues before efficient clinical translation. We aim to develop a novel, reproducible, and economical rat model of DCD protocol combined with normothermic ESHP.Methods: Circulatory death of the anesthetized rats in the DCD group was declared when systolic blood pressure below 30 mmHg or asystole was observed after asphyxiation. Additional 15 min of standoff period was allowed to elapse. After perfusion of cold cardioplegia, the DCD hearts were excised and perfused with allogenic blood-based perfusate at constant flow for 90 min in the normothermic ESHP system. Functional assessment and blood gas analysis were performed every 30 min during ESHP. The alteration of DCD hearts submitted to different durations of ESHP (30, 60, and 90 min) in oxidative stress, apoptosis, tissue energy state, inflammatory response, histopathology, cell swelling, and myocardial infarction during ESHP was evaluated. Rats in the non-DCD group were treated similarly but not exposed to warm ischemia and preserved by the normothermic ESHP system for 90 min.Results: The DCD hearts showed compromised function at the beginning of ESHP and recovered over time, while non-DCD hearts presented better cardiac function during ESHP. The alteration of DCD hearts in oxidative stress, apoptosis, tissue energy state, histopathological changes, cell swelling, and inflammatory response didn't differ among different durations of ESHP. At the end of 90-min ESHP, DCD, and non-DCD hearts presented similarly in apoptosis, oxidative stress, inflammatory response, myocardial infarction, and histopathological changes. Moreover, the DCD hearts had lower energy storage and more evident cell swelling compared to the non-DCD hearts.Conclusion: We established a reproducible, clinically relevant, and economical rat model of DCD protocol combined with normothermic ESHP, where the DCD hearts can maintain a stable state during 90-min ESHP.

scholarly journals Myocardial Functional Decline During Prolonged Ex Situ Heart Perfusion

2019 ◽  
Vol 108 (2) ◽  
pp. 499-507 ◽  
Author(s):  
Sanaz Hatami ◽  
Christopher W. White ◽  
Shubham Shan ◽  
Alois Haromy ◽  
Xiao Qi ◽  
...  
Keyword(s):  
Functional Decline ◽  
Ex Situ ◽  
Heart Perfusion

scholarly journals The Impact of Ex Situ Heart Perfusion in Pediatric Transplantation: An Analysis of the UNOS Registry

2021 ◽  
Vol 40 (4) ◽  
pp. S39
Author(s):  
J. Conway ◽  
Y. Hong ◽  
T. Pidborochynski ◽  
M. Khan ◽  
D.H. Freed
Keyword(s):  
Ex Situ ◽  
Pediatric Transplantation ◽  
Heart Perfusion ◽  
The Impact

Abstract P293: Endogenous Lats2 Plays an Important Role in Mediating Myocardial Injury Caused by Ischemia/Reperfusion Through Inhibition of FoxO3

2011 ◽  
Vol 109 (suppl_1) ◽  
Author(s):  
Dan Shao ◽  
Peiyong Zhai ◽  
Junichi Sadoshima
Keyword(s):  
Oxidative Stress ◽  
Myocardial Injury ◽  
Ischemia Reperfusion ◽  
Systolic Pressure ◽  
Left Ventricular ◽  
Dominant Negative ◽  
Area At Risk ◽  
Perfused Heart ◽  
Developed Pressure

Lats2 is a tumor suppressor and a serine/threonine kinase, acting downstream of mammalian sterile 20 like kinase1 (Mst1), which stimulates apoptosis and inhibits hypertrophy in cardiomyocytes (CM). We investigated the role of Lats2 in mediating myocardial injury after ischemia/reperfusion (IR). Phosphorylation of YAP, an in vivo substrate of Lats2, was increased after 45 minutes ischemia followed by 24 hours reperfusion in control mouse hearts compared with sham, but not in dominant negative (DN) Lats2 transgenic mouse (Tg) hearts, suggesting that Lats2 is activated by IR. The size of myocardial infarction (MI)/area at risk was significantly smaller in Tg mice than in NTg mice (19% and 49%, p<0.01). And there were fewer TUNEL positive cells in Tg than in NTg mice (0.04% and 0.11%, p<0.05). Following 30 min of global ischemia and 60 min of reperfusion in Langendorff perfused heart preparations, left ventricular (LV) systolic pressure (100 vs 71mmHg, p<0.05) and LV developed pressure (79 vs 47 mmHg, p<0.05) were significantly greater in Tg than in NTg mice, indicating that suppression of Lats2 induces better functional recovery after IR. Oxidative stress, as evaluated by 8-OHdG staining, was attenuated in Tg mice. In cultured CMs, DN-Lats2 significantly decreased H 2 O 2 -induced cell death. Overexpression of Lats2 significantly downregulated (51% and 75%, p<0.05), whereas that of DN-Last2 upregulated (100 and 70%, p<0.05), MnSOD and catalase, suggesting that Lats2 negatively regulates expression of antioxidants. Reporter gene assays showed that overexpression of Lats2 significantly inhibits (−70%), whereas knocking down Lats2 by sh-Lats2 increases (+60%), FoxO3-mediated transcriptional activity. Overexpression of Lats2 in CMs inhibited FoxO3 expression, whereas that of DN-Lats2 significantly inhibited FoxO3 downregulation after IR in vivo, suggesting that Lats2 negatively regulates FoxO3 protein expression, which may lead to the downregulation of MnSOD and catalase. Taken together, these results suggest that endogenous Lats2 plays an important role in mediating myocardial injury in response to IR, In part through downregulation of FoxO3 and consequent downregulation of antioxidants and increased oxidative stress in the heart.

scholarly journals Effects of Caloric Restriction on Cardiac Oxidative Stress and Mitochondrial Bioenergetics: Potential Role of Cardiac Sirtuins

2013 ◽  
Vol 2013 ◽  
pp. 1-11 ◽  
Author(s):  
Ken Shinmura
Keyword(s):  
Oxidative Stress ◽  
Free Radical ◽  
Oxidative Damage ◽  
Caloric Restriction ◽  
Functional Decline ◽  
Cellular Damage ◽  
Free Radical Theory ◽  
Radical Theory ◽  
Stress Theory

The biology of aging has not been fully clarified, but the free radical theory of aging is one of the strongest aging theories proposed to date. The free radical theory has been expanded to the oxidative stress theory, in which mitochondria play a central role in the development of the aging process because of their critical roles in bioenergetics, oxidant production, and regulation of cell death. A decline in cardiac mitochondrial function associated with the accumulation of oxidative damage might be responsible, at least in part, for the decline in cardiac performance with age. In contrast, lifelong caloric restriction can attenuate functional decline with age, delay the onset of morbidity, and extend lifespan in various species. The effect of caloric restriction appears to be related to a reduction in cellular damage induced by reactive oxygen species. There is increasing evidence that sirtuins play an essential role in the reduction of mitochondrial oxidative stress during caloric restriction. We speculate that cardiac sirtuins attenuate the accumulation of oxidative damage associated with age by modifying specific mitochondrial proteins posttranscriptionally. Therefore, the distinct role of each sirtuin in the heart subjected to caloric restriction should be clarified to translate sirtuin biology into clinical practice.

Abstract MP124: De-palmitoylation of Cysteine 202 of Cyclophilin-D by Calcium is Important for the Activation of the Permeability Transition Pore

2020 ◽  
Vol 127 (Suppl_1) ◽  
Author(s):  
Georgios Amanakis ◽  
Junhui Sun ◽  
Maria Fergusson ◽  
Chengyu Liu ◽  
Jeff D Molkentin ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Mitochondrial Permeability Transition ◽  
Ischemia Reperfusion ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Calcium Overload ◽  
Mitochondrial Calcium ◽  
Cyclophilin D ◽  
Perfused Heart ◽  
Knock Out

Cyclophilin-D (CypD) is a well-known regulator of the mitochondrial permeability transition pore (PTP), the main effector of cardiac ischemia/reperfusion (I/R) injury characterized by oxidative stress and calcium overload. However, the mechanism by which CypD activates PTP is poorly understood. Cysteine 202 of CypD (C202) is highly conserved across species and can undergo redox-sensitive post-translational modifications, such as S-nitrosylation and oxidation. To study the importance of C202, we developed a knock-in mouse model using CRISPR where CypD-C202 was mutated to a serine (C202S). Hearts from these mice are protected against I/R injury. We found C202 to be abundantly S-palmitoylated under baseline conditions while C202 was de-palmitoylated during ischemia in WT hearts. To further investigate the mechanism of de-palmitoylation during ischemia, we considered the increase of matrix calcium, oxidative stress and uncoupling of ATP synthesis from the electron transport chain. We tested the effects of these conditions on the palmitoylation of CypD in isolated cardiac mitochondria. The palmitoylation of CypD was assessed using a resin-assisted capture (Acyl-RAC). We report that oxidative stress (phenylarsenide) and uncoupling (CCCP) had no effect on CypD palmitoylation (p>0.05, n=3 and n=7 respectively). However, calcium overload led to de-palmitoylation of CypD to the level observed at the end ischemia (1±0.10 vs 0.63±0.09, p=0.012, n=9). To further test the hypothesis that calcium regulates S-palmitoylation of CypD we measured S-palmitoylation of CypD in non-perfused heart lysates from global germline mitochondrial calcium uniporter knock-out mice (MCU-KO), which have reduced mitochondrial calcium and we found an increase in S-palmitoylation of CypD (WT 1±0.04 vs MCU-KO 1.603±0.11, p<0.001, n=6). The data are consistent with the hypothesis that C202 is important for the CypD mediated activation of PTP. Ischemia leads to increased matrix calcium which in turn promotes the de-palmitoylation of CypD on C202. The now free C202 can further be oxidized during reperfusion leading to the activation of PTP. Thus, S-palmitoylation and oxidation of CypD-C202 possibly target CypD to the PTP, making them potent regulators of cardiac I/R injury.

Metabolic Alterations in Myocardial Metabolism during Ex Situ Heart Perfusion

2019 ◽  
Vol 38 (4) ◽  
pp. S237
Author(s):  
S. Hatami ◽  
C.W. White ◽  
X. Qi ◽  
M. Buchko ◽  
S. Himmat ◽  
...  
Keyword(s):  
Myocardial Metabolism ◽  
Ex Situ ◽  
Metabolic Alterations ◽  
Heart Perfusion

scholarly journals Oxidative Stress Induced Inflammation Initiates Functional Decline of Tear Production

PLoS ONE ◽  
2012 ◽  
Vol 7 (10) ◽  
pp. e45805 ◽  
Author(s):  
Yuichi Uchino ◽  
Tetsuya Kawakita ◽  
Masaki Miyazawa ◽  
Takamasa Ishii ◽  
Hiromi Onouchi ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Functional Decline ◽  
Tear Production

scholarly journals Echocardiographic Assessment of Left Ventricular Function in Ex Situ Heart Perfusion using Pump Supported and Passive Afterload Working Mode, a pilot study.

2020 ◽  
Author(s):  
Arnaud Romeo Mbadjeu Hondjeu ◽  
Azad Mashari ◽  
Ryan Ramos ◽  
Giulia Maria Ruggeri ◽  
Joshua Qua Hiansen ◽  
...  
Keyword(s):  
Pilot Study ◽  
Left Ventricular Function ◽  
Ventricular Function ◽  
Left Ventricular ◽  
Ex Situ ◽  
Heart Perfusion ◽  
Echocardiographic Assessment ◽  
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