Alda-1, an Activator of ALDH2, Improves Postresuscitation Cardiac and Neurological Outcomes by Inhibiting Pyroptosis in Swine

Diao, Mengyuan; Xu, Jing; Wang, Jiangang; Zhang, Minhai; Wu, Chenghao; Hu, Xin; Zhu, Ying; Zhang, Mao; Hu, Wei

doi:10.1007/s11064-021-03511-x

Cited by 12 publications

(14 citation statements)

References 40 publications

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“…If not, CPR was immediately restarted for 2 min prior to another electrical shock. This protocol was repeated until ROSC or for a total of 18 min ( 12 , 13 ). Following ROSC, the animals were monitored for 4 h, then intravascular catheters were removed, and thereafter the propofol was stopped.…”

Section: Methodsmentioning

confidence: 99%

The combination of chest compression synchronized ventilation and aortic balloon occlusion improve the outcomes of cardiopulmonary resuscitation in swine

Khan

Zhang

et al. 2022

Front. Med.

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AimThe primary mission of cardiopulmonary resuscitation (CPR) is to provide adequate blood flow and oxygen delivery for restoring spontaneous circulation from cardiac arrest (CA) events. Previously, studies demonstrated that chest compression synchronized ventilation (CCSV) improved systemic oxygen supply during CPR, and aortic balloon occlusion (ABO) augments the efficacy of external CPR by increasing blood perfusion to vital organs. However, both them failed to make a significant improvement in return of spontaneous circulation (ROSC). In this study, we investigated the effects of combined CCSV and ABO on the outcomes of CPR in swine.MethodsThirty-one male domestic swine were subjected to 8 min of electrically induced and untreated CA followed by 8 min of CPR. CPR was performed by continuous chest compressions and mechanical ventilation. At the beginning of CPR, the animals were randomized to receive intermittent positive pressure ventilation (IPPV, n = 10), CCSV (n = 7), IPPV + ABO (n = 7), or CCSV + ABO (n = 7). During CPR, gas exchange and systemic hemodynamics were measured, and ROSC was recorded. After resuscitation, the function and injury biomarkers of vital organs including heart, brain, kidney, and intestine were evaluated.ResultsDuring CPR, PaO2 was significantly higher accompanied by significantly greater regional cerebral oxygen saturation in the CCSV and CCSV + ABO groups than the IPPV group. Coronary perfusion pressure, end-tidal carbon dioxide, and carotid blood flow were significantly increased in the IPPV + ABO and CCSV + ABO groups compared with the IPPV group. ROSC was achieved in five of ten (IPPV), five of seven (CCSV), six of seven (IPPV + ABO), and seven of seven (CCSV + ABO) swine, with the rate of resuscitation success being significantly higher in the CCSV + ABO group than the IPPV group (P = 0.044). After resuscitation, significantly improved myocardial and neurological function, and markedly less cardiac, cerebral, renal, and intestinal injuries were observed in the CCSV + ABO group compared with the IPPV group.ConclusionThe combination of CCSV and ABO improved both ventilatory and hemodynamic efficacy during CPR, promoted ROSC, and alleviated post-resuscitation multiple organ injury in swine.

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Section: Methodsmentioning

confidence: 99%

The combination of chest compression synchronized ventilation and aortic balloon occlusion improve the outcomes of cardiopulmonary resuscitation in swine

Khan

Zhang

et al. 2022

Front. Med.

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“…In another study, the expression of cleaved Caspase-1 and GSDMD were reduced in myocardium through immunofluorescence staining Inhibiting the production of ROS could also inhibit the cleavage of Caspase-1, reducing the formation of pores in the membrane and the production of proinflammatory cytokines, and finally inhibit the pyroptosis of cells (36). The protective effect of ALDH2 was abolished with the addition of daidzin, which blocks the ALDH2 activation role of Alda-1 (42).…”

Section: Aldehyde Dehydrogenase 2 Reduces Oxidative Stress To Allevia...mentioning

confidence: 94%

“…Chen et al and Zhang et al (37,46) have confirmed that ALDH2 in addition to decomposing 4-HNE and MDA, can also reduce 4-HNE protein adduct formation, lessening the severity of oxidative damage by acetaldehyde and its metabolites (47). In addition, ALDH2 activation by Alda-1 is partially resolved by lessening of the production of ROS and extend the slowing or prevention of NLRP3 inflammasomeinduced pyroptosis (36).…”

Section: Aldehyde Dehydrogenase 2 Reduces Oxidative Stress To Allevia...mentioning

confidence: 95%

Aldehyde dehydrogenase 2 and NOD-like receptor thermal protein domain associated protein 3 inflammasome in atherosclerotic cardiovascular diseases: A systematic review of the current evidence

Shi

Yue

et al. 2023

Front. Cardiovasc. Med.

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Inflammation and dyslipidemia underlie the pathological basis of atherosclerosis (AS). Clinical studies have confirmed that there is still residual risk of atherosclerotic cardiovascular diseases (ASCVD) even after intense reduction of LDL. Some of this residual risk can be explained by inflammation as anti-inflammatory therapy is effective in improving outcomes in subjects treated with LDL-lowering agents. NOD-like receptor thermal protein domain associated protein 3 (NLRP3) inflammasome activation is closely related to early-stage inflammation in AS. Aldehyde dehydrogenase 2 (ALDH2) is an important enzyme of toxic aldehyde metabolism located in mitochondria and works in the metabolism of toxic aldehydes such as 4-HNE and MDA. Despite studies confirming that ALDH2 can negatively regulate NLRP3 inflammasome and delay the development of atherosclerosis, the mechanisms involved are still poorly understood. Reactive Oxygen Species (ROS) is a common downstream pathway activated for NLRP3 inflammasome. ALDH2 can reduce the multiple sources of ROS, such as oxidative stress, inflammation, and mitochondrial damage, thereby reducing the activation of NLRP3 inflammasome. Further, according to the downstream of ALDH2 and the upstream of NLRP3, the molecules and related mechanisms of ALDH2 on NLRP3 inflammasome are comprehensively expounded as possible. The potential mechanism may provide potential inroads for treating ASCVD.

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“…Aldehyde dehydrogenase 2 (ALDH2) has been proven to protect the heart and brain against regional I/R injury, in which the protective role is related to the inhibition of pyroptosis. ALDH2 activator N- (1,3-benzodioxol-5-ylmethyl)-2,6-dichloro-benzamide (Alda-1) would improve post-resuscitation cardiac and neurological outcomes in a clinically relevant swine model of cardiac arrest and resuscitation ( 115 ). Silencing CMKLR1 could inhibit the expression of activated Caspase-1 and IL-1β, and reduce the occurrence of pyroptosis ( 116 ).…”

Section: Potential Clinical Applications Of Pyroptosis To Ameliorate ...mentioning

confidence: 99%

Cardiac Remodeling in Heart Failure: Role of Pyroptosis and Its Therapeutic Implications

Chai

Xue

Shi

et al. 2022

Front. Cardiovasc. Med.

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Pyroptosis is a kind of programmed cell death closely related to inflammation. The pathways that mediate pyroptosis can be divided into the Caspase-1-dependent canonical pathway and the Caspase4/5/11-dependent non-canonical pathway. The most significant difference from other cell death is that pyroptosis rapidly causes rupture of the plasma membrane, cell expansion, dissolution and rupture of the cell membrane, the release of cell contents and a large number of inflammatory factors, and send pro-inflammatory signals to adjacent cells, recruit inflammatory cells and induce inflammatory responses. Cardiac remodeling is the basic mechanism of heart failure (HF) and the core of pathophysiological research on the underlying mechanism. A large number of studies have shown that pyroptosis can cause cardiac fibrosis, cardiac hypertrophy, cardiomyocytes death, myocardial dysfunction, excessive inflammation, and cardiac remodeling. Therefore, targeting pyroptosis has a good prospect in improving cardiac remodeling in HF. In this review, the basic molecular mechanism of pyroptosis is summarized, the relationship between pyroptosis and cardiac remodeling in HF is analyzed in-depth, and the potential therapy of targeting pyroptosis to improve adverse cardiac remodeling in HF is discussed, providing some ideas for improving the study of adverse cardiac remodeling in HF.

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Alda-1, an Activator of ALDH2, Improves Postresuscitation Cardiac and Neurological Outcomes by Inhibiting Pyroptosis in Swine

Cited by 12 publications

References 40 publications

The combination of chest compression synchronized ventilation and aortic balloon occlusion improve the outcomes of cardiopulmonary resuscitation in swine

The combination of chest compression synchronized ventilation and aortic balloon occlusion improve the outcomes of cardiopulmonary resuscitation in swine

Aldehyde dehydrogenase 2 and NOD-like receptor thermal protein domain associated protein 3 inflammasome in atherosclerotic cardiovascular diseases: A systematic review of the current evidence

Cardiac Remodeling in Heart Failure: Role of Pyroptosis and Its Therapeutic Implications

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