Oxidative stress-induced formation of a positive-feedback loop for the sustained activation of p38 MAPK leading to the loss of cell division in cardiomyocytes soon after birth

Matsuyama, Daisuke; Kikuchi, Kôichi

doi:10.1007/s00395-011-0178-8

Cited by 42 publications

(24 citation statements)

References 48 publications

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“…These hypoxia-mediated changes within the SSM allowed intact and functional mitochondria to be maintained under stress, resembling that induced by preconditioning [23,26]. Interestingly, the inner mitochondrial membrane protein connexin 43 is expressed at much higher levels in SSM than in IFM, and has been shown to be essential for ischemic preconditioning and regulates ROS generation; therefore, it could potentially contribute to the observed difference between the SSM and IFM in the present study [2,3,22,30,45].…”

Section: Discussionmentioning

confidence: 56%

Metabolic adaptation to chronic hypoxia in cardiac mitochondria

et al. 2012

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Chronic hypoxia decreases cardiomyocyte respiration, yet the mitochondrial mechanisms remain largely unknown. We investigated the mitochondrial metabolic pathways and enzymes that were decreased following in vivo hypoxia, and questioned whether hypoxic adaptation was protective for the mitochondria. Wistar rats were housed in hypoxia (7 days acclimatisation and 14 days at 11% oxygen), while control rats were housed in normoxia. Chronic exposure to physiological hypoxia increased haematocrit and cardiac vascular endothelial growth factor, in the absence of weight loss and changes in cardiac mass. In both subsarcolemmal (SSM) and interfibrillar (IFM) mitochondria isolated from hypoxic hearts, state 3 respiration rates with fatty acid were decreased by 17-18%, and with pyruvate were decreased by 29-15%, respectively. State 3 respiration rates with electron transport chain (ETC) substrates were decreased only in hypoxic SSM, not in hypoxic IFM. SSM from hypoxic hearts had decreased activities of ETC complexes I, II and IV, which were associated with decreased reactive oxygen species generation and protection against mitochondrial permeability transition pore (MPTP) opening. In contrast, IFM from hypoxic hearts had decreased activity of the Krebs cycle enzyme, aconitase, which did not modify ROS production or MPTP opening. In conclusion, cardiac mitochondrial respiration was decreased following chronic hypoxia, associated with downregulation of different pathways in the two mitochondrial populations, determined by their subcellular location. Hypoxic adaptation was not deleterious for the mitochondria, in fact, SSM acquired increased protection against oxidative damage under the oxygen-limited conditions.

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Section: Discussionmentioning

confidence: 56%

Metabolic adaptation to chronic hypoxia in cardiac mitochondria

et al. 2012

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“…For instance, it has been shown that cytokinesis failure leading to binucleated cell formation was associated with oxidative stress in CHO-K1 cells (Lin et al, 2009). In another study, scavenging of ROS during fetal-neonatal transition resulted in a decrease in the number of binucleated cardiomyocytes (Matsuyama and Kawahara, 2011). A correlative in vivo study was performed in mice, where the authors showed that vitamin C deficiency induces elevated ROS production, which causes oxidative liver injury and the increase of BN hepatocytes (Park et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

Smooth Muscle Cells Isolated from Thoracic Aortic Aneurysms Exhibit Increased Genomic Damage, but Similar Tendency for Apoptosis

Acılan

Serhatlı

Kaçar

et al. 2012

DNA and Cell Biology

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Aortic aneurysms (AA) are characterized by structural deterioration leading to progressive dilation. During the development of AA, two key structural changes are pronounced, one being degradation of extracellular matrix and the other loss of smooth muscle cells (SMCs) through apoptosis. Reactive oxygen species (ROS) are produced above physiological levels in dilated (aneurismal) part of the aorta compared to the nondilated part and they are known to be associated with both the extracellular matrix degradation and the loss of SMCs. In this study, we hypothesized that aneurismal SMCs are more prone to apoptosis and that at least some cells undergo apoptosis due to elevated ROS in the aortic wall. To test this hypothesis, we first isolated SMCs from thoracic aneurismal tissue and compared their apoptotic tendency with normal SMCs in response to H 2 O 2 , oxidized sterol, or UV treatment. Exposed cells exhibited morphological changes characteristic of apoptosis, such as cell shrinkage, membrane blebbing, chromatin condensation, and DNA fragmentation. Terminal deoxynucleotidyl transferased UTP nick end labeling (TUNEL) further confirmed the fragmentation of nuclear DNA in these cells. Vascular SMCs were analyzed for their micronuclei (MN) and binucleate (BN) frequency as indicators of genomic abnormality. These data were then compared to patient parameters, including age, gender, hypertension, or aortic diameter for existing correlations. While the tendency for apoptosis was not significantly different compared to normal cells, both the %MN and %BN were higher in aneurismal SMCs. The data suggest that there is increased DNA damage in TAA samples, which might play a pivotal role in disease development.

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“…Interestingly, p38 is part of a ROS-induced positive-feedback loop during heart development. Sustained activation of p38 soon after birth may contribute to the loss of cell division and binucleation in mammalian cardiomyocytes (Matsuyama and Kawahara, 2011). …”

Section: Mitochondria Modulate Mapk Signalingmentioning

confidence: 99%

Crosstalk between mitogen-activated protein kinases and mitochondria in cardiac diseases: Therapeutic perspectives

Javadov

Jang

Agostini

2014

Pharmacology & Therapeutics

132

125

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Cardiovascular diseases cause more mortality and morbidity worldwide than any other diseases. Although many intracellular signaling pathways influence cardiac physiology and pathology, the mitogen-activated protein kinase (MAPK) family has garnered significant attention because of its vast implications in signaling and cross-talk with other signaling networks. The extensively studied MAPKs ERK1/2, p38, JNK, and ERK5, demonstrate unique intracellular signaling mechanisms, responding to a myriad of mitogens and stressors and influencing the signaling of cardiac development, metabolism, performance, and pathogenesis. Definitive relationships between MAPK signaling and cardiac dysfunction remain elusive, despite 30 years of extensive clinical studies and basic research of various animal/cell models, severities of stress, and types of stimuli. Still, several studies have proven the importance of MAPK cross-talk with mitochondria, powerhouses of the cell that provide over 80% of ATP for normal cardiomyocyte function and play a crucial role in cell death. Although many questions remain unanswered, there exists enough evidence to consider the possibility of targeting MAPK-mitochondria interactions in the prevention and treatment of heart disease. The goal of this review is to integrate previous studies into a discussion of MAPKs and MAPK-mitochondria signaling in cardiac diseases, such as myocardial infarction (ischemia), hypertrophy and heart failure. A comprehensive understanding of relevant molecular mechanisms, as well as challenges for studies in this area, will facilitate the development of new pharmacological agents and genetic manipulations for therapy of cardiovascular diseases.

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Oxidative stress-induced formation of a positive-feedback loop for the sustained activation of p38 MAPK leading to the loss of cell division in cardiomyocytes soon after birth

Cited by 42 publications

References 48 publications

Metabolic adaptation to chronic hypoxia in cardiac mitochondria

Metabolic adaptation to chronic hypoxia in cardiac mitochondria

Smooth Muscle Cells Isolated from Thoracic Aortic Aneurysms Exhibit Increased Genomic Damage, but Similar Tendency for Apoptosis

Crosstalk between mitogen-activated protein kinases and mitochondria in cardiac diseases: Therapeutic perspectives

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