scholarly journals Paracrine effects of hypoxic fibroblast-derived factors on the MPT-ROS threshold and viability of adult rat cardiac myocytes

2008 ◽  
Vol 294 (6) ◽  
pp. H2653-H2658 ◽  
Author(s):  
K. Shivakumar ◽  
S. J. Sollott ◽  
M. Sangeetha ◽  
S. Sapna ◽  
B. Ziman ◽  
...  
Keyword(s):  
Dna Synthesis ◽  
Conditioned Medium ◽  
Cardiac Myocytes ◽  
Cytokine Production ◽  
Mitochondrial Permeability Transition ◽  
Cardiac Fibroblasts ◽  
Ischemia Reperfusion ◽  
Oxidant Stress ◽  
Cardiac Cells ◽  
Tnf Α

Cardiac fibroblasts contribute to multiple aspects of myocardial function and pathophysiology. The pathogenetic relevance of cytokine production by these cells under hypoxia, however, remains unexplored. With the use of an in vitro cell culture model, this study evaluated cytokine production by hypoxic cardiac fibroblasts and examined two distinct effects of hypoxic fibroblast-conditioned medium (HFCM) on cardiac myocytes and fibroblasts. Hypoxia caused a marked increase in the production of tumor necrosis factor (TNF)-α by cardiac fibroblasts. HFCM significantly enhanced the susceptibility of cardiac myocytes to reactive oxygen species (ROS)-induced mitochondrial permeability transition (MPT), determined by high-precision confocal line-scan imaging following controlled, photoexcitation-induced ROS production within individual mitochondria. Furthermore, exposure of cardiac myocytes to HFCM for 5 h led to loss of viability, as evidenced by change in morphology and annexin staining. HFCM also decreased DNA synthesis in cardiac fibroblasts. Normoxic fibroblast-conditioned medium spiked with TNF-α at 200 pg/ml, a concentration comparable to that in HFCM, promoted loss of myocyte viability and decreased DNA synthesis in cardiac fibroblasts. These effects of HFCM are similar to the reported effects of hypoxia per se on these cell types, showing that hypoxic fibroblast-derived factors may amplify the distinct effects of hypoxia on cardiac cells. Importantly, because both hypoxia and oxidant stress prevail in a setting of ischemia and reperfusion, the effects of soluble factors from hypoxic fibroblasts on the MPT-ROS threshold and viability of myocytes may represent a novel paracrine mechanism that could exacerbate ischemia-reperfusion injury to cardiomyocytes.

Neuroprotective effect of hydroxy safflor yellow A against cerebral ischemia-reperfusion injury in rats: putative role of mPTP

2016 ◽  
Vol 27 (1) ◽  
pp. 1-8 ◽  
Author(s):  
Sruthi Ramagiri ◽  
Rajeev Taliyan
Keyword(s):  
Oxidative Damage ◽  
Protective Effect ◽  
Mitochondrial Permeability Transition ◽  
Ischemia Reperfusion Injury ◽  
Neuroprotective Effect ◽  
Ischemia Reperfusion ◽  
Radical Scavenger ◽  
Neuroprotective Effects ◽  
Y Maze ◽  
Tnf Α

AbstractHydroxy safflor yellow A (HSYA) has been translated clinically for cardiovascular diseases. HSYA is also greatly acknowledged for its protective effects against cerebral ischemic-reperfusion (I/R) injury. Although the precise mechanism of cerebral I/R injury is not fully understood, oxygen-derived free radicals and mitochondrial permeability transition pore (mPTP) opening during I/R injury are widely recognized as an important contributor to neuronal injury. Thus, we speculated that the neuroprotective effects of HSYA against cerebral I/R injury may be associated with mPTP modulation.Induction of I/R injury was achieved by 60 min of middle cerebral artery occlusion, followed by reperfusion for 24 h. For behavior and cognitive assessment, neurological scoring (NSS), rotarod, and Y-maze task were performed. Oxidative damage was measured in terms of markers such as malondialdehyde, reduced glutathione, and catalase levels and cerebral infarct volumes were quantified using 2,3,5-triphenyl tetrazolinium chloride staining. I/R injury-induced inflammation was determined using tumor necrosis factor-α (TNF-α) levels.Animals exposed to I/R injury showed neurological severity, functional and cognitive disability, elevated oxidative markers, and TNF-α levels along with large infarct volumes. HSYA treatment during onset of reperfusion ameliorated performance in NSS, rotarod and Y-maze attenuated oxidative damage, TNF-α levels, and infarction rate. However, treatment with carboxyatractyloside, an mPTP opener, 20 min before HSYA, attenuated the protective effect of HSYA.Our study confirmed that protective effect of HSYA may be conferred through its free radical scavenger action followed by inhibiting the opening of mPTP during reperfusion and HSYA might act as a promising therapeutic agent against cerebral I/R injury.

scholarly journals Tsg101 Is Involved in the Sorting and Re-Distribution of Glucose Transporter-4 to the Sarcolemma Membrane of Cardiac Myocytes

Cells ◽  
2020 ◽  
Vol 9 (9) ◽  
pp. 1936
Author(s):  
Kobina Essandoh ◽  
Shan Deng ◽  
Xiaohong Wang ◽  
Yutian Li ◽  
Qianqian Li ◽  
...  
Keyword(s):  
Cardiac Myocytes ◽  
Glucose Transporter ◽  
Ischemia Reperfusion ◽  
Susceptibility Gene ◽  
Cardiac Cells ◽  
Acid Oxidation ◽  
Glucose Transporter 4 ◽  
Loss Of Function ◽  
Glut 4 ◽  
Insulin Dependent

Cardiac cells can adapt to pathological stress-induced energy crisis by shifting from fatty acid oxidation to glycolysis. However, the use of glucose-insulin-potassium (GIK) solution in patients undergoing cardiac surgery does not alleviate ischemia/reperfusion (I/R)-induced energy shortage. This indicates that insulin-mediated translocation of glucose transporter-4 (Glut-4) is impaired in ischemic hearts. Indeed, cardiac myocytes contain two intracellular populations of Glut-4: an insulin-dependent non-endosomal pool (also referred to as Glut-4 storage vesicles, GSVs) and an insulin-independent endosomal pool. Tumor susceptibility gene 101 (Tsg101) has been implicated in the endosomal recycling of membrane proteins. In this study, we aimed to examine whether Tsg101 regulated the sorting and re-distribution of Glut-4 to the sarcolemma membrane of cardiomyocytes under basal and ischemic conditions, using gain- and loss-of-function approaches. Forced overexpression of Tsg101 in mouse hearts and isolated cardiomyocytes could promote Glut-4 re-distribution to the sarcolemma, leading to enhanced glucose entry and adenosine triphosphate (ATP) generation in I/R hearts which in turn, attenuation of I/R-induced cardiac dysfunction. Conversely, knockdown of Tsg101 in cardiac myocytes exhibited opposite effects. Mechanistically, we identified that Tsg101 could interact and co-localize with Glut-4 in the sarcolemma membrane of cardiomyocytes. Our findings define Tsg101 as a novel regulator of cardiac Glut-4 trafficking, which may provide a new therapeutic strategy for the treatment of ischemic heart disease.

scholarly journals Multidimensional Regulation of Cardiac Mitochondrial Potassium Channels

Cells ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 1554
Author(s):  
Bogusz Kulawiak ◽  
Piotr Bednarczyk ◽  
Adam Szewczyk
Keyword(s):  
Potassium Channels ◽  
Reperfusion Injury ◽  
Mitochondrial Permeability Transition ◽  
Ischemia Reperfusion Injury ◽  
Current Knowledge ◽  
Ischemia Reperfusion ◽  
Permeability Transition ◽  
Cardiac Cells ◽  
Cardiac Ischemia ◽  
Inner Mitochondrial Membrane

Mitochondria play a fundamental role in the energetics of cardiac cells. Moreover, mitochondria are involved in cardiac ischemia/reperfusion injury by opening the mitochondrial permeability transition pore which is the major cause of cell death. The preservation of mitochondrial function is an essential component of the cardioprotective mechanism. The involvement of mitochondrial K+ transport in this complex phenomenon seems to be well established. Several mitochondrial K+ channels in the inner mitochondrial membrane, such as ATP-sensitive, voltage-regulated, calcium-activated and Na+-activated channels, have been discovered. This obliges us to ask the following question: why is the simple potassium ion influx process carried out by several different mitochondrial potassium channels? In this review, we summarize the current knowledge of both the properties of mitochondrial potassium channels in cardiac mitochondria and the current understanding of their multidimensional functional role. We also critically summarize the pharmacological modulation of these proteins within the context of cardiac ischemia/reperfusion injury and cardioprotection.

scholarly journals Differential Effects of Amrinone and Milrinone Upon Myocardial Inflammatory Signaling

Circulation ◽  
2002 ◽  
Vol 106 (12_suppl_1) ◽  
Author(s):  
Nikhil K. Chanani ◽  
Douglas B. Cowan ◽  
Koh Takeuchi ◽  
Dimitrios N. Poutias ◽  
Lina M. Garcia ◽  
...  
Keyword(s):  
Cytokine Production ◽  
Inflammatory Responses ◽  
Vascular Endothelial Cells ◽  
Myocardial Dysfunction ◽  
Ischemia Reperfusion ◽  
Phosphodiesterase Inhibitors ◽  
Mobility Shift ◽  
Inflammatory Signaling ◽  
Tnf Α ◽  
Cox 2

Background Mounting evidence links systemic and local inflammatory cytokine production to myocardial dysfunction and injury occurring during ischemia-reperfusion, cardiopulmonary bypass, and heart failure. Phosphodiesterase inhibitors (PDEIs), used frequently in these states, can modulate inflammatory signaling. The mechanisms for these effects are unclear. We therefore examined the effects of 2 commonly used PDEIs, amrinone and milrinone, on cardiac cell inflammatory responses. Methods and Results Primary rat cardiomyocyte cultures were treated with endotoxin (LPS) or tumor necrosis factor-α (TNF-α), alone or in the presence of clinically relevant concentrations of amrinone or milrinone. Regulation of nuclear factor-kappa B (NFκB), nitric oxide synthase and cyclooxygenase isoforms, and cytokine production were assessed by electrophoretic mobility shift assays, Western immunoblotting, and enzyme-linked immunoassays, respectively. Both LPS and TNF-α induced significant NFκB activation, cyclooxygenase-2 (COX-2) expression, and inducible NO synthase (iNOS) and cytokine production; with the exception of COX-2 expression, all were significantly reduced by amrinone, beginning at concentrations of 10 to 50 μmol/L. In contrast, milrinone increased nuclear NFκB translocation, iNOS and COX-2 expression, and cardiomyocyte production of interleukin-1β. Cell-permeable cAMP increased inflammatory gene expression, whereas cell-permeable cGMP had no effect, indicating that the effects of amrinone were not due to phosphodiesterase inhibition. Similar results were seen in macrophages and coronary vascular endothelial cells. Conclusions Both amrinone and milrinone have significant effects on cardiac inflammatory signaling. Overall, amrinone reduces activation of the key transcription factor NFκB and limits the production of pro-inflammatory cytokines, whereas milrinone does not.

scholarly journals Low frequency electromagnetic field decreases ischemia–reperfusion injury of human cardiomyocytes and supports their metabolic function

2018 ◽  
Vol 243 (10) ◽  
pp. 809-816 ◽  
Author(s):  
Dariusz Biały ◽  
Magdalena Wawrzyńska ◽  
Iwona Bil-Lula ◽  
Anna Krzywonos-Zawadzka ◽  
Agnieszka Sapa-Wojciechowska ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Electromagnetic Field ◽  
Reperfusion Injury ◽  
Cardiac Myocytes ◽  
Metabolic Activity ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Low Frequency ◽  
Cardiac Cells ◽  
Human Cardiomyocytes

Electromagnetic field at extremely low frequencies plays a significant role in the physiological function of human tissues and systems. It is shown that electromagnetic field inhibits production of reactive oxygen species which are involved in heart injury triggered by oxidative stress. We hypothesize that low frequency electromagnetic field protects function of cardiac cells from ischemia–reperfusion injury. Human cardiac myocytes, endothelial cells, and cardiac fibroblast underwent ischemia–reperfusion conditions in the presence or in the absence of low frequency electromagnetic field. LDH and MMP-2 activities (as markers of cell injury), and cell metabolic activity (by fluorescein diacetate staining) were measured to determine the protective role of low frequency electromagnetic field. Our data showed that short courses of low frequency electromagnetic field protect cardiac cells from cellular damage and preserve their metabolic activity during ischemia–reperfusion. This study demonstrates the possibility to use of low frequency electromagnetic field as strategy for the prevention or therapy of ischemia–reperfusion injury. Impact statement In our study, we showed that LF-EMF may be protective for heart during ischemia–reperfusion (I/R). Following is the short description of the main findings: (a) the response to the I/R injury was different for endothelial cells, fibroblasts, and cardiomyocytes; (b) I/R decreases MMP-2 activity in cardiac myocytes and fibroblasts; (c) I/R increases MMP-2 activity in endothelial cells; (d) LF-EMF reverses these changes; (e) LF-EMF protects cells from injury and preserves their metabolic activity.

scholarly journals MicroRNA-21 Mediates the Protective Effect of Cardiomyocyte-Derived Conditioned Medium on Ameliorating Myocardial Infarction in Rats

Cells ◽  
2019 ◽  
Vol 8 (8) ◽  
pp. 935 ◽  
Author(s):  
Chih-Hung Chen ◽  
Shu-Yuan Hsu ◽  
Chien-Chih Chiu ◽  
Steve Leu
Keyword(s):  
Myocardial Infarction ◽  
Protective Effect ◽  
Conditioned Medium ◽  
Rat Model ◽  
Intercellular Communication ◽  
Immune Cell ◽  
Cardiac Fibroblasts ◽  
Cardiac Cells ◽  
Cell Infiltration ◽  
Immune Cell Infiltration

Conditioned medium derived from ischemic myocardium improves rodent cardiac function after myocardial infarction. Exosomal miRNA-mediated intercellular communication is considered to mediate the protective effect of conditioned medium against ischemic injury. Oxygen–glucose-deprivation (OGD)-treated cardiac cells and a rat model with acute myocardial infarction (AMI) were applied. The expression profiles of myocardial-disease-associated miRNAs in cardiomyocytes, cardiac fibroblasts, ventricular myocardium, and conditioned medium derived from cardiomyocytes under ischemic stresses were analyzed. Primary cultured cell model and a rat model with myocardial infarction were applied to examine the role of miRNA in regulating cardiomyocyte apoptosis, fibroblast activation, immune cell infiltration, and myocardial infarction. Results showed that expression levels of miR-21 in cardiomyocytes, cardiac fibroblasts, and conditioned medium (CM) derived from cardiomyocytes were up-regulated with OGD treatment. With the depletion of miR-21, the protective effect of CM on cardiomyocytes against oxidative stress, enhanced fibroblast activation, and promotion of angiogenesis in endothelial cells were reduced. Administration of CM reduced the infarcted size and immune cell infiltration in myocardium of rats with AMI, while depletion of miR-21 reduced the effect of CM. In conclusion, miR-21 plays a role in intercellular communication among ischemic cardiac cells. The expression of miR-21 is important for the protective effect of conditioned medium against myocardial infarction.

Angiotensin II and mechanical stretch induce production of tumor necrosis factor in cardiac fibroblasts

1999 ◽  
Vol 276 (6) ◽  
pp. H1968-H1976 ◽  
Author(s):  
Tomoyuki Yokoyama ◽  
Kenichi Sekiguchi ◽  
Toru Tanaka ◽  
Koichi Tomaru ◽  
Masashi Arai ◽  
...  
Keyword(s):  
Tumor Necrosis Factor ◽  
Mechanical Stress ◽  
Cardiac Myocytes ◽  
Tumor Necrosis ◽  
Cardiac Fibroblasts ◽  
Mechanical Stretch ◽  
Intracellular Camp ◽  
Ang Ii ◽  
Tnf Α ◽  
Necrosis Factor

To determine whether ANG II as well as mechanical stress affect the production of tumor necrosis factor (TNF) in the heart, neonatal rat cardiac myocytes and fibroblasts were cultured separately and treated for 6 h with ANG II, lipopolysaccharide (LPS), or cyclic mechanical stretch. LPS induced the production of TNF in cardiac myocytes and fibroblasts. However, TNF synthesis in fibroblasts was 20- to 40-fold higher than in myocytes. ANG II (≥10−8 M) and mechanical stretch stimulated the production of TNF in cardiac fibroblasts but not in myocytes. Furthermore, both ANG II and LPS increased the expression of TNF-α mRNA in cardiac fibroblasts. Isoproterenol inhibited both LPS- and ANG II-induced production of TNF in cardiac fibroblasts with increasing intracellular cAMP level. Moreover, both isoproterenol and dibutyryl cAMP inhibited LPS-induced TNF-α mRNA expression. Thus activation of the renin-angiotensin system, as well as mechanical stress, can stimulate production of TNF in cardiac fibroblasts. Furthermore, β-adrenergic receptors may be responsible for the regulation of TNF synthesis at the transcriptional level by elevating intracellular cAMP.

Ischemic proximal tubular injury primes mice to endotoxin-induced TNF-α generation and systemic release

2005 ◽  
Vol 289 (2) ◽  
pp. F289-F297 ◽  
Author(s):  
R. A. Zager ◽  
Ali C. M. Johnson ◽  
Sherry Y. Hanson ◽  
Steve Lund
Keyword(s):  
Ischemia Reperfusion ◽  
Oxidant Stress ◽  
Sepsis Syndrome ◽  
Renal Ischemia ◽  
Mrna Levels ◽  
Tubular Injury ◽  
Ischemic Event ◽  
Tnf Α ◽  
Proximal Tubular

Endotoxemia (LPS) can exacerbate ischemic tubular injury and acute renal failure (ARF). The present study tested the following hypothesis: that acute ischemic damage sensitizes the kidney to LPS-mediated TNF-α generation, a process that can worsen inflammation and cytotoxicity. CD-1 mice underwent 15 min of unilateral renal ischemia. LPS (10 mg/kg iv), or its vehicle, was injected either 45 min before, or 18 h after, the ischemic event. TNF-α responses were gauged 2 h post-LPS injection by measuring plasma/renal cortical TNF-α and renal cortical TNF-α mRNA. Values were contrasted to those obtained in sham-operated mice or in contralateral, nonischemic kidneys. TNF-α generation by isolated mouse proximal tubules (PTs), and by cultured proximal tubule (HK-2) cells, in response to hypoxia-reoxygenation (H/R), oxidant stress, antimycin A (AA), or LPS was also assessed. Ischemia-reperfusion (I/R), by itself, did not raise plasma or renal cortical TNF-α or its mRNA. However, this same ischemic insult dramatically sensitized mice to LPS-mediated TNF-α increases in both plasma and kidney (∼2-fold). During late reperfusion, increased TNF-α mRNA levels also resulted. PTs generated TNF-α in response to injury. Neither AA nor LPS alone induced an HK-2 cell TNF-α response. However, when present together, AA+LPS induced approximately two- to fivefold increases in TNF-α/TNF-α mRNA. We conclude that modest I/R injury, and in vitro HK-2 cell mitochondrial inhibition (AA), can dramatically sensitize the kidney/PTs to LPS-mediated TNF-α generation and increases in TNF-α mRNA. That ischemia can “prime” tubules to LPS response(s) could have potentially important implications for sepsis syndrome, concomitant renal ischemia, and for the induction of ARF.

scholarly journals Melatonin Attenuates Cardiac Ischemia-Reperfusion Injury through Modulation of IP3R-Mediated Mitochondria-ER Contact

2021 ◽  
Vol 2021 ◽  
pp. 1-12
Author(s):  
Wenya Li ◽  
Botao Liu ◽  
Lin Wang ◽  
Jilie Liu ◽  
Xiuhui Yang ◽  
...  
Keyword(s):  
Reperfusion Injury ◽  
Mitochondrial Permeability Transition ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Permeability Transition ◽  
Cardiac Cells ◽  
Mitochondrial Potential ◽  
Rat Cardiomyocytes ◽  
Postischemic Reperfusion

Although the interplay between mitochondria and ER has been identified as a crucial regulator of cellular homeostasis, the pathogenic impact of alterations in mitochondria-ER contact sites (MERCS) during myocardial postischemic reperfusion (I/R) injury remains incompletely understood. Therefore, in our study, we explored the beneficial role played by melatonin in protecting cardiomyocytes against reperfusion injury via stabilizing mitochondria-ER interaction. In vitro exposure of H9C2 rat cardiomyocytes to hypoxia/reoxygenation (H/R) augmented mitochondrial ROS synthesis, suppressed both mitochondrial potential and ATP generation, and increased the mitochondrial permeability transition pore (mPTP) opening rate. Furthermore, H/R exposure upregulated the protein content of CHOP and caspase-12, two markers of ER stress, and enhanced the transcription of main MERCS tethering proteins, namely, Fis1, BAP31, Mfn2, and IP3R. Interestingly, all the above changes could be attenuated or reversed by melatonin treatment. Suggesting that melatonin-induced cardioprotection works through normalization of mitochondria-ER interaction, overexpression of IP3R abolished the protective actions offered by melatonin on mitochondria-ER fitness. These results expand our knowledge on the cardioprotective actions of melatonin during myocardial postischemic reperfusion damage and suggest that novel, more effective treatments for acute myocardial reperfusion injury might be achieved through modulation of mitochondria-ER interaction in cardiac cells.

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