Possible Pathway of Na&lt;sup&gt;+&lt;/sup&gt; Flux into Mitochondria in Ischemic Heart

Tanonaka, Kouichi; Motegi, Kanataka; Arino, Toru; Marunouchi, Tetsuro; Takagi, Norio; Takeo, Satoshi

doi:10.1248/bpb.b12-00010

Cited by 9 publications

(5 citation statements)

References 22 publications

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“…We showed in a previous study that SBFI fluorescence from isolated mitochondria prepared from rat hearts increased in the presence of sodium lactate. 21) Our findings using skinned fibers in this study were similar to those in the previous study using isolated mitochondria. Therefore, the increased fluorescent signal from the skinned fibers loaded with SBFI may be due to Na + accumulation in the cardiac mitochondria due to the presence of sodium lactate.…”

Section: Discussionsupporting

confidence: 91%

Effects of 2-Octynyladenosine (YT-146) on Mitochondrial Function in Ischemic/Reperfused Rat Hearts

Sasamori

Abe

Marunouchi

et al. 2015

Biological & Pharmaceutical Bulletin

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This study investigated the effects of an adenosine receptor agonist, 2-octynyladenosine (YT-146), on mitochondrial function in ischemic and ischemic/reperfused hearts. Isolated rat hearts were perfused in the Langendorff manner with a constant flow rate, and exposed to 30 min of ischemia followed by 60 min of reperfusion. Preischemic treatment with YT-146 significantly improved postischemic recovery of left ventricular developed pressure. The high-energy phosphate content in reperfused hearts treated with YT-146 was also more greatly restored than in untreated hearts. YT-146 treatment attenuated the Na content of a mitochondria-enriched fraction, but not the myocardial Na content, at the end of ischemia. These results suggest that preischemic YT-146 treatment preserves the energy-producing ability of mitochondria during ischemia in the Na -accumulated myocardium. YT-146 also attenuated both the sodium lactate-induced decrease in mitochondrial energy-producing ability and the increase in mitochondrial Na concentration in the myocardial skinned fibers. YT-146 may attenuate Na influx to myocardial mitochondria in ischemic cardiac cells, resulting in both preservation of the ability of mitochondria to produce energy and enhancement of the contractile recovery in reperfused hearts. Our findings suggest that the cardioprotective effects of YT-146 against ischemia/reperfusion injury are at least partially due to the preservation of mitochondrial function in the ischemic myocardium.Key words YT-146; adenosine receptor agonist; cardioprotection; mitochondrial function Many investigators have suggested a close relationship between preserved mitochondrial energy production in ischemic/ reperfused hearts and myocardial contractile recovery during the reperfusion phase. [1][2][3] Mitochondria are the primary intracellular organelles for energy production, which is necessary for both cardiac pump function and cell viability. 4,5) Therefore, protection of cardiac mitochondria against ischemia/ reperfusion-induced cellular deterioration may be a critical mechanism underlying cardioprotection in ischemic/reperfused hearts.Adenosine has multiple biological functions, including cardioprotection against ischemia/reperfusion injury in various animal models. [6][7][8] An adenosine receptor agonist 2-octynyladenosine (YT-146), has been shown to be resistant to adenosine deaminase in vivo. We have recently shown that preischemic treatment with 0.3 µM YT-146 may have cardioprotective effects against ischemia/reperfusion injury in isolated rat hearts perfused with a Langendorff mode. 9) In the previous study, we found that YT-146-induced cardioprotective effects against ischemia/reperfusion injury were canceled by treatment of perfused hearts with adenosine A 1 receptor antagonist and protein kinase C (PKC) inhibitor, respectively. The results of the study suggested that cardioprotection induced by YT-146 treatment might be due to an agonistic action by the adenosine A 1 receptor, followed by PKC activation. 9) However, the effects of Y...

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Section: Discussionsupporting

confidence: 91%

Effects of 2-Octynyladenosine (YT-146) on Mitochondrial Function in Ischemic/Reperfused Rat Hearts

Sasamori

Abe

Marunouchi

et al. 2015

Biological & Pharmaceutical Bulletin

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“…Of note, transmission electron microscopy and 3-dimensional reconstruction of mitochondrial networks of M(LPS) and M(IL4+IL13) MΦ showed no differences under NS and HS conditions after 3 hours of activation (Figure 3 A– 3 D), suggesting that HS-induced complex II inhibition and subsequent energetic collapse were independent of large structural changes. It is interesting that increased intracellular Na + levels not only occur on extracellular hypertonic conditions in immune cells 17 but also occur under ischemic isotonic conditions, eg, in the heart 43 and astrocytes. Furthermore, it has been reported earlier that on hypoxia, mitochondrial sodium calcium exchanger-dependent Na + entry into the mitochondrial matrix leads to a reduction in inner mitochondrial membrane fluidity.…”

Section: Resultsmentioning

confidence: 99%

“… 37 Pharmacological and genetic inhibition of Slc8a1/NCX1 provided mechanistic insights on Na + influx in mononuclear phagocyte cells, 37 although we cannot exclude that other channels or mechanisms also promote the redistribution of Na + from the extracellular to intracellular compartment. Interestingly, mitochondrial mitochondrial sodium calcium exchanger has been shown to be crucial for mitochondrial salinization on isotonic hypoxia, 43 with subsequent deficiency in electron transfer from complex II to complex III and superoxide burst. 44 Increased intracellular Na + levels not only occur on extracellular hypertonic conditions in immune cells, 17 but also occur under ischemic NS conditions, eg, in the heart.…”

Section: Discussionmentioning

confidence: 99%

“… 44 Increased intracellular Na + levels not only occur on extracellular hypertonic conditions in immune cells, 17 but also occur under ischemic NS conditions, eg, in the heart. 43 , 47 Excitation coupling of healthy cardiac myocytes consumes large amounts of ATP, which is replenished by mitochondrial oxidative phosphorylation. 48 During cardiac ischemia, intracellular and mitochondrial Na + levels increase along with a reduction in mitochondrial respiratory function with reduced ATP, which might be a reason for the imbalance of the energy demand and thus further contribute to heart failure.…”

Section: Discussionmentioning

confidence: 99%

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Salt Transiently Inhibits Mitochondrial Energetics in Mononuclear Phagocytes

et al. 2021

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Background: Dietary high salt (HS) is a leading risk factor for mortality and morbidity. Serum sodium transiently increases postprandially, but can also accumulate at sites of inflammation affecting differentiation and function of innate and adaptive immune cells. Here, we focus on how changes in extracellular sodium, mimicking alterations in the circulation and tissues, affect the early metabolic, transcriptional and functional adaption of human and murine mononuclear phagocytes (MNP). Methods: Using Seahorse technology, pulsed stable isotope-resolved metabolomics and enzyme activity assays we characterize the central carbon metabolism and mitochondrial function of human and murine MNP under HS in vitro . HS as well as pharmacologic uncoupling of the electron transport chain (ETC) under normal salt (NS) is used to analyze mitochondrial function on immune cell activation and function (as determined by E.coli killing and CD4 + T cell migration capacity). In two independent clinical studies we analyze the impact of a HS diet over two weeks (NCT02509962) and short-term salt challenge by a single meal (NCT04175249) on mitochondrial function of human monocytes in vivo . Results: Extracellular sodium was taken up into the intracellular compartment followed by the inhibition of mitochondrial respiration in murine and human macrophages (MΦ). Mechanistically, HS reduces mitochondrial membrane potential, ETC complex II activity, oxygen consumption, and ATP production independently of the polarization status of MΦ. Subsequently, cell activation is altered with improved bactericidal function in HS-treated M1-like MΦ and diminished CD4+ T cell migration in HS-treated M2-like MΦ. Pharmacologic uncoupling of the ETC under NS phenocopies HS-induced transcriptional changes and bactericidal function of human and murine MNP. Clinically, also in vivo rise in plasma sodium concentration within the physiological range reversibly reduces mitochondrial function in human monocytes. In both, a 14-day and single meal HS challenge, healthy volunteers displayed a plasma sodium increase of ̃x = 2 mM and ̃x = 2.3 mM , respectively, that correlated with decreased monocytic mitochondrial oxygen consumption. Conclusions: Our data identify the disturbance of mitochondrial respiration as the initial step by which HS mechanistically influences immune cell function. While these functional changes might help to resolve bacterial infections, a shift towards pro-inflammation could accelerate inflammatory CVD.

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“…It is known that ischemic damage of heart is characterized by the suppression of ATP-sensitive processes including the work of intracellular ion transport systems. It leads to the increase in intracellular concentrations of Na + and Са 2+ [ 25 – 27 ]. ES contractions of papillary muscles of the rats from the III group have their own peculiarities.…”

Section: Resultsmentioning

confidence: 99%

Coupling of the Functional Stability of Rat Myocardium and Activity of Lipid Peroxidation in Combined Development of Postinfarction Remodeling and Diabetes Mellitus

Afanasiev

Кондратьева

Rebrova

et al. 2016

Journal of Diabetes Research

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Coupling of the functional stability of rat myocardium and activity of lipid peroxidation processes in combined development of postinfarction remodeling and diabetes mellitus has been studied. The functional stability of myocardium was studied by means of the analysis of inotropic reaction on extrasystolic stimulus, the degree of left ventricular hypertrophy, and the size of scar zone. It was shown that in combined development of postinfarction cardiac remodeling of heart (PICR) with diabetes mellitus (DM) animal body weight decreased in less degree than in diabetic rats. Animals with combined pathology had no heart hypertrophy. The amplitude of extrasystolic contractions in rats with PICR combined with DM had no differences compared to the control group. In myocardium of rats with PICR combined with DM postextrasystolic potentiation was observed in contrast with the rats with PICR alone. The rats with combined pathology had the decreased value of TBA-active products. Thus, the results of study showed that induction of DM on the stage of the development of postinfarction remodeling increases adaptive ability of myocardium. It is manifested in inhibition of increase of LPO processes activity and maintaining of force-interval reactions of myocardium connected with calcium transport systems of sarcoplasmic reticulum of cardiomyocytes.

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Possible Pathway of Na<sup>+</sup> Flux into Mitochondria in Ischemic Heart

Cited by 9 publications

References 22 publications

Effects of 2-Octynyladenosine (YT-146) on Mitochondrial Function in Ischemic/Reperfused Rat Hearts

Effects of 2-Octynyladenosine (YT-146) on Mitochondrial Function in Ischemic/Reperfused Rat Hearts

Salt Transiently Inhibits Mitochondrial Energetics in Mononuclear Phagocytes

Coupling of the Functional Stability of Rat Myocardium and Activity of Lipid Peroxidation in Combined Development of Postinfarction Remodeling and Diabetes Mellitus

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