Exercise alters the regulation of myocardial Na+/H+ exchanger-1 activity

The myocardial Na+/H+ exchanger-1 (NHE1) plays a major role in regulation of intracellular pH, and its upregulation has been implicated in increased ischemia-reperfusion injury and other pathologies. Hydrogen peroxide (H2O2) increases NHE1 activity acutely via ERK1/2 signaling. Chronic strenuous exercise upregulates NHE1 in skeletal muscle, but we hypothesize this will not occur in the heart, because exercise creates a cardioprotective phenotype. NHE1 activity and its regulation by H2O2 were examined at physiological pH using isolated cardiomyocytes from female Sprague-Dawley rats exercised on a treadmill for 5 wk (E; n = 11). Compared with sedentary (S; n = 15), E displayed increases ( P < 0.05) in heart-to-body weight ratio (6.8%) and plantaris mitochondria content (89%). NHE1 activity (acid efflux rate following an acid load) was 209% greater in E (0.65 ± 0.12 vs. 2.01 ± 0.29 fmol/min). The difference was attributed primarily to greater cell volume (22.2 ± 0.6 vs. 34.3 ± 1.1 pl) and intracellular pH-buffering capacity (33.94 ± 1.59 vs. 65.82 ± 5.20 mM/pH unit) of E myocytes. H2O2 stimulation (100 μM) raised NHE1 activity significantly less in E (45%) than S (167%); however, activity remained 185% greater in E. ERK1/2 inhibition abrogated the increases. H2O2-stimulated ERK1/2 phosphorylation levels normalized to total ERK1/2 were similar between groups. Content of NHE1 and activities of H2O2 scavengers were also similar. We observed that intracellular pH-buffering capacity differences between groups became progressively less with declining pH, which may be an exercise-induced cardioprotective adaptation to lower NHE1 activity during certain pathological situations. We conclude that strenuous endurance exercise increases myocardial NHE1 activity at physiological pH, which would likely enhance cardiac performance under physiological conditions.

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Dexmedetomidine Attenuates Lung Ischemia-reperfusion Injury in Rats by Reducing Mitochondrial Dysfunction

10.21203/rs.3.rs-120188/v1 ◽

2020 ◽

Author(s):

Yan Zhang ◽

Yao Lu ◽

Kai Wang ◽

Mei-yan Zhou ◽

Cong-you Wu ◽

...

Keyword(s):

Mitochondrial Dysfunction ◽

Reperfusion Injury ◽

Mitochondrial Biogenesis ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Weight Ratio ◽

Oxygenation Index ◽

Lung Damage ◽

Peroxisome Proliferator ◽

Sprague Dawley

Abstract Background: Lung ischemia-reperfusion injury (LIRI) is a significant clinical problem occurring after lung transplantation. LIRI is mediated by the overproduction of reactive oxygen species (ROS) and inflammatory activation. Previous studies have confirmed that dexmedetomidine (DEX) exerts a protective effect on LIRI, which potentially causes severe mitochondrial dysfunction. However, the specific mechanisms remain unclear. Our study was to explore whether dexmedetomidine exerts a beneficial effect on LIRI by reducing mitochondrial dysfunction. Methods: Two different models were used in our study. For the in vivo experiment, thirty-two male Sprague-Dawley rats were randomly divided into Sham, ischemia-reperfusion (I/R), DEX+I/R and DEX+yohimbine+I/R (DY+I/R) groups. Similarly, pulmonary vascular endothelial cells (PVECs) from SD rats were divided into Control, oxygen glucose deprivation (OGD), D+OGD and DY+OGD groups.Results: In our experiment, we confirmed severe lung damage after LIRI that was characterized by significantly pulmonary histopathology injury, a decrease in the oxygenation index (PaO2/FiO2) and an increase in the wet-to-dry weight ratio, while DEX treatment mitigated this damage. In addition, the DEX pretreatment significantly attenuated I/R-induced oxidative stress by decreasing the level of ROS in the mitochondria in vitro. Moreover, the DEX treatment enhanced mitochondrial biogenesis and autophagy by increasing the expression of peroxisome proliferator-activated receptor-gamma coactivator-1α (PGC-1α), mitochondrial transcription factor A (Tfam), PTEN-induced putative kinase 1 (PINK1), Parkin and dynamin 1-like protein 1 (Drp1). Conclusions: These data suggest that DEX may alleviate LIRI by reducing mitochondrial dysfunction through the induction of mitochondrial biogenesis and autophagy.

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Establishing Growing Substrate pH with Compost and Limestone and the Impact on pH Buffering Capacity

HortScience ◽

10.21273/hortsci10990-16 ◽

2016 ◽

Vol 51 (9) ◽

pp. 1153-1158 ◽

Cited By ~ 2

Author(s):

Matthew D. Taylor ◽

Rachel Kreis ◽

Lidia Rejtö

Keyword(s):

Factorial Design ◽

Weight Ratio ◽

Green Plant ◽

Buffering Capacity ◽

Ph Buffering ◽

Initial Substrate ◽

Initial Ph ◽

The Impact ◽

Substrate Ph ◽

Ph Buffering Capacity

The pH of peatmoss generally ranges from 3.0 to 4.0 and limestone is typically added to raise pH to a suitable range. Compost is also used as a substrate component and typically has a high pH of 6.0 to 8.0. When using compost, lime rates must be reduced or eliminated. The two objectives of this study were to determine the resulting pH of substrates created with varying amounts of limestone and compost and assess the impact of the various amounts of limestone and compost on pH buffering capacity. Compost was created from a 1:1:1 weight ratio of a mixture of green plant material and restaurant food waste:horse manure:wood chips. The first experiment was a factorial design with five compost rates (0%, 10%, 20%, 30%, and 40% by volume), four limestone rates (0, 1.2, 2.4, and 3.6 g·L−1 substrate) with five replications. The experiment was conducted three times, each with a different batch of compost. With 0 lime, initial substrate pH increased from 4.5 to 6.7 as compost rate increased. This trend occurred at all other lime rates, which had pH ranges of 5.2–6.9, 5.6–7.0, and 6.1–7.1 for rates of 1.2, 2.4, and 3.6 g·L−1 substrate, respectively. Substrate pH increased significantly as either compost or lime rates increased. The second experiment was a factorial design with four compost rates by volume (0%, 10%, 20%, and 30%), the same four limestone rates as Expt. 1, and five replications. Each substrate treatment was titrated through incubations with six sulfuric acid rates (0, 0.1, 0.2, 0.4, or 0.7 mol of H+ per gram of dry substrate). Substrates with a similar initial pH had very similar buffering capacities regardless of the compost or limestone rate. These results indicate compost can be used to establish growing substrate pH similar to limestone, and this change will have little to no effect on pH buffering capacity.

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Light adaptation of invertebrate photoreceptors: influence of intracellular pH buffering capacity.

The Journal of Physiology ◽

10.1113/jphysiol.1982.sp014342 ◽

1982 ◽

Vol 330 (1) ◽

pp. 297-305 ◽

Cited By ~ 1

Author(s):

S R Bolsover ◽

J E Brown

Keyword(s):

Intracellular Ph ◽

Light Adaptation ◽

Buffering Capacity ◽

Ph Buffering ◽

Ph Buffering Capacity

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Effects of increased intracellular pH-buffering capacity on the light response of Limulus ventral photoreceptor

Biochimica et Biophysica Acta (BBA) - Biomembranes ◽

10.1016/0005-2736(76)90226-1 ◽

1976 ◽

Vol 436 (1) ◽

pp. 140-153 ◽

Cited By ~ 9

Author(s):

Jonathan A. Coles ◽

Joel E. Brown

Keyword(s):

Intracellular Ph ◽

Light Response ◽

Buffering Capacity ◽

Ph Buffering ◽

Ph Buffering Capacity

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Monocytic MDSC mobilization promotes tumor recurrence after liver transplantation via CXCL10/TLR4/MMP14 signaling

Cell Death and Disease ◽

10.1038/s41419-021-03788-4 ◽

2021 ◽

Vol 12 (5) ◽

Author(s):

Hui Liu ◽

Chang Chun Ling ◽

Wai Ho Oscar Yeung ◽

Li Pang ◽

Jiang Liu ◽

...

Keyword(s):

Liver Transplantation ◽

Tumor Recurrence ◽

Ischemia Reperfusion Injury ◽

Therapeutic Potential ◽

Ischemia Reperfusion ◽

Weight Ratio ◽

Liver Graft ◽

Mouse Tumor ◽

Hepatic Ischemia ◽

Tlr4 Signaling

AbstractTumor recurrence is the major obstacle for pushing the envelope of liver transplantation for hepatocellular carcinoma (HCC) patients. The inflammatory cascades activated by acute liver graft injury promote tumor recurrence. We aimed to explore the role and mechanism of myeloid-derived suppressor cell (MDSC) mobilization induced by liver graft injury on tumor recurrence. By analyzing 331 HCC patients who received liver transplantation, the patients with graft weight ratio (GWR, the weight of liver graft divided by the estimated standard liver weight of recipient) <60% had higher tumor recurrence than GWR ≥60% ones. MDSCs and CXCL10/TLR4 levels were significantly increased in patients with GWR <60% or tumor recurrence. These findings were further validated in our rat orthotopic liver transplantation model. In CXCL10−/− and TLR4−/− mice of hepatic ischemia/reperfusion injury plus major hepatectomy (IRH) model, monocytic MDSCs, instead of granulocytic MDSCs, were significantly decreased. Importantly, CXCL10 deficiency reduced the accumulation of TLR4+ monocytic MDSCs, and CXCL10 increased MDSC mobilization in the presence of TLR4. Moreover, MMP14 was identified as the key molecule bridging CXCL10/TLR4 signaling and MDSC mobilization. Knockout or inhibition of CXCL10/TLR4 signaling significantly reduced the tumor growth with decreased monocytic MDSCs and MMP14 in the mouse tumor recurrent model. Our data indicated that monocytic MDSCs were mobilized and recruited to liver graft during acute phase injury, and to promote HCC recurrence after transplantation. Targeting MDSC mobilization via CXCL10/TLR4/MMP14 signaling may represent the therapeutic potential in decreasing post-transplant liver tumor recurrence.

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Renal endothelial dysfunction and impaired autoregulation after ischemia-reperfusion injury result from excess nitric oxide

AJP Renal Physiology ◽

10.1152/ajprenal.00302.2005 ◽

2006 ◽

Vol 291 (3) ◽

pp. F619-F628 ◽

Cited By ~ 32

Author(s):

Zhengrong Guan ◽

Glenda Gobé ◽

Desley Willgoss ◽

Zoltán H. Endre

Keyword(s):

Nitric Oxide ◽

Renal Failure ◽

Angiotensin Ii ◽

Endothelial Dysfunction ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Artery Occlusion ◽

Tubuloglomerular Feedback ◽

Sprague Dawley ◽

Endothelial Nitric Oxide

Endothelial dysfunction in ischemic acute renal failure (IARF) has been attributed to both direct endothelial injury and to altered endothelial nitric oxide synthase (eNOS) activity, with either maximal upregulation of eNOS or inhibition of eNOS by excess nitric oxide (NO) derived from iNOS. We investigated renal endothelial dysfunction in kidneys from Sprague-Dawley rats by assessing autoregulation and endothelium-dependent vasorelaxation 24 h after unilateral (U) or bilateral (B) renal artery occlusion for 30 (U30, B30) or 60 min (U60, B60) and in sham-operated controls. Although renal failure was induced in all degrees of ischemia, neither endothelial dysfunction nor altered facilitation of autoregulation by 75 pM angiotensin II was detected in U30, U60, or B30 kidneys. Baseline and angiotensin II-facilitated autoregulation were impaired, methacholine EC50 was increased, and endothelium-derived hyperpolarizing factor (EDHF) activity was preserved in B60 kidneys. Increasing angiotensin II concentration restored autoregulation and increased renal vascular resistance (RVR) in B60 kidneys; this facilitated autoregulation, and the increase in RVR was abolished by 100 μM furosemide. Autoregulation was enhanced by Nω-nitro-l-arginine methyl ester. Peri-ischemic inhibition of inducible NOS ameliorated renal failure but did not prevent endothelial dysfunction or impaired autoregulation. There was no significant structural injury to the afferent arterioles with ischemia. These results suggest that tubuloglomerular feedback is preserved in IARF but that excess NO and probably EDHF produce endothelial dysfunction and antagonize autoregulation. The threshold for injury-producing, detectable endothelial dysfunction was higher than for the loss of glomerular filtration rate. Arteriolar endothelial dysfunction after prolonged IARF is predominantly functional rather than structural.

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Cardiac phosphatase-deficient 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase increases glycolysis, hypertrophy, and myocyte resistance to hypoxia

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.91501.2007 ◽

2008 ◽

Vol 294 (6) ◽

pp. H2889-H2897 ◽

Cited By ~ 24

Author(s):

Qianwen Wang ◽

Rajakumar V. Donthi ◽

Jianxun Wang ◽

Alex J. Lange ◽

Lewis J. Watson ◽

...

Keyword(s):

Transgenic Mice ◽

Cardiac Fibrosis ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Weight Ratio ◽

Cardiac Metabolism ◽

Heart Weight ◽

Acid Oxidation ◽

Important Regulator

During ischemia and heart failure, there is an increase in cardiac glycolysis. To understand if this is beneficial or detrimental to the heart, we chronically elevated glycolysis by cardiac-specific overexpression of phosphatase-deficient 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFK-2) in transgenic mice. PFK-2 controls the level of fructose-2,6-bisphosphate (Fru-2,6-P2), an important regulator of phosphofructokinase and glycolysis. Transgenic mice had over a threefold elevation in levels of Fru-2,6-P2. Cardiac metabolites upstream of phosphofructokinase were significantly reduced, as would be expected by the activation of phosphofructokinase. In perfused hearts, the transgene caused a significant increase in glycolysis that was less sensitive to inhibition by palmitate. Conversely, oxidation of palmitate was reduced by close to 50%. The elevation in glycolysis made isolated cardiomyocytes highly resistant to contractile inhibition by hypoxia, but in vivo the transgene had no effect on ischemia-reperfusion injury. Transgenic hearts exhibited pathology: the heart weight-to-body weight ratio was increased 17%, cardiomyocyte length was greater, and cardiac fibrosis was increased. However, the transgene did not change insulin sensitivity. These results show that the elevation in glycolysis provides acute benefits against hypoxia, but the chronic increase in glycolysis or reduction in fatty acid oxidation interferes with normal cardiac metabolism, which may be detrimental to the heart.

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Abstract 300: Topical Application of IcyHot Reduces Myocardial Infarct Size in Rodents by a TRPA1-dependent Mechanism

Circulation Research ◽

10.1161/res.121.suppl_1.300 ◽

2017 ◽

Vol 121 (suppl_1) ◽

Author(s):

Yun Wu ◽

Yao Lu ◽

Eric R Gross

Keyword(s):

Infarct Size ◽

Transient Receptor Potential ◽

Ischemia Reperfusion Injury ◽

Calcium Influx ◽

Myocardial Infarct ◽

Ischemia Reperfusion ◽

Myocardial Infarct Size ◽

Sprague Dawley ◽

Area At Risk ◽

Reactive Aldehydes

Toxic reactive aldehydes are formed during ischemia-reperfusion. The ion channel transient receptor potential ankryin 1 (TRPA1) is irreversibly modified by reactive aldehydes which can cause calcium influx and cell death. Here we tested whether topically applied creams containing a reversible TRPA1 agonist could reduce myocardial infarct size. Male Sprague-Dawley rats 8-10 weeks age were subjected to an in vivo myocardial ischemia-reperfusion model of 30 minutes of left anterior descending (LAD) coronary artery ischemia followed by 2 hours reperfusion. Prior to ischemia, rats were untreated or had 1g of cream applied to the abdomen. The creams tested were IcyHot, Bengay, Tiger Balm, or preparation H (Fig. 1A). Hearts were negatively stained for the area at risk and the infarct size was determined by using TTC staining (Fig. 1B). A subset of rodents prior to receiving IcyHot also received an intravenous bolus of the TRPA1 antagonist TCS-5861528 (1mg/kg) or AP-18 (1mg/kg). Interestingly, both IcyHot and Bengay reduced myocardial infarct size compared to untreated rodents (Fig. 1C and 1D IcyHot: 41±3%*, Bengay: 50±2%* versus control 62±1%, n=6/group, *P<0.001). Both preparation H and Tiger Balm failed to reduce myocardial infarct size (Tiger Balm: 63±2%, preparation H 59±2%). Giving a TRPA1 antagonist prior to IcyHot also blocked the reduction in infarct size. Our additional data also indicates the methyl salicylate (mint) in IcyHot and Bengay is the agent that limits myocardial infarct size. Since IcyHot and Bengay are safely used by humans, targeting TRPA1 by using products such as these could be quickly translatable and widely used to reduce ischemia-reperfusion injury.

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Abstract 193: Antithrombin Perfluorocarbon Nanoparticles Ameliorate Renal Injury Following Transient Warm Ischemia

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvb.34.suppl_1.193 ◽

2014 ◽

Vol 34 (suppl_1) ◽

Author(s):

Chandu Vemuri ◽

Junjie Chen ◽

Rohun U Palekar ◽

John S Allen ◽

Xiaoxia Yang ◽

...

Keyword(s):

Reperfusion Injury ◽

Renal Injury ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Kidney Injury ◽

Warm Ischemia ◽

P Value ◽

Sprague Dawley ◽

Histologic Analysis ◽

Microvascular Thrombosis

Objective: Thrombin mediated microvascular thrombosis plays a crucial role in the pathogenesis of acute renal reperfusion injury following transient ischemia. We hypothesize that anti-thrombin nanoparticles will ameliorate acute renal injury by inhibiting microvascular thrombosis. Methods: Adult, male Sprague Dawley rats were randomized into two groups of 5 to receive tail vein injections of saline or nanoparticles loaded with Phe[D]-Pro-Arg-Chloromethylketone (NP-PPACK). Immediately following injection, all animals underwent operative bilateral renal artery occlusion to create 45 minutes of warm ischemia, followed by restoration of renal blood flow. Blood samples were drawn daily and animals were euthanized on day 1 or 7 for histologic analysis of kidney injury (H&E, TUNEL and thrombin staining). Results: Histologic analysis of renal tissue revealed significant apoptosis, necrosis and thrombin accumulation 1 day after ischemia-reperfusion, confirming acute kidney injury. The peak creatinine (mg/dl) on day 1 was significantly lower in NP-PPACK treated animals (0.57 +/- 0.07 (SEM)) than in saline treated controls (1.40 +/- 0.20 (SEM); p-value <0.01). Furthermore, animals treated with NP-PPACK continued to exhibit less renal dysfunction for 7 days after injury (Figure 1). Conclusion: Histologically confirmed intrarenal thrombosis was detected one day after ischemia-reperfusion injury. Targeted inhibition of thrombin with NP-PPACK prevented a decline in renal function following transient occlusion. Future work will focus on defining the underlying mechanisms of this effect.

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