Abstract P060: High Salt Induces An Endothelial HDAC1-stimulating Circulating Factor Leading To Disrupted Renal Microvascular Nitric Oxide Signaling

Hypertension ◽  
2020 ◽  
Vol 76 (Suppl_1) ◽  
Author(s):  
Luke S Dunaway ◽  
Anthony K Cook ◽  
Edward W Inscho ◽  
Jennifer Pollock
Keyword(s):  
Nitric Oxide ◽  
Endothelial Dysfunction ◽  
Specific Inhibitor ◽  
High Salt ◽  
Afferent Arteriole ◽  
Sprague Dawley ◽  
Salt Diet ◽  
Nitric Oxide Signaling ◽  
No Signaling

High salt diet (HS) decreases endothelial nitric oxide (NO) signaling as described in human and rodent studies. We have previously shown that inhibition of HDAC1 restores NO signaling in the afferent arteriole of HS fed rats. It remains unknown, however, how HS initiates endothelial dysfunction and activates HDAC1. We first investigated if HS induced endothelial dysfunction is acutely regulated by a circulating factor. To test this, male Sprague Dawley rats were fed normal salt diet (NS; 0.49% NaCl) or 2 weeks of HS (4.0% NaCl). Afferent arteriole vasoconstrictor responses to the NOS inhibitor, L-NAME, were monitored using the in vitro, blood perfused juxtamedullary nephron preparation. Perfusing arterioles from NS fed rats with HS blood blunted constriction to L-NAME (88 ± 1% of Con) compared to perfusing with NS blood (76 ± 2% of Con; P=0.0003), but not completely as seen in arterioles from HS fed rats perfused with HS blood (96 ± 2% of Con; P=0.0095). HS arterioles perfused with NS blood had similar L-NAME-induced constriction (75 ± 2% of Con) compared to arterioles from NS fed rats perfused with NS blood (P=0.9107). These results suggest HS induces endothelial function through an acute-acting circulating factor. This was not due to increased plasma arginase activity (NS: 7.96 ± 3.73 U/L vs HS: 5.42 ± 1.83 U/L P=0.5813) which competes with NO synthase 3 for arginine, nor was it due to decreased superoxide scavenging capacity of the plasma (NS: 7.96 ± 3.73 U/L vs HS: 5.42 ± 1.83 U/L P=0.5813) as measured by a cytochrome c reduction based assay. We then investigated if HS increased endothelial HDAC1 activity. Renal endothelial cells were isolated via magnetic activated cell sorting from NS and HS fed rats and incubated in plasma from the same rat. HDAC1 activity was monitored as the MS-275 (HDAC1 specific inhibitor) inhibitable portion of total HDAC activity. We found HS significantly increased renal endothelium HDAC1 activity (NS: 0.38 ± 0.03 pmol/min vs HS:0.94 ± 0.19 pmol/min, P=0.01). We conclude that HS disruption of renal microvascular NO signaling is initiated by a circulating factor(s) that is dependent upon increased endothelial HDAC1 activity.

scholarly journals Altered carnitine homeostasis is associated with decreased mitochondrial function and altered nitric oxide signaling in lambs with pulmonary hypertension

2008 ◽  
Vol 294 (1) ◽  
pp. L46-L56 ◽  
Author(s):  
Shruti Sharma ◽  
Neetu Sud ◽  
Dean A. Wiseman ◽  
A. Lee Carter ◽  
Sanjiv Kumar ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Blood Flow ◽  
Pulmonary Hypertension ◽  
Endothelial Dysfunction ◽  
Mitochondrial Dysfunction ◽  
Pulmonary Blood Flow ◽  
Heat Shock Protein 90 ◽  
Nitric Oxide Signaling ◽  
Carnitine Metabolism ◽  
No Signaling

Utilizing aortopulmonary vascular graft placement in the fetal lamb, we have developed a model (shunt) of pulmonary hypertension that mimics congenital heart disease with increased pulmonary blood flow. Our previous studies have identified a progressive development of endothelial dysfunction in shunt lambs that is dependent, at least in part, on decreased nitric oxide (NO) signaling. The purpose of this study was to evaluate the possible role of a disruption in carnitine metabolism in shunt lambs and to determine the effect on NO signaling. Our data indicate that at 2 wk of age, shunt lambs have significantly reduced expression ( P < 0.05) of the key enzymes in carnitine metabolism: carnitine palmitoyltransferases 1 and 2 as well as carnitine acetyltransferase (CrAT). In addition, we found that CrAT activity was inhibited due to increased nitration. Furthermore, free carnitine levels were significantly decreased whereas acylcarnitine levels were significantly higher in shunt lambs ( P < 0.05). We also found that alterations in carnitine metabolism resulted in mitochondrial dysfunction, since shunt lambs had significantly decreased pyruvate, increased lactate, and a reduced pyruvate/lactate ratio. In pulmonary arterial endothelial cells cultured from juvenile lambs, we found that mild uncoupling of the mitochondria led to a decrease in cellular ATP levels and a reduction in both endothelial NO synthase-heat shock protein 90 (eNOS-HSP90) interactions and NO signaling. Similarly, in shunt lambs we found a loss of eNOS-HSP90 interactions that correlated with a progressive decrease in NO signaling. Our data suggest that mitochondrial dysfunction may play a role in the development of endothelial dysfunction and pulmonary hypertension and increased pulmonary blood flow.

Genistein attenuates hypoxic pulmonary hypertension via enhanced nitric oxide signaling and the erythropoietin system

2014 ◽  
Vol 306 (11) ◽  
pp. L996-L1005 ◽  
Author(s):  
Sachiko Kuriyama ◽  
Yoshiteru Morio ◽  
Michie Toba ◽  
Tetsutaro Nagaoka ◽  
Fumiyuki Takahashi ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Pulmonary Hypertension ◽  
Umbilical Vein ◽  
Sprague Dawley ◽  
Human Hepatoma Cells ◽  
Pulmonary Hemodynamics ◽  
Nitric Oxide Signaling ◽  
Cell Counts

Upregulation of the erythropoietin (EPO)/EPO receptor (EPOR) system plays a protective role against chronic hypoxia-induced pulmonary hypertension (hypoxic PH) through enhancement of endothelial nitric oxide (NO)-mediated signaling. Genistein (Gen), a phytoestrogen, is considered to ameliorate NO-mediated signaling. We hypothesized that Gen attenuates and prevents hypoxic PH. In vivo, Sprague-Dawley rats raised in a hypobaric chamber were treated with Gen (60 mkg/kg) for 21 days. Pulmonary hemodynamics and vascular remodeling were ameliorated in Gen-treated hypoxic PH rats. Gen also restored cGMP levels and phosphorylated endothelial NO synthase (p-eNOS) at Ser1177 and p-Akt at Ser473 expression in the lungs. Additionally, Gen potentiated plasma EPO concentration and EPOR-positive endothelial cell counts. In experiments with hypoxic PH rats' isolated perfused lungs, Gen caused NO- and phosphatidylinositol 3-kinase (PI3K)/Akt-dependent vasodilation that reversed abnormal vasoconstriction. In vitro, a combination of EPO and Gen increased the p-eNOS and the EPOR expression in human umbilical vein endothelial cells under a hypoxic environment. Moreover, Gen potentiated the hypoxic increase in EPO production from human hepatoma cells. We conclude that Gen may be effective for the prevention of hypoxic PH through the improvement of PI3K/Akt-dependent, NO-mediated signaling in association with enhancement of the EPO/EPOR system.

High Salt Diet Induces HDAC1‐Dependent Disruption of Nitric Oxide Signaling in the Renal Microvasculature

2019 ◽  
Vol 33 (S1) ◽  
Author(s):  
Luke S Dunaway ◽  
Anthony K Cook ◽  
David M Pollock ◽  
Kelly A Hyndman ◽  
Edward W Inscho ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
High Salt ◽  
High Salt Diet ◽  
Salt Diet ◽  
Nitric Oxide Signaling ◽  
Renal Microvasculature

Abstract 12185: Restoration of Autophagy in Endothelial Cells From Patients With Diabetes Improves Nitric Oxide Signaling

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Jessica L Fetterman ◽  
Nir Flint ◽  
Monica Holbrook ◽  
Erika A Linder ◽  
Brittany D Berk ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Endothelial Cells ◽  
Endothelial Dysfunction ◽  
Vascular Function ◽  
Diabetic Patients ◽  
Autophagic Flux ◽  
Compensatory Response ◽  
Nitric Oxide Signaling ◽  
Patients With Diabetes ◽  
No Signaling

Diabetes is associated with oxidative stress and decreased nitric oxide bioactivity in the vasculature. Autophagy is a critical multistep pathway that eliminates damaged proteins and organelles from the cell. Emerging evidence suggests impaired autophagy in non-vascular tissues contributes to the pathogenesis of diabetes. We hypothesized that impaired autophagy contributes to endothelial dysfunction associated with diabetes in humans. We measured vascular function and autophagy markers in freshly isolated endothelial cells (ECs) from patients with diabetes and non-diabetic controls. Diabetes was associated with endothelial dysfunction characterized by lower brachial artery flow-mediated dilation and impaired activation of eNOS by insulin in ECs. ECs from diabetic patients had higher levels of p62 (Figure), a protein that accumulates with reduced autophagic flux. Measures of autophagy initiation including rapamycin stimulation, beclin 1 levels, and LC3 puncta were not different. Global activation of autophagy with spermidine reversed endothelial dysfunction in freshly isolated ECs from diabetic patients (Figure). In ECs from controls, inhibiting autophagy with bafilomycin impaired eNOS activation confirming that intact autophagy promotes NO signaling. Evidence from cultured endothelial cells in high glucose conditions suggested that lysosomal function is intact as measured by lysosomal number and acidification. Blocking the terminal step of autophagy with bafilomycin in ECs from diabetics led to a further accumulation of p62, suggesting intact but insufficient levels of autophagy. Lamp2a, which facilitates the merger of autophagosomes and lysosomes, was higher in diabetic cells, possibly reflecting a compensatory response to reduced flux. These findings provide evidence for inadequate autophagic flux in ECs from diabetic patients that contributes to impaired NO signaling and may be a target for therapy of diabetic vascular disease.

scholarly journals Targeting Pulmonary Endothelial Hemoglobin α Improves Nitric Oxide Signaling and Reverses Pulmonary Artery Endothelial Dysfunction

2017 ◽  
Vol 57 (6) ◽  
pp. 733-744 ◽  
Author(s):  
Roger A. Alvarez ◽  
Megan P. Miller ◽  
Scott A. Hahn ◽  
Joseph C. Galley ◽  
Eileen Bauer ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Endothelial Dysfunction ◽  
Pulmonary Artery ◽  
Nitric Oxide Signaling

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

2006 ◽  
Vol 291 (3) ◽  
pp. F619-F628 ◽  
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.

Renal endothelin in chronic angiotensin II hypertension

2002 ◽  
Vol 283 (1) ◽  
pp. R243-R248 ◽  
Author(s):  
Jennifer M. Sasser ◽  
Jennifer S. Pollock ◽  
David M. Pollock
Keyword(s):  
Sodium Intake ◽  
Renal Tissue ◽  
High Salt ◽  
Ang Ii ◽  
Sprague Dawley ◽  
Outer Medulla ◽  
High Salt Diet ◽  
Salt Diet ◽  
Sprague Dawley Rats ◽  
Saline Vehicle

To determine the influence of chronic ANG II infusion on urinary, plasma, and renal tissue levels of immunoreactive endothelin (ET), ANG II (65 ng/min) or saline vehicle was delivered via osmotic minipump in male Sprague-Dawley rats given either a high-salt diet (10% NaCl) or normal-salt diet (0.8% NaCl). High-salt diet alone caused a slight but not statistically significant increase (7 ± 1%) in mean arterial pressure (MAP). MAP was significantly increased in ANG II-infused rats (41 ± 10%), and the increase in MAP was significantly greater in ANG II rats given a high-salt diet (59 ± 1%) compared with the increase observed in rats given a high-salt diet alone or ANG II infusion and normal-salt diet. After a 2-wk treatment, urinary excretion of immunoreactive ET was significantly increased by ∼50% in ANG II-infused animals and by over 250% in rats on high-salt diet, with or without ANG II infusion. ANG II infusion combined with high-salt diet significantly increased immunoreactive ET content in the cortex and outer medulla, but this effect was not observed in other groups. In contrast, high-salt diet, with or without ANG II infusion, significantly decreased immunoreactive ET content within the inner medulla. These data indicate that chronic elevations in ANG II levels and sodium intake differentially affect ET levels within the kidney and provide further support for the hypothesis that the hypertensive effects of ANG II may be due to interaction with the renal ET system.

scholarly journals Endothelial dysfunction precedes hypertension in diet-induced insulin resistance

1998 ◽  
Vol 275 (3) ◽  
pp. R788-R792 ◽  
Author(s):  
Prasad V. G. Katakam ◽  
Michael R. Ujhelyi ◽  
Margarethe E. Hoenig ◽  
Allison Winecoff Miller
Keyword(s):  
Insulin Resistance ◽  
Endothelial Dysfunction ◽  
Serum Insulin ◽  
Serum Glucose ◽  
Mesenteric Arteries ◽  
Control Group ◽  
Sprague Dawley ◽  
Insulin Resistant ◽  
Glucose Levels

The insulin-resistant (IR) syndrome may be an impetus for the development of hypertension (HTN). Unfortunately, the mechanism by which this could occur is unclear. Our laboratory and others have described impaired endothelium-mediated relaxation in IR, mildly hypertensive rats. The purpose of the current study is to determine if HTN is most likely a cause or result of impaired endothelial function. Sprague-Dawley rats were randomized to receive a fructose-rich diet for 3, 7, 10, 14, 18, or 28 days or were placed in a control group. The control group received rat chow. After diet treatment, animals were instrumented with arterial cannulas, and while awake and unrestrained, their blood pressure (BP) was measured. Subsequently, endothelium-mediated relaxation to acetylcholine was determined (in vitro) by measuring intraluminal diameter of phenylephrine-preconstricted mesenteric arteries (∼250 μM). Serum insulin levels were significantly elevated in all groups receiving fructose feeding compared with control, whereas there were no differences in serum glucose levels between groups. Impairment of endothelium-mediated relaxation starts by day 14 [mean percent maximal relaxation (Emax): 69 ± 10% of baseline] and becomes significant by day 18 (Emax: 52 ± 11% of baseline; P < 0.01). However, the mean BP (mmHg) does not become significantly elevated until day 28 [BP: 132 ± 1 ( day 28) vs. 116 ± 3 (control); P < 0.05]. These findings demonstrate that both IR and endothelial dysfunction occur before HTN in this model and suggest that endothelial dysfunction may be a mechanism linking insulin resistance and essential HTN.

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