Primed Polymorphonuclear Leukocytes, Oxidative Stress, and Inflammation Antecede Hypertension in the Sabra Rat

Sela, Shifra; Mazor, Rafi; Amsalam, Mazal; Yagil, Chana; Yagil, Yoram; Kristal, Batya

doi:10.1161/01.hyp.0000144480.10207.34

Cited by 34 publications

(43 citation statements)

References 43 publications

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“…12,13 Animals were placed in a restrainer and allowed 10 minutes of acclimatization. We derived SBP from Ն3 replicate measurements.…”

Section: Blood Pressure Measurementmentioning

confidence: 99%

“…Malondialdehyde (MDA) levels were measured using the assay for thiobarbituric acid-reacting substances, as described previously, 12 and further detailed in the online Data Supplement.…”

Section: Plasma Malondialdehyde Levelsmentioning

confidence: 99%

“…11 We have reported previously that, in the Sabra rat model of hypertension, priming of PMNLs precedes the development of hypertension and is associated with an increased rate of superoxide release from PMNLs as result of PMNL priming and NADPH oxidase activation. 12,13 We have also shown that inhibition of this enzyme with apocynin (APO) attenuates the development of hypertension, concomitantly with a decline in leukocyte count and cell priming. 13 Nevertheless, the priming agent for the PMNL NADPH oxidase and the specific contribution of this enzyme to OS and inflammation in the Sabra rats are still poorly understood.…”

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Tumor Necrosis Factor-α

et al. 2010

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Abstract-In the Sabra rat, oxidative stress (OS) and inflammation precede the development of hypertension. Inhibition of the phagocytic NADPH oxidase attenuates the rise in blood pressure. The present study was set to identify possible priming agents for this enzyme and to test the hypothesis that the phagocytic NADPH oxidase contributes to OS and inflammation. Sabra salt-sensitive and Sabra salt-resistant rats were salt loaded or provided regular chow for 60 days with or without apocynin to inhibit NADPH oxidase. Levels of interleukin 6, tumor necrosis factor-␣, and interferon-␥ served as indices of inflammation. Extracellular and intracellular levels of the polymorphonuclear leukocyte tumor necrosis factor-␣ receptors (p55 and p75) were assessed by flow cytometry in young and adult rats. NADPH oxidase activity and expression of p47phox were measured in polymorphonuclear leukocytes and aortic rings. Malondialdehyde and carbonylated fibrinogen served as indices of OS. Inflammatory and OS indices excluding interferon-␥ were higher in the hypertensive state and reduced by apocynin. Levels of malondialdehyde and tumor necrosis factor-␣ were elevated already in the prehypertensive state. No differences were found in the levels of p75. The extracellular expression of p55 was higher in adult Sabra salt-resistant compared with Sabra salt-sensitive rats (7.46Ϯ2.2% versus 2.1Ϯ0.5%; PϽ0.05), whereas levels of the intracellular p55 were higher in adult Sabra salt-sensitive rats (3.2Ϯ2% versus 1.1Ϯ0.5%; PϽ0.05). In young normotensive rats, the extracellular levels of p55 were higher in Sabra salt-sensitive compared with Sabra salt-resistant rats (10.6Ϯ5.2% versus 2.9Ϯ1.5%; PϽ0.01). Tumor necrosis factor-␣ plays a role in activation of the polymorphonuclear leukocyte NADPH oxidase, thereby contributing to systemic OS, inflammation, and the development of hypertension in this model. We have shown that the polymorphonuclear leukocyte (PMNL) is a significant contributor to OS and inflammation in hypertensive humans and in animal models of hypertension. In pathological disorders associated with atherosclerosis and cardiovascular diseases, such as hypertension, diabetes mellitus, and end-stage renal disease, PMNLs are primed. [7][8][9] In the primed state, PMNLs are more sensitive to local or systemic stimuli because of a previous exposure to a priming agent. Hence, on encountering an additional stimulus, full cell activation occurs, resulting in a robust release of reactive oxygen species and tertiary granule contents into the bloodstream. 10 The primary source for reactive oxygen species in PMNL is the NADPH oxidase, an enzymatic complex, is composed of 3 cytosolic subunits (p40phox, p47phox, and p67phox) and 2 membrane subunits (p22phox and gp91). On cell activation, the cytosolic subunits translocate to the membrane, and the activated enzyme produces superoxide in a process known as the "respiratory burst." 11 We have reported previously that, in the Sabra rat model of hypertension, priming of PMNLs precedes the development o...

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“…12,13 Animals were placed in a restrainer and allowed 10 minutes of acclimatization. We derived SBP from Ն3 replicate measurements.…”

Section: Blood Pressure Measurementmentioning

confidence: 99%

“…Malondialdehyde (MDA) levels were measured using the assay for thiobarbituric acid-reacting substances, as described previously, 12 and further detailed in the online Data Supplement.…”

Section: Plasma Malondialdehyde Levelsmentioning

confidence: 99%

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“…In a hypertension model using Sabra hypertension-prone rats, superoxide release from PMNL and inflammation anteceded the onset of hypertension (brought on by salt loading). 16,17 Results indicated that genetic factors contributed to the activation of PMNL and production of ROS. The p22phox is a major component of NADPH oxidase and is essential for O 2À generation.…”

Section: Essential Hypertension (Eh [Min1455]mentioning

confidence: 99%

An intronic variable number of tandem repeat polymorphisms of the cold-induced autoinflammatory syndrome 1 (CIAS1) gene modifies gene expression and is associated with essential hypertension

et al. 2006

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Cold-induced autoinflammatory syndrome 1 (CIAS1) gene is a member of the NALP subfamily of the CATERPILLER protein family that is expressed predominantly in peripheral blood leukocytes, which is to regulate apoptosis or inflammation through the activation of NF-jB and caspase. Recent genetic analyses suggested an association between inflammation and oxidative stress-related genes in the development of hypertension. This is the first genetic study indicating an association between the CIAS1 gene and susceptibility to essential hypertension (EH). The frequency of subject with the homozygote of 12 repeat allele was significantly higher in patients with hypertension compared with control subjects (987 cases, 924 controls) (P ¼ 0.030; odds ratio ¼ 1.24) at a novel VNTR polymorphism of CIAS1 intron 4 loci. We also found that the mean of systolic blood pressure of homozygotes of 12 repeat allele was 6.4 mmHg higher than those of homozygotes of non-12 repeat allele in male random population (P ¼ 0.009). The frequency of six SNPs spanning of the CIAS1 gene was not significantly between patients and controls. The real-time PCR analysis showed that among healthy young adults, 12-12 subjects expressed CIAS1 mRNA in peripheral leukocytes significantly more abundantly than homozygote of non-12 repeat alleles subjects (Po0.05). Reporter gene assay of the CIAS1-VNTR in HL60 stimulated by lipopolysaccharides showed that the intronic sequence involving 12 repeat increased the expression of luciferase compared with 9, 7, and 6 repeats.

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“…Hypertension is considered nowadays to be an inflammatory disease, and increasing knowledge on hypertension has led to appreciation of the relevant role in this process of circulating leukocytes in general, and of neutrophils in particular (Sela et al 2004, Tsukimori et al 2007). Angiotensin II (Ang II) is a potent vasoconstrictor and regulator of cellular immune responses through a CN-dependent pathway (Nataraj et al 1999).…”

Section: Introductionmentioning

confidence: 99%

Calcineurin expression and activity is regulated by the intracellular redox status and under hypertension in human neutrophils

Álba

Santa-María

Reyes-Quiróz

et al. 2012

Journal of Endocrinology

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Calcineurin (protein phosphatase 2B) (CN) comprises a family of serine/threonine phosphatases that play a pivotal role in signal transduction cascades in a variety of cells, including neutrophils. Angiotensin II (Ang II) increases both activity and de novo synthesis of CN in human neutrophils. This study focuses on the role that intracellular redox status plays in the induction of CN activity by Ang II. Both de novo synthesis of CN and activity increase promoted by Ang II were downregulated when cells were treated with L-buthionine-(S,R)-sulfoximine, an inhibitor of synthesis of the antioxidant glutathione. We have also investigated the effect of pyrrolidine dithiocarbamate and phenazine methosulfate, which are antioxidant and oxidant compounds, respectively, and concluded that the intracellular redox status of neutrophils is highly critical for Ang II-induced increase of CN expression and activity. Results obtained in neutrophils from hypertensive patients were very similar to those obtained in these cells on treatment with Ang II. We have also addressed the possible functional implication of CN activation in the development of hypertension. Present findings indicate that downregulation of hemoxygenase-1 expression in neutrophils from hypertensive subjects is likely mediated by CN, which acts by hindering translocation to the nucleus of the transcription factor NRF2. These data support and extend our previous results and those from other authors on modulation of CN expression and activity levels by the intracellular redox status.

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Primed Polymorphonuclear Leukocytes, Oxidative Stress, and Inflammation Antecede Hypertension in the Sabra Rat

Cited by 34 publications

References 43 publications

Tumor Necrosis Factor-α

Tumor Necrosis Factor-α

An intronic variable number of tandem repeat polymorphisms of the cold-induced autoinflammatory syndrome 1 (CIAS1) gene modifies gene expression and is associated with essential hypertension

Calcineurin expression and activity is regulated by the intracellular redox status and under hypertension in human neutrophils

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