Heme-arginate suppresses phospholipase C and oxidative stress in the mesenteric arterioles of mineralcorticoid-induced hypertensive rats

Ndisang, Joseph Fomusi; Jadhav, Ashok

doi:10.1038/hr.2010.1

Cited by 11 publications

(5 citation statements)

References 48 publications

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“…Perirenal fat HO-1 concentration was determined by enzyme-linked immunosorbent assay (ELISA) (EKS-810A, Stressgen-Assay Design, Ann Arbor, MI, USA) according to the manufacturer’s instructions as we previously reported [34], [38], [39].…”

Section: Methodsmentioning

confidence: 99%

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The Heme Oxygenase System Suppresses Perirenal Visceral Adiposity, Abates Renal Inflammation and Ameliorates Diabetic Nephropathy in Zucker Diabetic Fatty Rats

2014

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The growing incidence of chronic kidney disease remains a global health problem. Obesity is a major risk factor for type-2 diabetes and renal impairment. Perirenal adiposity, by virtue of its anatomical proximity to the kidneys may cause kidney disease through paracrine mechanisms that include increased production of inflammatory cytokines. Although heme-oxygenase (HO) is cytoprotective, its effects on perirenal adiposity and diabetic nephropathy in Zucker-diabetic fatty rats (ZDFs) remains largely unclear. Upregulating the HO-system with hemin normalised glycemia, reduced perirenal adiposity and suppressed several pro-inflammatory/oxidative mediators in perirenal fat including macrophage-inflammatory-protein-1α (MIP-1α), endothelin (ET-1), 8-isoprostane, TNF-α, IL-6 and IL-1β. Furthermore, hemin reduced ED1, a marker of pro-inflammatory macrophage-M1-phenotype, but interestingly, enhanced markers associated with anti-inflammatory M2-phenotype such as ED2, CD206 and IL-10, suggesting that hemin selectively modulates macrophage polarization towards the anti-inflammatory M2-phenotype. These effects were accompanied by increased adiponectin, HO-1, HO-activity, atrial-natriuretic peptide (ANP), and its surrogate marker, urinary-cGMP. Furthermore, hemin reduced renal histological lesions and abated pro-fibrotic/extracellular-matrix proteins like collagen and fibronectin that deplete nephrin, an important transmembrane protein which forms the scaffolding of the podocyte slit-diaphragm allowing ions to filter but not massive excretion of proteins, hence proteinuria. Correspondingly, hemin increased nephrin expression in ZDFs, reduced markers of renal damage including, albuminuria/proteinuria, but increased creatinine-clearance, suggesting improved renal function. Conversely, the HO-blocker, stannous-mesoporphyrin nullified the hemin effects, aggravating glucose metabolism, and exacerbating renal injury and function. The hemin effects were less-pronounced in Zucker-lean controls with healthy status, suggesting greater selectivity of HO in ZDFs with disease. We conclude that the concomitant reduction of pro-inflammatory/oxidative mediators, macrophage infiltration and profibrotic/extracellular-matrix proteins, coupled to increased nephrin, adiponectin, ANP, cGMP and creatinine clearance may account for improved renal function in hemin-treated ZDFs. These findings suggest that HO-inducers like hemin may be explored against the co-morbidity of perirenal adiposity and diabetic nephropathy.

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Section: Methodsmentioning

confidence: 99%

“…Perirenal fat ET-1 was determined by EIA (Cayman Chemical, Ann Arbor, MI, USA) as we previously reported [38], [39]. This immunometric assay is based on a double-antibody ‘sandwich’ technique that detects ET-1 within the range of 0–250 pg/ml.…”

Section: Methodsmentioning

confidence: 99%

The Heme Oxygenase System Suppresses Perirenal Visceral Adiposity, Abates Renal Inflammation and Ameliorates Diabetic Nephropathy in Zucker Diabetic Fatty Rats

2014

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“…Induction of HO‐1 protects the liver from excessive formation of inflammatory cytokines (Yeligar et al, ). Induction of HO‐1 is an important cellular defence mechanism against oxidative stress (Ndisang and Jadhav, ) and is a possible risk factor in tumour development (Liu et al, ; Ku et al, ; Yao et al, , ). The role of HO‐1 in regulating cellular growth and proliferation seems to be mediated via its anti‐apoptotic and pro‐angiogenic properties (Lee et al, ).…”

Section: Introductionmentioning

confidence: 99%

Upregulation of HO‐1 is accompanied by activation of p38MAPK and mTOR in human oesophageal squamous carcinoma cells

Xiao²,

et al. 2013

Cell Biology International

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Induction of HO-1 protein can have both beneficial and detrimental effects for cells, including regulating proliferation and apoptosis of several tumours. We have investigated the regulation of HO-1, p38MAPK and mTOR in the context of proliferation, cell cycle events and apoptosis of oesophageal squamous cell carcinoma cells. Real-time PCR and Western blots were used to determine the expression levels of HO-1, p38MAPK, p-p38MAPK and p-mTOR. MTT assays were used to measure proliferation, FACS for cell cycle events and Annexin V staining for apoptosis. Proliferation of Eca109 cells was inhibited and apoptosis was induced in the presence of p38MAPK inhibitor (SB203580) and mTOR inhibitor (Rapamycin, RAPA). HO-1 expression was downregulated in cells treated with SB203580 and RAPA. HO-1 overexpression inhibited apoptosis and induced G2/M arrest in SB203580 and RAPA-treated cells. HO-1 expression was upregulated in the presence of ethanol, and was accompanied by activation of p38MAPK and mTOR. However, ethanol-treated cells exposed to HO-1 inhibitor showed no effect on p38MAPK and mTOR activation. The data suggest that ethanol-induced upregulation of HO-1 in oesophageal squamous cell carcinoma is accompanied by the activation of the p38MAPK and mTOR pathways.

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“…It has been shown that presence of Hcy in atherosclerotic plaque can recruit macrophages, induce M0 macrophages to M1 (pro-inflammatory) polarization, increase inflammatory response, and induce macrophage mitochondrial damage and apoptosis, and finally lead to the formation of LRNC ( 27 ). Furthermore, hypertension can trigger or induce loss of vasomotor activity, perpetuate endothelial damage which might contribute to the inflammation and formation of foam cells in atherosclerotic plaque, thus indirectly enhance the opportunity of formation of LRNC ( 28 – 31 ). Hence, both high levels of Hcy in serums and hypertension can accelerate the progression of LRNC in carotid atherosclerotic plaque either by the indirect or direct pathway of pro-inflammatory.…”

Section: Discussionmentioning

confidence: 99%

Co-existing Hypertension and Hyperhomocysteinemia Increases the Risk of Carotid Vulnerable Plaque and Subsequent Vascular Event: An MR Vessel Wall Imaging Study

Qiao

Yang

et al. 2022

Front. Cardiovasc. Med.

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PurposeThis study sought to determine the associations of co-existing hypertension and hyperhomocysteinemia (H-Hcy) with carotid vulnerable plaque features and subsequent vascular events.MethodsSymptomatic patients with carotid atherosclerosis were enrolled and underwent carotid magnetic resonance (MR) vessel wall imaging. The patients were divided into the following groups: co-existing hypertension and H-Hcy group; isolated hypertension group; isolated H-Hcy group; and control group. The morphological and compositional characteristics of carotid plaques were assessed on MR images and compared among different groups. Univariate and multivariate cox regressions were used to calculate the hazard ratio (HR) and corresponding 95% confidence interval (CI) of co-existing hypertension and H-Hcy in predicting subsequent vascular events after at least 1-year followed-up.ResultsIn total, 217 patients (mean age, 59.4 ± 11.9 years; 154 males) were recruited. Patients in co-existing hypertension and H-Hcy group had a significantly higher prevalence of carotid lipid-rich necrotic core (LRNC) than isolated H-Hcy and control group (73.2 vs. 43.3 vs. 50%, p = 0.015). During the median follow-up time of 12.2 ± 4.3 months, 61 (39.8%) patients experienced vascular events. After adjusting for baseline confounding factors, co-existing hypertension and H-Hcy (HR, 1.82; 95% CI, 1.01–3.27; p = 0.044), presence of carotid LRNC (HR, 2.25; 95% CI, 1.09–4.65; p = 0.029), and combination of co-existing hypertension and H-Hcy and carotid LRNC (HR, 2.39; 95% CI, 1.26–4.43; p = 0.007) were significantly associated with subsequent vascular events.ConclusionsCo-existing hypertension and H-Hcy are associated with carotid vulnerable plaque features, such as LRNC. Combining co-existing hypertension and H-Hcy with carotid vulnerable plaque features has a stronger predictive value for subsequent vascular events than each measurement alone.

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Heme-arginate suppresses phospholipase C and oxidative stress in the mesenteric arterioles of mineralcorticoid-induced hypertensive rats

Cited by 11 publications

References 48 publications

The Heme Oxygenase System Suppresses Perirenal Visceral Adiposity, Abates Renal Inflammation and Ameliorates Diabetic Nephropathy in Zucker Diabetic Fatty Rats

The Heme Oxygenase System Suppresses Perirenal Visceral Adiposity, Abates Renal Inflammation and Ameliorates Diabetic Nephropathy in Zucker Diabetic Fatty Rats

Upregulation of HO‐1 is accompanied by activation of p38MAPK and mTOR in human oesophageal squamous carcinoma cells

Co-existing Hypertension and Hyperhomocysteinemia Increases the Risk of Carotid Vulnerable Plaque and Subsequent Vascular Event: An MR Vessel Wall Imaging Study

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