Relationship between NOX4 level and angiotensin II signaling in Gitelman's syndrome. Implications with hypertension

Recent evidence showed that endogenous nicotinamide adenine dinucleotide phosphate-oxidase 4 (NOX4) may exert a protective role on the cardiovascular system inducing vasodilation, reduction of blood pressure, and anti-proliferative actions. However, the functional significance of NOX4 in the cardiovascular system in humans remains elusive. Mononuclear cell levels of NOX4 were assessed by immunoblotting in 14 Gitelman's patients (GS), a unique human model of endogenous Ang II signaling antagonism and activation of anti-atherosclerotic and anti-remodeling defenses, and compared to 11 untreated essential hypertensive patients as well as to 11 healthy normotensive subjects. The association between NOX4 and its effector heme oxygenase (HO-1) (sandwich immunoassay) was also evaluated. NOX4 protein levels were decreased in hypertensive patients as compared to both GS and healthy subjects (1.06±0.31 AU vs. 1.76±0.54, P=0.002 and vs. 1.61±0.54, P=0.018, respectively). NOX4 protein level did not differ between GS and healthy subjects. HO-1 levels were increased in GS patients as compared to both hypertensive patients and healthy subjects (8.65±3.08 ng/ml vs 3.70±1.19, P<0.0001, and vs 5.49±1.04, P=0.008, respectively. NOX4 levels correlate with HO-1 levels only in GS (r(2)=0.63; P=0.001), (r(2)=0.088; P=ns, in hypertensive patients and r(2)=0.082; P=ns, in healthy subjects). Our findings show that NOX4 and its effector HO-1 are reduced in hypertensive patients compared to GS patients, a human model opposite to hypertension. Although the functional significance of NOX4 needs further clarification, our preliminary data in a unique human model of anti-atherosclerotic and anti-remodeling defenses activation, highlight the potentially protective role of NOX4 in the human cardiovascular system

Longevity pathways and metabolic syndrome

The metabolic syndrome is becoming increasingly prevalent in the general population and carries significant incremental morbidity and mortality. It is associated with multi-organ involvement and increased all-cause mortality, resembling a precocious aging process. The mechanisms that account for this phenomenon are incompletely known, but it is becoming clear that longevity genes might be involved. Experiments with overactivation or disruption of key lifespan determinant pathways, such as silent information regulator (SIR)T1, p66Shc, and mammalian target of rapamycin (TOR), lead to development of features of the metabolic syndrome in mice. These genes integrate longevity pathways and metabolic signals in a complex interplay in which lifespan appears to be strictly dependent on substrate and energy bioavailability. Herein, we describe the roles and possible interconnections of selected lifespan determinant molecular networks in the development of the metabolic syndrome and its complications, describing initial available data in humans. Additional pathways are involved in linking nutrient availability and longevity, certainly including insulin and Insulin-like Growth Factor-1 (IGF-1) signaling, as well as FOXO transcription factors. The model described in this viewpoint article is therefore likely to be an oversimplification. Nevertheless, it represents one starting platform for understanding cell biology of lifespan in relation to the metabolic syndrome

The blocking of angiotensin II type 1 receptor and RhoA/Rho kinase activity in hypertensive patients: Effect of olmesartan medoxomil and implication with cardiovascular-renal remodeling

Hypothesis/Introduction: The pathophysiological role of oxidative stress (OxSt) in hypertension and target organ damage is recognized. Angiotensin II (Ang II) induces OxSt via NAD(P)H oxidase activation and production of proinflammatory cytokines/growth factors leading to cardiovascular-renal remodeling. Ang II stimulates the RhoA/Rho kinase (ROCK) pathway, which is deeply involved in the development of cardiovascular-renal remodeling via OxSt induction. Olmesartan, an Ang II type 1 receptor blocker, possesses antioxidant and activating nitric oxide system-related effects, which we have shown in terms of p22 phox reduction, heme oxygenase-1 and calcitonin gene-related peptide increase. This study evaluates in 15 untreated hypertensive patients the effect of olmesartan treatment on p63RhoGEF, key in Ang II-induced ROCK activation, and MYPT-1 phosphorylation, a marker of ROCK activity. Materials and methods: The p63RhoGEF protein level and MYPT-1 phosphorylation (Western blot) were evaluated at baseline, and after three and six months of olmesartan treatment. Results: Olmesartan normalized systolic and diastolic BP ( p < 0.001), reduced p63RhoGEF level: 1.3±0.25 d.u. (baseline) vs 1.0±0.29 (three months), p < 0.0001 vs 1.0±0.22, (six months), p < 0.0001 and MYPT-1 phosphorylation: 1.2 ±0.14 (baseline) vs 0.9±0.19 (three months), p = 0.008, vs 0.8±0.16 (six months), p = 0.001. Conclusions: These data added to our previous results further provide a mechanistic rationale for olmesartan's antioxidant/anti-inflammatory potential translation, in the long term, toward anti-atherosclerotic/anti-remodeling effects reported by clinical trials

Endothelin-1 Drives Epithelial-Mesenchymal Transition In Hypertensive Nephroangiosclerosis

BACKGROUND: Tubulointerstitial fibrosis, the final outcome of most kidney diseases, involves activation of epithelial mesenchymal transition (EMT). Endothelin‐1 (ET‐1) activates EMT in cancer cells, but it is not known whether it drives EMT in the kidney. We therefore tested the hypothesis that tubulointerstitial fibrosis involves EMT driven by ET‐1. METHODS AND RESULTS: Transgenic TG[mRen2]27 (TGRen2) rats developing fulminant angiotensin II–dependent hypertension with prominent cardiovascular and renal damage were submitted to drug treatments targeted to ET‐1 and/or angiotensin II receptor or left untreated (controls). Expressional changes of E‐cadherin and α‐smooth muscle actin (αSMA) were examined as markers of renal EMT. In human kidney HK‐2 proximal tubular cells expressing the ET(B) receptor subtype, the effects of ET‐1 with or without ET‐1 antagonists were also investigated. The occurrence of renal fibrosis was associated with EMT in control TGRen2 rats, as evidenced by decreased E‐cadherin and increased αSMA expression. Irbesartan and the mixed ET‐1 receptor antagonist bosentan prevented these changes in a blood pressure–independent fashion (P < 0.001 for both versus controls). In HK‐2 cells ET‐1 blunted E‐cadherin expression, increased αSMA expression (both P < 0.01), collagen synthesis, and metalloproteinase activity (P < 0.005, all versus untreated cells). All changes were prevented by the selective ET(B) receptor antagonist BQ‐788. Evidence for involvement of the Rho‐kinase signaling pathway and dephosphorylation of Yes‐associated protein in EMT was also found. CONCLUSIONS: In angiotensin II–dependent hypertension, ET‐1 acting via ET(B) receptors and the Rho‐kinase and Yes‐associated protein induces EMT and thereby renal fibrosis

STAT3 mutation impacts biological and clinical features of T-LGL leukemia

STAT3 mutations have been described in 30-40% of T-large granular lymphocyte (T-LGL) leukemia patients, leading to STAT3 pathway activation. Considering the heterogeneity of the disease and the several immunophenotypes that LGL clone may express, the aim of this work was to evaluate whether STAT3 mutations might be associated with a distinctive LGL immunophenotype and/or might be indicative for specific clinical features.Our series of cases included a pilot cohort of 101 T-LGL leukemia patients (68 CD8+/CD4- and 33 CD4+/CD8\ub1) from Padua Hematology Unit (Italy) and a validation cohort of additional 20 patients from Rennes Hematology Unit (France).Our results indicate that i) CD8+ T-LGL leukemia patients with CD16+/CD56- immunophenotype identify a subset of patients characterized by the presence of STAT3 mutations and neutropenia, ii) CD4+/CD8\ub1 T-LGL leukemia are devoid of STAT3 mutations but characterized by STAT5b mutations, and iii) a correlation exists between STAT3 activation and presence of Fas ligand, this molecule resulting highly expressed in CD8+/CD16+/CD56- patients. Experiments with stimulation and inhibition of STAT3 phosphorylation confirmed this relationship. In conclusion, our data show that T-LGL leukemia with specific molecular and phenotypic patterns is associated with discrete clinical features contributing to get insights into molecular bases accounting for the development of Fas ligand-mediated neutropenia

Effects of androgens on endothelial progenitor cells in vitro and in vivo

The beneficial or detrimental effects of androgens on the cardiovascular system are debated. Endothelial progenitor cells are bone-marrow-derived cells involved in endothelial healing and angiogenesis, which promote cardiovascular health. Oestrogens are potent stimulators of endothelial progenitor cells, and previous findings have indicated that androgens may improve the biology of these cells as well. In the present study, we show that testosterone and its active metabolite dihydrotestosterone exert no effects on the expansion and function of late endothelial progenitors isolated from the peripheral blood of healthy human adult males, whereas they positively modulate early ‘monocytic’ endothelial progenitor cells. In parallel, we show that castration in rats is followed by a decrease in circulating endothelial progenitor cells, but that testosterone and dihydrotestosterone replacement fails to restore endothelial progenitor cells towards normal levels. This is associated with persistently low oestrogen levels after androgen replacement in castrated rats. In a sample of 62 healthy middle-aged men, we show that circulating endothelial progenitor cell levels are more directly associated with oestradiol, rather than with testosterone, concentrations. In conclusion, our results collectively demonstrate that androgens exert no direct effects on endothelial progenitor cell biology in vitro and in vivo

Monocyte NADPH oxidase subunit p22(phox) and inducible hemeoxygenase-1 gene expressions are increased in type II diabetic patients: Relationship with oxidative stress

IF: 5,1

Oxidative stress and profibrotic action of aldosterone

We have read with great interest the recent paper of Iglarz et al1 published in the July issue of the Journal detailing their studies on the profibrotic action of aldosterone. They concluded that the profibrotic activity of aldosterone involves oxidative stress, at least in part, via an interaction with the renin-angiotensin system. We would like to provide further support to the contention of a specific profibrotic action of aldosterone with the demonstration ex vivo in human mononuclear cells, recently published from our laboratory,2 that indicates that aldosterone has a direct effect on oxidative stress through its ability to increase the levels of p22phox, an important subunit of NADPH oxidase, as well as of a recognized profibrotic protein, PAI-1, which may provide a direct link to the profibrotic action of aldosterone. Our findings were further strengthened by the observations demonstrating similar effects of glycyrrhetinic acid,2 a constituent of licorice root, which is known to have a direct mineralocorticoid-like effect when consumed in high amounts.3 Thus, the report of Iglarz et al1 in combination with our study provides clear evidence for the centrality of ROS mediated events in the pathophysiology of aldosterone-related profibrotic effects. These findings are important given the growing recognition of the role of aldosterone in the pathophysiology of cardiovascular disease, as demonstrated by the results of the recently concluded the Randomized Aldactone Evaluation Study (RALES)4 and the EPlerenone neuroHormonal Efficacy and SUrvival Study (EPHESUS)5 documenting a decline in overall mortality associated with the use of mineralcorticoid receptor antagonists in patients with advanced heart failure. The findings from these trials, in fact, indicated that the treatment to directly reduce aldosterone's effects through receptor blocking in addition to treating with drugs that reduce the activity of the renin-angiotensin system, will provide additional benefits to patients with cardiovascular disease