Babbette LaMarca

Tumor Necrosis Factor-α Antagonist Etanercept Decreases Blood Pressure and Protects the Kidney in a Mouse Model of Systemic Lupus Erythematosus

Chronic inflammation has been implicated in the pathology of hypertension; however, the role for specific cytokines remains unclear. We tested whether tumor necrosis factor-&agr; blockade with etanercept (Etan) reduces mean arterial pressure in a female mouse model of systemic lupus erythematosus (SLE). SLE is a chronic inflammatory disorder with prevalent hypertension. Thirty-week-old SLE (NZBWF1) and control mice (NZW/LacJ) received Etan (0.8 mg/kg SC weekly) for 4 weeks or vehicle. Mean arterial pressure (in millimeters of mercury) was increased in SLE mice (150±5 versus 113±5 in controls; P<0.05) and was lower in Etan-treated SLE mice (132±3) but not controls (117±5). Albuminuria (in micrograms per milligram of creatinine) was elevated in SLE mice (28 742±9032 versus 1075±883; P<0.05) and was lower in Etan-treated SLE mice (8154±3899) but not control animals (783±226). Glomerulosclerosis (in percentage of glomeruli) was evident in SLE mice (2.5±1.6 versus 0.0±0.0 in controls; P<0.05) and was ameliorated in Etan-treated SLE mice (0.1±0.1). Renal cortex CD68+ cell staining (in percentage of area) was elevated in SLE mice (4.75±0.80 versus 0.79±0.12 in controls; P<0.05) and was lower in Etan-treated SLE mice (2.28±0.32) but not controls (1.43±0.25). Renal cortex NADPH oxidase activity (relative light units per milligram of protein) was higher in SLE mice compared with controls (10 718±1276 versus 7584±229; P<0.05) and lowered in Etan-treated SLE mice (6645±490). Renal cortex nuclear factor &kgr;B (phosphorylated and nonphosphorylated) was increased in SLE mice compared with controls and lower in Etan-treated SLE mice. These data suggest that TNF-&agr; mechanistically contributes to the development of hypertension in a chronic inflammatory disease through increased renal nuclear factor &kgr;B, oxidative stress, and inflammation.

Changes in cardiac structure in hypertension produced by placental ischemia in pregnant rats: effect of tumor necrosis factor blockade.

Objectives Chronic reduction of uteroplacental perfusion pressure (RUPP) in pregnant rats leads to placental ischemia, maternal endothelial cell dysfunction, hypertension and elevated levels of tumor necrosis factor-alpha (TNF-α). In this study we investigated the hypothesis that placental ischemia in pregnant rat, a model of preeclampsia, stimulates cardiac hypertrophy and fibrosis via a TNF-α-dependent mechanism. Methods Normal pregnant Sprague-Dawley rats and RUPP rats were evaluated on day 19 of gestation. To test the role of TNF-α in mediating change in the RUPP rat heart, a TNF-α inhibitor, etanercept, was administered on day 18 of gestation at a dose of 0.8 mg/kg, s.c. Results In comparison to normal pregnant rats, RUPP animals display enlarged cardiomyocytes, microvascular rarefaction, fibrosis, apoptosis as well as increased expression of markers of heart hypertrophy and fibrosis. Etanercept (E) treatment prevented enlargement of cardiomyocytes, fibrosis and apoptosis and this was accompanied by significantly lowered blood pressure in RUPP rats. Etanercept treatment lowered expression of mRNA for brain natriuretic peptide, a marker of cardiac hypertrophy. It also heightened expression of endothelial nitric oxide synthase and its phosphorylation as well as oxytocin receptor identified in cardiac microvessels. TNF-α inhibition prevented microvascular rarefaction in the heart as indicated by augmented CD31, a marker of angiogenesis. Conclusions These results suggest that RUPP leads to microvascular rarefaction in the heart, exaggerated cardiomyocyte size, apoptosis, fibrosis, and the alteration of cardiac gene expression that are modulated by the inflammatory cytokine TNFα.

ACE2 and ANG-(1-7) in the gravid uterus: the new players on the block

there has been long-standing interest in the widely recognized role of the renin-angiotensin system (RAS) in electrolyte homeostasis and regulation of hemodynamics in both diseased and nondiseased states ([5][1]). While the role of the RAS in the long-term regulation of renal function and arterial

CYP2J2 Expression and Circulating Epoxyeicosatrienoic Metabolites in Preeclampsia

Background —Preeclampsia is a multisystem disorder of pregnancy, originating in the placenta. Cytochrome P450 (CYP)-dependent eicosanoids regulate vascular function, inflammation, and angiogenesis that are mechanistically important in preeclampsia. nnMethods and Results —We performed microarray screening of placenta and decidua (maternal placenta) from 25 preeclamptic women and 23 controls. The CYP subfamily 2J polypeptide 2 (CYP2J2) was upregulated in preeclamptic placenta and decidua. RT-PCR confirmed the upregulation and immunohistochemistry localized CYP2J2 in trophoblastic villi and deciduas at 12 weeks and term. The CYP2J2 metabolites, 5,6-epoxyeicosatrienoic acids (EET), 14,15-EET, and the corresponding dihydroxyeicosatrienoic acids (DHET), were elevated in preeclamptic women compared to controls in the latter two-thirds of pregnancy and after delivery. Stimulating a trophoblast-derived cell line with the preeclampsia-associated cytokine, tumor necrosis factor-α enhanced CYP2J2 gene and protein expression. In two independent rat models of preeclampsia, reduced uterine-perfusion rat and the transgenic Ang II rat, we observed elevated EET, DHET, and preeclamptic features that were ameliorated by the CYP epoxygenase inhibitor, MsPPOH. Uterine arterial rings of these rats also dilated in response to MsPPOH. Furthermore, 5,6-EET could be metabolized to a thromboxane analog. In a bioassay, 5,6-EET increased the beating rate of neonatal cardiomyocytes. Blocking thromboxane synthesis reversed that finding and also normalized large-conductance calcium-activated potassium channel (KCa1.1) activity. nnConclusions —Our data implicate CYP2J2 in the pathogenesis of preeclampsia and as a potential candidate for the disturbed uteroplacental remodeling, leading to hypertension and endothelial dysfunction.Background— Preeclampsia is a multisystem disorder of pregnancy, originating in the placenta. Cytochrome P450 (CYP)-dependent eicosanoids regulate vascular function, inflammation, and angiogenesis, which are mechanistically important in preeclampsia. Methods and Results— We performed microarray screening of placenta and decidua (maternal placenta) from 25 preeclamptic women and 23 control subjects. The CYP subfamily 2J polypeptide 2 (CYP2J2) was upregulated in preeclamptic placenta and decidua. Reverse-transcription polymerase chain reaction confirmed the upregulation, and immunohistochemistry localized CYP2J2 in trophoblastic villi and deciduas at 12 weeks and term. The CYP2J2 metabolites, 5,6-epoxyeicosatrienoic acid (EET), 14,15-EET, and the corresponding dihydroxyeicosatrienoic acids, were elevated in preeclamptic women compared with controls in the latter two thirds of pregnancy and after delivery. Stimulating a trophoblast-derived cell line with the preeclampsia-associated cytokine tumor necrosis factor-&agr; enhanced CYP2J2 gene and protein expression. In 2 independent rat models of preeclampsia, reduced uterine-perfusion rat and the transgenic angiotensin II rat, we observed elevated EET, dihydroxyeicosatrienoic acid, and preeclamptic features that were ameliorated by the CYP epoxygenase inhibitor N-(methylsulfonyl)-2-(2-propynyloxy)-benzenehexanamide (MsPPOH). Uterine arterial rings of these rats also dilated in response to MsPPOH. Furthermore, 5,6-EET could be metabolized to a thromboxane analog. In a bioassay, 5,6-EET increased the beating rate of neonatal cardiomyocytes. Blocking thromboxane synthesis reversed that finding and also normalized large-conductance calcium-activated potassium channel activity. Conclusions— Our data implicate CYP2J2 in the pathogenesis of preeclampsia and as a potential candidate for the disturbed uteroplacental remodeling, leading to hypertension and endothelial dysfunction.