Sleep apnea, defined as intermittent respiratory arrest during sleep, is associated with increased incidence of hypertension and peripheral vascular disease. Exposure of rodents to brief periods of intermittent hypercarbia/hypoxia (H-IH) during sleep mimics the cyclical hypoxia-normoxia of sleep apnea. Endothelin-1, an upstream activator of nuclear factor of activated T cells (NFAT), is increased during H-IH. Therefore, we hypothesized that NFATc3 is activated by H-IH and is required for H-IH-induced hypertension. Consistent with this hypothesis, we found that H-IH (20 brief exposures per hour to 5% O2-5% CO2 for 7 h/day) induces systemic hypertension in mice [mean arterial pressure (MAP) ϭ 97 Ϯ 2 vs. 124 Ϯ 2 mmHg, P Ͻ 0.05, n ϭ 5] and increases NFATc3 transcriptional activity in aorta and mesenteric arteries. Cyclosporin A, an NFAT inhibitor, and genetic ablation of NFATc3 [NFATc3 knockout (KO)] prevented NFAT activation. More importantly, H-IHinduced hypertension was attenuated in cyclosporin A-treated mice and prevented in NFATc3 KO mice. MAP was significantly elevated in wild-type mice (⌬ ϭ 23.5 Ϯ 6.1 mmHg), but not in KO mice (⌬ ϭ Ϫ3.9 Ϯ 5.7). These results indicate that H-IH-induced increases in MAP require NFATc3 and that NFATc3 may contribute to the vascular changes associated with H-IH-induced hypertension.nuclear factor of activated T cells; hypercarbic; mouse; endothelin-1; sleep apnea SLEEP APNEA (SA), defined as intermittent respiratory arrest during sleep, affects up to 20% of the adult population. Among the major consequences of SA are decreased O 2 saturation (hypoxia) and increased CO 2 saturation (hypercapnia). In SA patients, incidence of hypertension, peripheral vascular disease, stroke, and sudden cardiac death is increased (for review see Refs. 21 and 44). Thus SA appears to directly initiate vascular changes that predispose individuals to cardiovascular disease.Recently, it was demonstrated that exposure of rodents to periods of intermittent hypoxia with CO 2 supplementation [intermittent hypercarbia/hypoxia (H-IH)] during sleep mimics the cyclical hypoxia-normoxia of SA. In rats exposed to H-IH, blood pressure (34, 35) and circulating endothelin-1 (ET-1) are elevated (35), vasoconstrictor sensitivity to ET-1 is increased (2), and blood pressure is normalized with ET antagonists (35). These studies, together with clinical studies showing increased circulating ET-1 in SA (10, 55), suggest that augmented ET-1 vasoconstriction contributes to SA hypertension. The sustained increased blood pressure observed in SA patients and animal models also appears to involve activation of the sympathetic nervous and renin-angiotensin systems and diminished activity of nitric oxide synthase (for review see Refs. 44 and 52).ET-1 acts through G␣ q -coupled receptors as a Ca 2ϩ -mobilizing agent and as a potent activator of the nuclear factor of activated T cells (NFAT) (1, 25, 57). ANG II, glucose through UTP release, and ␣ 1 -adrenergic agonists are also potent stimuli of NFAT activation (1,25,27,46,57).NFAT...
The Fulani are semi-nomadic pastoralists of West Africa whose diet, culture, and economy are centred on cattle. Previous studies have shown that the Fulani of northern Nigeria derive 50% of their total calories from fat and 30% of their calories from milk, cheese, yogurt, and butter oil that contain significant amounts of trans fatty acids (TFAs), primarily vaccenic acid, which raise total serum cholesterol and low-density lipoproteincholesterol (LDL-C), and lower high-density lipoprotein-cholesterol (HDL-C). The study was conducted to know how the consumption of relatively large amounts of dairy products by adult Fulani affected the TFA content of their serum phospholipids. Blood samples were collected from 22 male and 29 female Fulani, aged 35-60 years, who were living in rural areas of Gombe state in northeastern Nigeria. The total serum phospholipid fraction was isolated, and its fatty acid composition was determined. Surprisingly, vaccenic acid was not detected, and three other TFAs-18:1-t6, 18:1-t9, and 18:2-t9,t12-together accounted for only 0.16% of the total fatty acid. The mean serum total cholesterol, LDL-C, and triglyceride concentrations of the subjects were within the normal range for populations in developed countries; however, at 32 mg/dL, the mean serum HDL-C concentration of the Fulani males was slightly below the lower limit of the reference range. No correlations were observed between the total TFA percentage or that of the three individual TFAs and any of the parameters of the serum lipid profile. These findings indicate that, with respect to TFAs at least, the fatty acid pattern of the serum phospholipids of Fulani pastoralists does not reflect the high TFA content of their traditional diet. Despite the consumption of rumenic acid-rich dairy products, for unknown reasons, the semi-nomadic Fulani manage to maintain a low level of TFAs in their blood and a relatively healthful serum lipid profile. While the mechanism that accounts for this disconnect between the consumption of TFAs by Fulani pastoralists and the proportion of TFAs in their serum phospholipids is obscure, possibilities include discrimination against rumenic acid during the process of triglyceride synthesis and chylomicron synthesis in the intestine and the preferential oxidation of TFAs by Fulani the people compared to other ethnic groups.
Mastocytosis is a relatively common disorder characterized by mast cell collections in the skin and other organ systems. Affected children are more likely than adults to have limited cutaneous disease. We report two patients with localized vulvar mastocytosis in the absence of other cutaneous findings and review previous reports of vulvar involvement in cutaneous mastocytosis.
Sleep apnea (SA) is an intermittent respiratory arrest during sleeping associated with increased incidence of hypertension and peripheral vascular disease. Exposing rodents to brief periods of IH during sleep mimics the cyclical hypoxia/normoxia of SA. We have previously shown that IH induces systemic hypertension in mice, increases NFAT transcriptional activity in aorta (Ao) and mesenteric arteries (MA) and cyclosporin A (CsA), NFAT inhibitor, prevents IH‐induced hypertension. In addition, we have established that smooth muscle (SM) α‐actin and soluble guanylyl cyclase α‐1 (sGC) are positively regulated by NFAT to potentially maintain SM contractile phenotype. The goal of this study was to determine if NFATc3 mediates IH‐induced hypertension and its target genes. Mean arterial pressure (MAP) was measured in NFATc3 knockout (KO) and wild type (WT) mice exposed to air for 5 days and then up to 7 days of IH cycling (20 exposures/h to 5% O2/5% CO2) for 7 h/day. WT showed a significant elevation in MAP (Δ 23.5±6.1 mmHg) at every time point whereas MAP failed to increase in the KO (Δ −3.9±5.7). Expression levels of SM‐α‐actin and sGC were determined in MA and Ao of air, V‐IH and CsA‐IH mice (25 mg/kg/day). SM‐α‐actin mRNA was elevated in MA (2−ddCT 3.3±0.3) and Ao (2.0±0.3) of V‐IH mice and CsA significantly attenuated that increase (MA 2.1±0.2; Ao 0.7±0.2). sGC was only elevated in MA from V‐IH, suggesting that both genes are up‐regulated by NFAT during IH. These results indicate that IH‐induced increase in MAP requires NFATc3 and that NFATc3 may contribute to the vascular changes associated with IH‐induced hypertension. Supported by SDG AHA.
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