Novel blocker of NFAT activation inhibits IL-6 production in human myometrial arteries and reduces vascular smooth muscle cell proliferation

Nilsson, Lisa M.; Sun, Z.Y.; Nilsson, Jenny; Nordström, Ina; Chen, Yung-Wu; Molkentin, Jeffery D.; Wide‐Swensson, Dag; Hellstrand, Per; Lydrup, Marie‐Louise; Gomez, Maria F.

doi:10.1152/ajpcell.00590.2005

Cited by 81 publications

(102 citation statements)

References 41 publications

(40 reference statements)

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“…3D). These results are consistent with previous reports showing that ET-1 induces an increase in NFATc3 nuclear accumulation in vascular smooth muscle (25,48). Taken together, these results suggest that ET-1 may be an upstream mediator of H-IH-induced NFAT activation in aorta and mesenteric artery.…”

Section: H-ih Induces Hypertension In Micesupporting

confidence: 93%

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NFATc3 is required for intermittent hypoxia-induced hypertension

Garcı́a¹,

Duling²,

Alò³

et al. 2008

American Journal of Physiology-Heart and Circulatory Physiology

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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...

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Section: H-ih Induces Hypertension In Micesupporting

confidence: 93%

“…The number of NFATc3-positive nuclei was determined in aortic sections as previously described (11,20,27,47,48).…”

Section: Methodsmentioning

confidence: 99%

NFATc3 is required for intermittent hypoxia-induced hypertension

Garcı́a¹,

Duling²,

Alò³

et al. 2008

American Journal of Physiology-Heart and Circulatory Physiology

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“…NFAT expression was found to be linked to the regulation of IL-6 expression, as it has been shown that application of NFAT inhibitors such as cyclosporin A resulted in a decrease of IL-6 expression. Likewise, overexpression of NFAT blockers caused a reduction in IL-6 mRNA (45). In addition, previous data Figure 5.…”

Section: Discussionsupporting

confidence: 61%

Transcription Factor NFATc2 Controls the Emergence of Colon Cancer Associated with IL-6–Dependent Colitis

et al. 2012

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NFAT transcription factors control T-cell activation and function. Specifically, the transcription factor NFATc2 affects the regulation of cell differentiation and growth and plays a critical role in the development of colonic inflammation. Here, we used an experimental model of colitis-associated colorectal carcinoma to investigate the contribution of NFATc2 to the promotion of colonic tumors. Compared with wild-type animals that readily presented with multiple colon tumors, NFATc2-deficient mice were protected from tumor development. This observed decrease in colonic tumor progression was associated with reduced endoscopic inflammation, increased apoptosis of lamina propria T lymphocytes, and significantly reduced levels of the critical proinflammatory cytokines interleukin (IL)-21 and IL-6. Administration of hyper IL-6 abrogated protection from tumor progression in NFATc2-knockout mice and restored tumor incidence to control levels. Taken together, our findings highlight a pivotal role for NFATc2 in the establishment of inflammation-associated colorectal tumors mediated by control of IL-6 expression. Cancer Res; 72(17); 4340-50. Ó2012 AACR.

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“…72 However, in the adult it is an important mediator of cardiac hypertrophy. 9,73 Wnt-5a-mediated non-canonical signaling has been reported to regulate human endothelial cell proliferation and migration.…”

Section: Canonical Wnt Pathwaymentioning

confidence: 99%

Potential cross-talk between (pro)renin receptors and Wnt/frizzled receptors in cardiovascular and renal disorders

Balakumar

Jagadeesh

2011

Hypertens Res

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The renin-angiotensin system and Wnt/frizzled receptor signaling pathways are important in the development of essential organs, and their aberrant activation results in cardiovascular and renal pathologies. The (pro)renin receptor ((P)RR)-bound (pro)renin is enzymatically active generating angiotensin-II and activating mitogen-activated protein kinases, leading to cell proliferation and to upregulation of profibrotic genes expression, resulting in end-organ damage. The (P)RR does more than bind to (pro)renin, because it is functionally linked to the vacuolar-H + -ATPase (v-H + -ATPase) that regulates pH of cellular and intracellular vesicles, and to Wnt signaling. This signaling pathway is essential for cell survival, embryonic development and has had a role in various disease states as evidenced by mutation or genetic ablation of the (P)RR gene. This suggests two types of functions of (P)RRs, first one as a receptor for (pro)renin and second one as an accessory subunit of the v-H + -ATPase and a cofactor of the Wnt/Fz receptor complex. This review will discuss both of these functions of (P)RRs thereby giving new perspectives as to the roles of (P)RRs in cardiovascular and renal pathologies.

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Novel blocker of NFAT activation inhibits IL-6 production in human myometrial arteries and reduces vascular smooth muscle cell proliferation

Cited by 81 publications

References 41 publications

NFATc3 is required for intermittent hypoxia-induced hypertension

NFATc3 is required for intermittent hypoxia-induced hypertension

Transcription Factor NFATc2 Controls the Emergence of Colon Cancer Associated with IL-6–Dependent Colitis

Potential cross-talk between (pro)renin receptors and Wnt/frizzled receptors in cardiovascular and renal disorders

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