Increased Superoxide and Endothelial NO Synthase Uncoupling in Blood Vessels of Bmal1-Knockout Mice

Anea, Ciprian B.; Cheng, Bo; Sharma, Shruti; Kumar, Sanjiv; Caldwell, Robert W.; Yao, Lin; Ali, Mohammed Farid; Merloiu, Ana M.; Stepp, David W.; Black, Stephen M.; Fulton, David; Rudic, R. Daniel

doi:10.1161/circresaha.111.261750

Cited by 98 publications

(87 citation statements)

References 65 publications

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“…An increase in nitric oxide production in tubular cells is an alternative mechanism that could explain this phenomenon. 34,35 Collectively, functional analysis of Bmal1 lox/lox /Ren1 d Cre mice has shown that the local renal circadian clocks are involved in a variety of specific renal functions and BP control. The specificity in establishing genotype-phenotype correlations in circadian clock-deficient models consists in the highly pleiotropic role of circadian clocks on both transcriptional/ translational and functional levels.…”

Section: Discussionmentioning

confidence: 99%

Local Renal Circadian Clocks Control Fluid–Electrolyte Homeostasis and BP

Tokonami¹,

Mordasini²,

Pradervand

et al. 2014

Journal of the American Society of Nephrology

105

101

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The circadian timing system is critically involved in the maintenance of fluid and electrolyte balance and BP control. However, the role of peripheral circadian clocks in these homeostatic mechanisms remains unknown. We addressed this question in a mouse model carrying a conditional allele of the circadian clock gene Bmal1 and expressing Cre recombinase under the endogenous Renin promoter (Bmal1 Cre mice exhibited multiple abnormalities, including increased urine volume, changes in the circadian rhythm of urinary sodium excretion, increased GFR, and significantly reduced plasma aldosterone levels. These changes were accompanied by a reduction in BP. These results show that local renal circadian clocks control body fluid and BP homeostasis. Circadian rhythmicity is a feature of a wide variety of physiologic functions. Many of the functional rhythms are driven by the circadian timing system, a complex mechanism that coordinates all major cellular processes with geophysical time. It is thought that this coordination allows for the anticipatory adaptation of cells and tissues to the circadian changes in functional requirements. The circadian timing system is organized in a hierarchical manner. The master clock of the system is located in the suprachiasmatic nucleus of the hypothalamus and synchronized to the daily light/dark cycle through the retinohypothalamic tract. The peripheral circadian clocks, which are present in virtually all peripheral tissues, are synchronized to geophysical time through a wide range of master clock-dependent stimuli, many of which remain unknown (reviewed in ref. 1 ). It is important to note, however, that, despite the hierarchical structure of the circadian timing system and its continuous resetting by environmental time cues, the intrinsic activity of both central and peripheral circadian clocks is largely self-sustained. On the molecular level, the master clock and peripheral clocks share similar machinery based on transcriptional/translational feedback loops involving transcriptional activators BMAL1, CLOCK, and NPAS2 and their own repressors PER1 and PER2 as well as CRY1 and CRY2 (reviewed in ref. 2 ).The circadian timing system is critically involved in the maintenance of fluid and electrolyte balance

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Section: Discussionmentioning

confidence: 99%

Local Renal Circadian Clocks Control Fluid–Electrolyte Homeostasis and BP

Tokonami¹,

Mordasini²,

Pradervand

et al. 2014

Journal of the American Society of Nephrology

105

101

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“…These frozen tissues were sectioned at a thickness of 8 μm and incubated with dihydroethidium (DHE; 5 μM; Life Technologies) for 30 min at 37°C. 2 Some sections were pretreated with superoxide dismutase-polyethylene glycol (PEG-SOD; 300 U/ml)/catalase-polyethylene glycol (PEG-CAT; 200 U/ml) or Apocynin (250 μM) or L-NG-Nitroarginine Methyl Ester (L-NAME; 1 mM) before incubation with DHE for 10 min at 37°C. The aortic specimen were visualized by Olympus IX81 confocal fluorescence microscopy using an excitation at 546 ± 25 nm band-pass filter, emission at 590 nm long-pass filter followed by a 640 ± 25 nm band-pass filter.…”

Section: Measurement Of Superoxide In In Vitro Cell Cultures Andmentioning

confidence: 99%

“…1 Uncoupling of eNOS has been shown to be central to robust superoxide generation and the associated vascular dysfunction. 2 Increased levels of asymmetric NG, NG-dimethyl arginine (ADMA-a substrate analog of L-arginine) in circulation have also been shown in diabetic patients limiting the availability of L-arginine to eNOS. 3 In vitro studies from our laboratory and reports from other investigators have shown that the regulation of eNOS activity is mediated by heat shock protein-90 (Hsp-90).…”

mentioning

confidence: 99%

Enhancing eNOS activity with simultaneous inhibition of IKKβ restores vascular function in Ins2Akita+/− type-1 diabetic mice

Krishnan

Janardhanan

Roman

et al. 2015

Laboratory Investigation

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The balance of nitric oxide (NO) versus superoxide generation has a major role in the initiation and progression of endothelial dysfunction. Under conditions of high glucose, endothelial nitric oxide synthase (eNOS) functions as a chief source of superoxide rather than NO. In order to improve NO bioavailability within the vessel wall in type-1 diabetes, we investigated treatment strategies that improve eNOS phosphorylation and NO-dependent vasorelaxation. We evaluated methods to increase the eNOS activity by (1) feeding Ins2Akita spontaneously diabetic (type-1) mice with L-arginine in the presence of sepiapterin, a precursor of tetrahydrobiopterin; (2) preventing eNOS/NO deregulation by the inclusion of inhibitor kappa B kinase beta (IKKβ) inhibitor, salsalate, in the diet regimen in combination with L-arginine and sepiapterin; and (3) independently increasing eNOS expression to improve eNOS activity and associated NO production through generating Ins2Akita diabetic mice that overexpress human eNOS predominantly in vascular endothelial cells. Our results clearly demonstrated that diet supplementation with L-arginine, sepiapterin along with salsalate improved phosphorylation of eNOS and enhanced vasorelaxation of thoracic/abdominal aorta in type-1 diabetic mice. More interestingly, despite the overexpression of eNOS, the in-house generated transgenic eNOS-GFP (TgeNOS-GFP)-Ins2 Akita cross mice showed an unanticipated effect of reduced eNOS phosphorylation and enhanced superoxide production. Our results demonstrate that enhancement of endogenous eNOS activity by nutritional modulation is more beneficial than increasing the endogenous expression of eNOS by gene therapy modalities. Endothelial nitric oxide synthase (eNOS) that utilizes L-arginine as a substrate to generate nitric oxide (NO) is a key regulator of vascular function. Even though endothelial cells, a predominant source of eNOS exhibit constitutive enzyme activity, several other regulators are necessary to induce eNOS activity based on local demand for NO. Reduced bioavailability of NO that causes endothelial dysfunction is a hallmark of diabetes. Several mechanisms have been implicated causing 'endothelial dysfunction' in diabetes. The reduced availability of the substrate L-arginine and the cofactor tetrahydrobiopterin (BH4) has been implicated due to increased arginase activity and enhanced superoxide generation. 1 Uncoupling of eNOS has been shown to be central to robust superoxide generation and the associated vascular dysfunction. 2 Increased levels of asymmetric NG, NG-dimethyl arginine (ADMA-a substrate analog of L-arginine) in circulation have also been shown in diabetic patients limiting the availability of L-arginine to eNOS. 3 In vitro studies from our laboratory and reports from other investigators have shown that the regulation of eNOS activity is mediated by heat shock protein-90 (Hsp-90). 4,5 The interaction of eNOS with Hsp-90 favors the phosphorylation of eNOS at Ser1177 by Akt kinase. This phosphorylation process is a key event which a...

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“…As such, Period2 is important for healthy functions and recruitment of endothelial progenitor cells to growing vessels in mice; animals in which the period2 gene has been mutated and rendered dysfunctional exhibit vascular senescence and a lack of ischemia-induced angiogenesis in the hind-limb muscle tissue [37]. In addition to the direct regulation of tumor cell dedifferentiation by the pathological tumor cell circadian clock [3], clock disruption also lead to elevated intracellular ROS [38], which in turn could drive de-differentiation. In fact, the circadian clock has been extensively implicated in redox-biology.…”

Section: Role Of Circadian Clocks In Cancermentioning

confidence: 99%

The circadian clock and hypoxia in tumor cell de-differentiation and metastasis

Jensen¹

2015

Biochimica et Biophysica Acta (BBA) - General Subjects

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Increased Superoxide and Endothelial NO Synthase Uncoupling in Blood Vessels of Bmal1-Knockout Mice

Cited by 98 publications

References 65 publications

Local Renal Circadian Clocks Control Fluid–Electrolyte Homeostasis and BP

Local Renal Circadian Clocks Control Fluid–Electrolyte Homeostasis and BP

Enhancing eNOS activity with simultaneous inhibition of IKKβ restores vascular function in Ins2Akita+/− type-1 diabetic mice

The circadian clock and hypoxia in tumor cell de-differentiation and metastasis

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