scholarly journals BMAL1 Disrupted Intrinsic Diurnal Oscillation in Rat Cerebrovascular Contractility of Simulated Microgravity Rats by Altering Circadian Regulation of miR-103/CaV1.2 Signal Pathway

2019 ◽  
Vol 20 (16) ◽  
pp. 3947 ◽  
Author(s):  
Li Chen ◽  
Bin Zhang ◽  
Lu Yang ◽  
Yun-Gang Bai ◽  
Ji-Bo Song ◽  
...  
Keyword(s):  
Circadian Rhythm ◽  
Space Flight ◽  
Simulated Microgravity ◽  
Orthostatic Intolerance ◽  
Cerebral Arteries ◽  
Signal Pathway ◽  
Circadian Regulation ◽  
Transcriptional Level ◽  
Cardiovascular Risks ◽  
Diurnal Oscillation

The functional and structural adaptations in cerebral arteries could be one of the fundamental causes in the occurrence of orthostatic intolerance after space flight. In addition, emerging studies have found that many cardiovascular functions exhibit circadian rhythm. Several lines of evidence suggest that space flight might increase an astronaut’s cardiovascular risks by disrupting circadian rhythm. However, it remains unknown whether microgravity disrupts the diurnal variation in vascular contractility and whether microgravity impacts on circadian clock system. Sprague-Dawley rats were subjected to 28-day hindlimb-unweighting to simulate the effects of microgravity on vasculature. Cerebrovascular contractility was estimated by investigating vasoconstrictor responsiveness and myogenic tone. The circadian regulation of CaV1.2 channel was determined by recording whole-cell currents, evaluating protein and mRNA expressions. Then the candidate miRNA in relation with Ca2+ signal was screened. Lastly, the underlying pathway involved in circadian regulation of cerebrovascular contractility was determined. The major findings of this study are: (1) The clock gene BMAL1 could induce the expression of miR-103, and in turn modulate the circadian regulation of CaV1.2 channel in rat cerebral arteries at post-transcriptional level; and (2) simulated microgravity disrupted intrinsic diurnal oscillation in rat cerebrovascular contractility by altering circadian regulation of BMAL1/miR-103/CaV1.2 signal pathway.

Activation of BKCa channel is associated with increased apoptosis of cerebrovascular smooth muscle cells in simulated microgravity rats

2010 ◽  
Vol 298 (6) ◽  
pp. C1489-C1500 ◽  
Author(s):  
Man-Jiang Xie ◽  
Yu-Guang Ma ◽  
Fang Gao ◽  
Yun-Gang Bai ◽  
Jiu-Hua Cheng ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Animal Studies ◽  
Simulated Microgravity ◽  
Orthostatic Intolerance ◽  
Cerebral Arteries ◽  
Muscle Cells ◽  
Hek293 Cells ◽  
Bkca Channel ◽  
Sprague Dawley

Cerebral arterial remodeling is one of the critical factors in the occurrence of postspaceflight orthostatic intolerance. We hypothesize that large-conductance calcium-activated K+ (BKCa) channels in vascular smooth muscle cells (VSMCs) may play an important role in regulating cerebrovascular adaptation during microgravity exposure. The aim of this work was to investigate whether activation of BKCa channels is involved in regulation of apoptotic remodeling of cerebral arteries in simulated microgravity rats. In animal studies, Sprague-Dawley rats were subjected to 1-wk hindlimb unweighting to simulate microgravity. Alterations of BKCa channels in cerebral VSMCs were investigated by patch clamp and Western blotting; apoptosis was assessed by electron microscopy and terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick-end labeling (TUNEL). To evaluate the correlation of BKCa channel and apoptosis, channel protein and cell nucleus were double-stained. In cell studies, hSloα+β1 channel was coexpressed into human embryonic kidney 293 (HEK293) cells to observe the effects of BKCa channels on apoptosis. In rats, enhanced activities and expression of BKCa channels were found to be correlated with increased apoptosis in cerebral VSMCs after simulated microgravity. In transfected HEK293 cells, activation of cloned BKCa channel induced apoptosis, whereas inhibition of cloned BKCa channel decreased apoptosis. In conclusion, activation of BKCa channels is associated with increased apoptosis in cerebral VSMCs of simulated microgravity rats.

scholarly journals Circadian Regulation of Mitochondrial Uncoupling and Lifespan

2020 ◽  
Vol 4 (Supplement_1) ◽  
pp. 740-741
Author(s):  
Matthew Ulgherait
Keyword(s):  
Stem Cells ◽  
Circadian Rhythm ◽  
Uncoupling Protein ◽  
Intestinal Stem Cells ◽  
Intestinal Stem Cell ◽  
Cellular Respiration ◽  
Circadian Regulation ◽  
Lifespan Extension ◽  
Diet Restriction ◽  
Mitochondrial Uncoupling

Abstract Because old age is associated with defects in circadian rhythm, loss of circadian regulation is thought to be pathogenic and contribute to mortality. We show instead that loss of specific circadian clock components Period (Per) and Timeless (Tim) in male Drosophila significantly extends lifespan. This lifespan extension is not mediated by canonical diet-restriction longevity pathways, but is due to altered cellular respiration via increased mitochondrial uncoupling. Lifespan extension of per mutants depends on mitochondrial uncoupling in the intestine. Moreover, up-regulated uncoupling protein UCP4C in intestinal stem cells and enteroblasts is sufficient to extend lifespan and preserve proliferative homeostasis in the gut with age. Consistent with inducing a metabolic state that prevents over-proliferation, mitochondrial uncoupling drugs also extend lifespan and inhibit intestinal stem cell overproliferation due to aging or even tumorigenesis. These results demonstrate that circadian-regulated intestinal mitochondrial uncoupling controls longevity in Drosophila and suggest a new potential anti-aging therapeutic target.

A NEW MODEL FOR THE ROLE OF INDIVIDUAL PREDISPOSITION IN ORTHOSTATIC INTOLERANCE BEFORE AND AFTER EXPOSURE TO SIMULATED MICROGRAVITY.

2004 ◽  
Vol 52 ◽  
pp. S384-S385
Author(s):  
S. M. Grenon ◽  
N. Sheynberg ◽  
X. Xiao ◽  
C. D. Ramsdell ◽  
S. Hurwitz ◽  
...  
Keyword(s):  
Simulated Microgravity ◽  
Orthostatic Intolerance ◽  
New Model ◽  
Before And After

Endothelium-dependent vasodilation of cerebral arteries is altered with simulated microgravity through nitric oxide synthase and EDHF mechanisms

2006 ◽  
Vol 101 (1) ◽  
pp. 348-353 ◽  
Author(s):  
Rhonda D. Prisby ◽  
M. Keith Wilkerson ◽  
Elke M. Sokoya ◽  
Robert M. Bryan ◽  
Emily Wilson ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Methyl Ester ◽  
Nitric Oxide Synthase ◽  
Cerebral Perfusion ◽  
Simulated Microgravity ◽  
Cerebral Arteries ◽  
Caveolin 1 ◽  
Fluid Shifts ◽  
Oxide Synthase

Cephalic elevations in arterial pressure associated with microgravity and prolonged bed rest alter cerebrovascular autoregulation in humans. Using the head-down tail-suspended (HDT) rat to chronically induce headward fluid shifts and elevate cerebral artery pressure, previous work has likewise shown cerebral perfusion to be diminished. The purpose of this study was to test the hypothesis that 2 wk of HDT reduces cerebral artery vasodilation. To test this hypothesis, dose-response relations for endothelium-dependent (2-methylthioadenosine triphosphate and bradykinin) and endothelium-independent (nitroprusside) vasodilation were determined in vitro in middle cerebral arteries (MCAs) from HDT and control rats. All in vitro measurements were done in the presence and absence of the nitric oxide synthase inhibitor NG-nitro-l-arginine methyl ester (10−5 M) and cyclooxygenase inhibitor indomethacin (10−5 M). MCA caveolin-1 protein content was measured by immunoblot analysis. Endothelium-dependent vasodilation to 2-methylthioadenosine triphosphate and bradykinin were both lower in MCAs from HDT rats. These lower vasodilator responses were abolished with NG-nitro-l-arginine methyl ester but were unaffected by indomethacin. In addition, HDT was associated with lower levels of MCA caveolin-1 protein. Endothelium-independent vasodilation was not altered by HDT. These results indicate that chronic cephalic fluid shifts diminish endothelium-dependent vasodilation through alterations in the endothelial nitric oxide synthase signaling mechanism. Such decrements in endothelium-dependent vasodilation of cerebral arteries could contribute to the elevations in cerebral vascular resistance and reductions in cerebral perfusion that occur after conditions of simulated microgravity in HDT rats.

Abstract 19324: Effects of Simulated Microgravity on Ckit+ Cardiac Progenitor Cells

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Konstantinos E Hatzistergos ◽  
Lauro M Takeuchi ◽  
Wayne Balkan ◽  
Joshua M Hare
Keyword(s):  
Progenitor Cells ◽  
Microarray Analysis ◽  
Space Flight ◽  
Simulated Microgravity ◽  
Neural Crest Cell ◽  
Embryoid Bodies ◽  
Egfp Expression ◽  
Cardiac Progenitor Cells ◽  
Time Points ◽  
Increased Risk

Introduction: Space flight has profound negative impacts on cardiac health. Whereas microgravity appears to benefit cardiomyogenesis, long-duration space flight results in increased risk for cardiomyopathy. Here, we focused on cKit+ cardiac progenitor cells (CPCs) to elucidate the effects of microgravity in the heart. Hypothesis: Microgravity inhibits migration, proliferation and differentiation of CPCs. Methods: Adult heart tissue or induced pluripotent stem cells (iPSCs) from cKitCreErt2;IRG mice were grown for up to 24- (n=5) or 21-days (n=6), respectively, in static (SC) or a rotary cell-culture system (RCCS, simulated microgravity) in the presence of 4-OH tamoxifen to irreversibly label CPCs with EGFP. Expression of EGFP was quantified at selected time points in heart explants and iPSC-derived beating embryoid bodies (EBs). In addition, microarray analysis was performed on EBs at selected time points (n=11). Results: We found that, although explants in SC consistently produced EGFP+ CPCs with full capacity to proliferate and migrate, expression of EGFP was abolished in RCCS (p<0.05). Similarly, when day-4 EBs (formed via the hanging-drop method) were transferred to RCCS, they generated significantly fewer spontaneously beating EBs compared to EBs grown in SC (p=0.0005), whereas expression of EGFP in beating EBs was downregulated ~10-fold (p=0.01). Microarray analysis of EBs illustrated that the effect of CPs was accompanied by downregulation of genes related to migration, differentiation and development of the cardiac neural crest cell (CNC) lineage (i.e. Pax3, semaphorins, endothelin) without affecting the expression of cardiac mesoderm-related genes (i.e. GATA4, NKX2-5, MEF2C). Intriguingly, the effect of RCCS in CNC-related genes could be partly rescued upon transfer of EBs from RCCS to SC. Conclusions: cKit expression and CNC pathways are inhibited under simulated microgravity but can be reversed by returning to normal gravity. Our findings provide novel insights into the role of gravity in cardiomyogenesis and suggest that CPCs should be targeted therapeutically for the prevention and treatment of microgravity-induced cardiomyopathy.

46 A NEW MODEL FOR THE ROLE OF INDIVIDUAL PREDISPOSITION IN ORTHOSTATIC INTOLERANCE BEFORE AND AFTER EXPOSURE TO SIMULATED MICROGRAVITY.

2004 ◽  
Vol 52 (Suppl 2) ◽  
pp. S384.6-S385
Author(s):  
S. M. Grenon ◽  
N. Sheynberg ◽  
X. Xiao ◽  
C. D. Ramsdell ◽  
S. Hurwitz ◽  
...  
Keyword(s):  
Simulated Microgravity ◽  
Orthostatic Intolerance ◽  
New Model ◽  
Before And After
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