Abstract 112: Cardiac-specific Constitutive Activation of Nrf2 Induces Reductive Stress and Pathological Cardiac Remodeling

2017 ◽  
Vol 121 (suppl_1) ◽  
Author(s):  
Gobinath Shanmugam ◽  
Madhusudhanan Narasimhan ◽  
Jolyn Fernandes ◽  
Kevin Whitehead ◽  
Silvio H Litovsky ◽  
...  
Keyword(s):  
Cardiac Remodeling ◽  
Function Analysis ◽  
Radical Scavenging ◽  
Structure And Function ◽  
Heart Weight ◽  
Wall Thickening ◽  
Antioxidant Genes ◽  
Reductive Stress ◽  
Chronic Activation ◽  
And Function

Background: Heart failure is a growing cause of human morbidity and mortality. Supplementations of free radical scavenging antioxidants have largely failed to protect the myocardium from oxidative stress diseases. While endogenous transcriptional activation of antioxidants appears to be promising, their chronic effects are unknown. Here, we tested a hypothesis that chronic activation of antioxidant system will result in reductive stress (RS) and lead to pathological cardiac hypertrophy. Methods: Novel transgenic (TG) mice expressing constitutively active Nrf2 in the heart (α-MHC-caNrf2-TG) and their littermates were used to study the effects on structure and function of the myocardium. Myocardial glutathione redox state (GSH/GSSG), transcript levels (qPCR), and protein (immunoblotting) for Nrf2-related antioxidants and structure and function analysis (echocardiography - Vevo2100 Imager) in Non-transgenic (NTg), TG-low and TG-high mice (n=6-12/gp.) were performed at 6-8 months of age. Further, changes in cardiomyocytes and rate of survival in TG mice were analyzed. Results: Kaplan-Meier survival plots demonstrated 10 and 40% mortality in TG-low and TG-high, respectively, compared to NTG by 60 weeks of age. The myocardial glutathione and its redox ratio (GSH/GSSG) were significantly increased (p<0.05) in the TG-low and TG-high compared with NTg mice indicates development of RS. A significant increase in Nrf2-ARE (promoter) binding with increased expression of antioxidant genes and proteins (p<0.05) were noted in TG vs. NTg mice. Increased heart-to-body weight and heart weight to tibia length ratios were prominent in TG-high relative to NTg or TG-low mice. Histological analyses (WGA, H&E staining) showed increased cardiomyocyte size, ventricular wall thickening and decreased chamber volume in TG mice. Echocardiography analyses revealed significant hypertrophic cardiomyopathy with abnormally increased ejection fraction (HCM i EF) due to chronic reductive stress. Conclusion: Thus, basal attenuation of the obligatory oxidative signaling with chronic activation of Nrf2-antioxidants could shift the redox equilibrium to “reductive” side and thereby causing pathological cardiac remodeling.

Abstract 539: Buthionine Sulfoximine (BSO) Prevents Reductive Stress-induced Pathological Hypertrophic Cardiomyopathy

2020 ◽  
Vol 127 (Suppl_1) ◽  
Author(s):  
Gobinath Shanmugam ◽  
Silvio Litovsky ◽  
Steven M Pogwizd ◽  
Namakkal S. Rajasekaran
Keyword(s):  
Diastolic Dysfunction ◽  
Weight Ratio ◽  
Buthionine Sulfoximine ◽  
Structure And Function ◽  
Heart Weight ◽  
Cardiac Structure ◽  
Ros Signaling ◽  
Reductive Stress ◽  
Cardiac Structure And Function ◽  
And Function

Background: Chronic reductive stress (RS) induces pathological cardiac remodeling and diastolic dysfunction. Here, we hypothesized that preventing RS via glutathione (GSH) depletion, through selective inhibition of γ-glutamyl cysteine ligase (γGCL), mitigates cardiac pathology in cRS mice. Methods: Cardiac-specific constitutively active Nrf2 TG-mice (α-MHc-caNrf2-TG), at 6 weeks of age, were administered with buthionine sulfoximine (BSO; 5.0 mM/Kg; daily for 16-weeks). At the end of 22 weeks, cardiac structure and function (systole & diastole using echocardiography), myocardial redox state, levels of ROS (using dihydroethidium (DHE) fluorescence), and antioxidant proteome were assessed in TG mice treated with PBS or BSO and compared with the age matched NTG littermates (n=6/group). Results: While the TG mice experiencing RS (GSH; 426.3±22.55 vs. 141.8±3.9 & GSH/GSSG; 61.04±5.4 vs. 23.27±1.3 in TG vs. NTG), this was significantly curtailed in BSO-treated TG mice (GSH 161.8±12.6 & GSH/GSSG; 25.1±4.3). This was coupled with the normal cardiac functions (EF; ~53% & MV E/A; 1.57) in the BSO-treated TG when compared to TG mice experiencing a hyper systolic function (>80% ejection fraction) with decreased cardiac volume and diastolic dysfunction with restricted filling (MV E/A ratio; >3.0), Of note, BSO treatment did not alter the protein levels of antioxidants (i.e. GCLC, GCLM, NQO1 and CAT), but only depleted the GSH pool (via inhibiting GCL activity) and restored the basal ROS signaling in the myocardium. Moreover, the BSO-treated TG mice did not develop cardiac hypertrophy, which was assessed by heart weight/body weight ratio, qPCR-based gene expression for hypertrophy ( Anf, Bnf, α-MHc and β-Mhc ). Conclusion: Our results suggest that pharmacological manipulation of myocardial redox and repletion of basal ROS signaling prevented RS-mediated pathological processes and rescued the cardiac structure and function.

Structure and function analysis of a CC-NBS-LRR protein AT1G12290

2021 ◽  
Vol 534 ◽  
pp. 206-211
Author(s):  
Jianzhong Huang ◽  
Xiaoqiu Wu ◽  
Kaiting Sun ◽  
Zhiyong Gao
Keyword(s):  
Function Analysis ◽  
Structure And Function ◽  
And Function ◽  
Lrr Protein

Abstract 999: Gated Micro Computed Tomography Scanning: An Emerging Tool for Longitudinal Assessment of Murine Cardiac Remodeling.

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Ahmad Y Sheikh ◽  
Timothy C Doyle ◽  
Maryam K Sheikh ◽  
Feng Cao ◽  
Katherine J Ransohoff ◽  
...  
Keyword(s):  
Computed Tomography ◽  
Cardiac Remodeling ◽  
High Energy ◽  
Left Ventricular ◽  
Structure And Function ◽  
Coronary Artery Ligation ◽  
Micro Ct ◽  
Ventricular Ejection Fraction ◽  
Computed Tomography Scanning ◽  
And Function

Background: Recent advances in high energy X-ray source computed tomography (CT) technology have made it possible to accurately image murine cardiac structure and function. We describe the use of a gated Micro CT system to assess cardiac remodeling in a murine model of myocardial infarction (MI). Methods: Adult FVB mice (n = 10) were randomized to surgically induced MI by left coronary artery ligation or sham procedure. Dual gated cardiac and respiratory Micro CT scans were performed pre-operatively and at weeks 4, 8 and 12 post-procedure. End-diastolic and end-systolic images were acquired by gating on the ECG P-and S’-waves, respectively. Post-acquisition analysis was performed using image analysis software and the following parameters were quantified: left ventricular (LV) volume and mass, right ventricular volume and mass, right and left atrial volumes, and ventricular ejection fraction (EF). Results: Images were successfully acquired with a resolution of 100 microns allowing for identification and quantification of key cardiac structures (Fig 1A ). Following MI, animals exhibited left ventricular failure with significantly increased* end systolic and diastolic volumes by week 4. Ventricular dilation continued through week 8, plateauing by week 12. Left ventricular mass increased steadily over 12 weeks*, with a significantly decreased* LVEF of 28.0 ± .05% by week 12 (pre-MI: 66.7 ± .06%,*p < 0.01). Post-MI left ventricular change is detailed in Fig 1B . Conclusions: MicroCT scanning can be successfully used to characterize murine myocardial structure and function, making it a useful tool to assess cardiac phenotypes and models of cardiovascular disease.

scholarly journals Structure-function analysis of Arabidopsis TOPLESS reveals fundamental conservation of repression mechanisms across eukaryotes

2020 ◽  
Author(s):  
Alexander R. Leydon ◽  
Wei Wang ◽  
Hardik P. Gala ◽  
Sabrina Gilmour ◽  
Samuel Juarez-Solis ◽  
...  
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Function Analysis ◽  
Structure And Function ◽  
Environmental Cues ◽  
Auxin Response ◽  
Middle Domain ◽  
N Terminus ◽  
And Function ◽  
The Relationship ◽  
Repression Domain

SummaryThe plant corepressor TOPLESS (TPL) is recruited to a large number of loci that are selectively induced in response to developmental or environmental cues, yet the mechanisms by which it inhibits expression in the absence of these stimuli is poorly understood. Previously, we had used the N-terminus of Arabidopsis thaliana TPL to enable repression of a synthetic auxin response circuit in Saccharomyces cerevisiae (yeast). Here, we leveraged the yeast system to interrogate the relationship between TPL structure and function, specifically scanning for repression domains. We identified a potent repression domain in Helix 8 located within the CRA domain, which directly interacted with the Mediator middle domain subunits Med21 and Med10. Interactions between TPL and Mediator were required to fully repress transcription in both yeast and plants. In contrast, we found that multimer formation, a conserved feature of many corepressors, had minimal influence on the repression strength of TPL.

scholarly journals Purana Pura Suniantara Analisis Struktur dan Fungsi

HUMANIS ◽  
2019 ◽  
pp. 140
Author(s):  
Ni Luh Gede Yunita Kazi Wiguna ◽  
I Gde Nala Antara ◽  
I Ketut Ngurah Sulibra
Keyword(s):  
Function Analysis ◽  
Structure And Function ◽  
Text Structure ◽  
Narrative Text ◽  
Inductive Method ◽  
Moral Value ◽  
Language Variety ◽  
Faithful Servant ◽  
Observation Method ◽  
And Function

This research analyzes traditional Balinese literature works in the form of narrative text. The analyzed text is Purana Pura Suniantara Analysis of Structure and Function. It tells the story about Dalem Suniantara Temple during the reign of I Gusti Agung Jambe Tangkeban along with a faithful servant, I Gede Batan Nyuh. This research used structural theory by Teeuw and Nurgiyantoro. Method and technique used is falls into three stages, which are data obtained by using observation method, supported by reading and note taking technique. Data analyzed stage uses qualitative method and analytic descriptive technique, while result provision of data analysis used informal method and supported by deductive as well as inductive method. The result obtained from this research is structure and function of test, including to structure format which are consist of Purana Pura Suniantara teks, as well as its text’s form and language variety. Based on its language variety, Purana Pura Suniantara teks used Kawi – Bali language which is a mixture of Sanskrit, Old Javanese, Middle Javanesse, and Balinese. Narrative text structure consists of plot, background, characterization, theme, and moral value. Further, function analysis consists of historical, social, and religious function.

scholarly journals Kashmiri Wazwan: Are We Listening to Our Endothelium?

JMS SKIMS ◽  
2013 ◽  
Vol 16 (2) ◽  
pp. 72-74
Author(s):  
M Fuad Jan ◽  
Suhail Allaqband
Keyword(s):  
Insulin Resistance ◽  
Cardiac Remodeling ◽  
Experimental Models ◽  
Structure And Function ◽  
Cardiac Structure ◽  
Unsaturated Lipid ◽  
Diet Induced Obesity ◽  
Blood Pressure Homeostasis ◽  
Cardiac Structure And Function ◽  
And Function

In animal models of diet-induced obesity, hypercaloric (4.6 Kcal/g) diets have been shown to have metabolic hormonal effects, including hyperglycemia, insulin resistance and changes in leptin profiles 1, as well as undesirable effects on blood pressure homeostasis and even cardiac remodeling. Such effects have been directly and inversely correlated with saturated and unsaturated lipid consumption, respectively. In these experimental models, it also has been elegantly demonstrated that a variety of alterations in cardiac structure and function occur due to reduced myofilament Ca2+ sensitivity, alterations in Ca2+ handling proteins and beta-adrenergic receptors2-5. JMS 2013;16(2):72-74

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