Catalogue Search | MBRL
Are you sure you want to remove the book from the shelf?
{{itemTitle}}
307
result(s) for
"Chappell, Mark"
Sort by:
Chymase-Dependent Generation of Angiotensin II from Angiotensin-(1-12) in Human Atrial Tissue
Since angiotensin-(1-12) [Ang-(1-12)] is a non-renin dependent alternate precursor for the generation of cardiac Ang peptides in rat tissue, we investigated the metabolism of Ang-(1-12) by plasma membranes (PM) isolated from human atrial appendage tissue from nine patients undergoing cardiac surgery for primary control of atrial fibrillation (MAZE surgical procedure). PM was incubated with highly purified ¹²⁵I-Ang-(1-12) at 37°C for 1 h with or without renin-angiotensin system (RAS) inhibitors [lisinopril for angiotensin converting enzyme (ACE), SCH39370 for neprilysin (NEP), MLN-4760 for ACE2 and chymostatin for chymase; 50 µM each]. ¹²⁵I-Ang peptide fractions were identified by HPLC coupled to an inline γ-detector. In the absence of all RAS inhibitor, ¹²⁵I-Ang-(1-12) was converted into Ang I (2±2%), Ang II (69±21%), Ang-(1-7) (5±2%), and Ang-(1-4) (2±1%). In the absence of all RAS inhibitor, only 22±10% of ¹²⁵I-Ang-(1-12) was unmetabolized, whereas, in the presence of the all RAS inhibitors, 98±7% of ¹²⁵I-Ang-(1-12) remained intact. The relative contribution of selective inhibition of ACE and chymase enzyme showed that ¹²⁵I-Ang-(1-12) was primarily converted into Ang II (65±18%) by chymase while its hydrolysis into Ang II by ACE was significantly lower or undetectable. The activity of individual enzyme was calculated based on the amount of Ang II formation. These results showed very high chymase-mediated Ang II formation (28±3.1 fmol × min⁻¹ × mg⁻¹, n = 9) from ¹²⁵I-Ang-(1-12) and very low or undetectable Ang II formation by ACE (1.1±0.2 fmol×min⁻¹ × mg⁻¹). Paralleling these findings, these tissues showed significant content of chymase protein that by immunocytochemistry were primarily localized in atrial cardiac myocytes. In conclusion, we demonstrate for the first time in human cardiac tissue a dominant role of cardiac chymase in the formation of Ang II from Ang-(1-12).
Journal Article
Reply to: angiotensinogen: a new era beyond lactate as a biomarker?
Dear Editor, We appreciate the comments from Drs. Shen and Ding [1] regarding our brief research report, “Stronger association of intact angiotensinogen with mortality than lactate or renin in critical illness: post-hoc analysis from the VICTAS trial [2]. Nonetheless, there was significant mortality in this cohort of sepsis patients that was strongly associated with circulating levels of intact angiotensinogen, suggesting under these conditions that intact angiotensinogen as a biomarker outperformed both renin and lactate according to model performance metrics including area under the curve and the Youden index. [...]we believe intact angiotensinogen may constitute an additional clinical tool in the care of patients in early sepsis or septic shock. Renin kinetics are superior to lactate kinetics for predicting in-hospital mortality in hypotensive critically Ill patients.
Journal Article
Guitar all-in-one for dummies
A one-stop resource to learn to play guitar! This guide puts everything you need to start playing and continue improving at your fingertips.
Book
Attenuation of Salt-Induced Cardiac Remodeling and Diastolic Dysfunction by the GPER Agonist G-1 in Female mRen2.Lewis Rats
The G protein-coupled estrogen receptor (GPER) is expressed in various tissues including the heart. Since the mRen2.Lewis strain exhibits salt-dependent hypertension and early diastolic dysfunction, we assessed the effects of the GPER agonist (G-1, 40 nmol/kg/hr for 14 days) or vehicle (VEH, DMSO/EtOH) on cardiac function and structure.
Intact female mRen2.Lewis rats were fed a normal salt (0.5% sodium; NS) diet or a high salt (4% sodium; HS) diet for 10 weeks beginning at 5 weeks of age.
Prolonged intake of HS in mRen2.Lewis females resulted in significantly increased blood pressure, mildly reduced systolic function, and left ventricular (LV) diastolic compliance (as signified by a reduced E deceleration time and E deceleration slope), increased relative wall thickness, myocyte size, and mid-myocardial interstitial and perivascular fibrosis. G-1 administration attenuated wall thickness and myocyte hypertrophy, with nominal effects on blood pressure, LV systolic function, LV compliance and cardiac fibrosis in the HS group. G-1 treatment significantly increased LV lusitropy [early mitral annular descent (e')] independent of prevailing salt, and improved the e'/a' ratio in HS versus NS rats (P<0.05) as determined by tissue Doppler.
Activation of GPER improved myocardial relaxation in the hypertensive female mRen2.Lewis rat and reduced cardiac myocyte hypertrophy and wall thickness in those rats fed a high salt diet. Moreover, these advantageous effects of the GPER agonist on ventricular lusitropy and remodeling do not appear to be associated with overt changes in blood pressure.
Journal Article
Characterization of the Cardiac Renin Angiotensin System in Oophorectomized and Estrogen-Replete mRen2.Lewis Rats
The cardioprotective effects of estrogen are well recognized, but the mechanisms remain poorly understood. Accumulating evidence suggests that the local cardiac renin-angiotensin system (RAS) is involved in the development and progression of cardiac hypertrophy, remodeling, and heart failure. Estrogen attenuates the effects of an activated circulating RAS; however, its role in regulating the cardiac RAS is unclear. Bilateral oophorectomy (OVX; n = 17) or sham-operation (Sham; n = 13) was performed in 4-week-old, female mRen2.Lewis rats. At 11 weeks of age, the rats were randomized and received either 17 β-estradiol (E2, 36 µg/pellet, 60-day release, n = 8) or vehicle (OVX-V, n = 9) for 4 weeks. The rats were sacrificed, and blood and hearts were used to determine protein and/or gene expression of circulating and tissue RAS components. E2 treatment minimized the rise in circulating angiotensin (Ang) II and aldosterone produced by loss of ovarian estrogens. Chronic E2 also attenuated OVX-associated increases in cardiac Ang II, Ang-(1-7) content, chymase gene expression, and mast cell number. Neither OVX nor OVX+E2 altered cardiac expression or activity of renin, angiotensinogen, angiotensin-converting enzyme (ACE), and Ang II type 1 receptor (AT1R). E2 treatment in OVX rats significantly decreased gene expression of MMP-9, ACE2, and Ang-(1-7) mas receptor, in comparison to sham-operated and OVX littermates. E2 treatment appears to inhibit upsurges in cardiac Ang II expression in the OVX-mRen2 rat, possibly by reducing chymase-dependent Ang II formation. Further studies are warranted to determine whether an E2-mediated reduction in cardiac chymase directly contributes to this response in OVX rats.
Journal Article
Establishment of Early Endpoints in Mouse Total-Body Irradiation Model
Acute radiation sickness (ARS) following exposure to ionizing irradiation is characterized by radiation-induced multiorgan dysfunction/failure that refers to progressive dysfunction of two or more organ systems, the etiological agent being radiation damage to cells and tissues over time. Radiation sensitivity data on humans and animals has made it possible to describe the signs associated with ARS. A mouse model of total-body irradiation (TBI) has previously been developed that represents the likely scenario of exposure in the human population. Herein, we present the Mouse Intervention Scoring System (MISS) developed at the Veterinary Sciences Department (VSD) of the Armed Forces Radiobiology Research Institute (AFRRI) to identify moribund mice and decrease the numbers of mice found dead, which is therefore a more humane refinement to death as the endpoint. Survival rates were compared to changes in body weights and temperatures in the mouse (CD2F1 male) TBI model (6-14 Gy, 60Co γ-rays at 0.6 Gy min-1), which informed improvements to the Scoring System. Individual tracking of animals via implanted microchips allowed for assessment of criteria based on individuals rather than by group averages. From a total of 132 mice (92 irradiated), 51 mice were euthanized versus only four mice that were found dead (7% of non-survivors). In this case, all four mice were found dead after overnight periods between observations. Weight loss alone was indicative of imminent succumbing to radiation injury, however mice did not always become moribund within 24 hours while having weight loss >30%. Only one survivor had a weight loss of greater than 30%. Temperature significantly dropped only 2-4 days before death/euthanasia in 10 and 14 Gy animals. The score system demonstrates a significant refinement as compared to using subjective assessment of morbidity or death as the endpoint for these survival studies.
Journal Article
Diet, obesity, and the gut microbiome as determinants modulating metabolic outcomes in a non-human primate model
Background
The objective of this study was to increase understanding of the complex interactions between diet, obesity, and the gut microbiome of adult female non-human primates (NHPs). Subjects consumed either a Western (
n
=15) or Mediterranean (
n
=14) diet designed to represent human dietary patterns for 31 months. Body composition was determined using CT, fecal samples were collected, and shotgun metagenomic sequencing was performed. Gut microbiome results were grouped by diet and adiposity.
Results
Diet was the main contributor to gut microbiome bacterial diversity. Adiposity within each diet was associated with subtle shifts in the proportional abundance of several taxa. Mediterranean diet-fed NHPs with lower body fat had a greater proportion of
Lactobacillus animalis
than their higher body fat counterparts. Higher body fat Western diet-fed NHPs had more
Ruminococcus champaneliensis
and less
Bacteroides uniformis
than their low body fat counterparts. Western diet-fed NHPs had significantly higher levels of
Prevotella copri
than Mediterranean diet NHPs. Western diet-fed subjects were stratified by
P. copri
abundance (
P. copri
HIGH
versus
P. copri
LOW
), which was not associated with adiposity. Overall, Western diet-fed animals in the
P. copri
HIGH
group showed greater proportional abundance of
B. ovatus
,
B. faecis
,
P. stercorea
,
P. brevis
, and
Faecalibacterium prausnitzii
than those in the Western
P. copri
LOW
group. Western diet
P. copri
LOW
subjects had a greater proportion of
Eubacterium siraeum
.
E. siraeum
negatively correlated with
P. copri
proportional abundance regardless of dietary consumption. In the Western diet group, Shannon diversity was significantly higher in
P. copri
LOW
when compared to
P. copri
HIGH
subjects. Furthermore, gut
E. siraeum
abundance positively correlated with HDL plasma cholesterol indicating that those in the
P. copri
LOW
population may represent a more metabolically healthy population. Untargeted metabolomics on urine and plasma from Western diet-fed
P. copri
HIGH
and
P. copri
LOW
subjects suggest early kidney dysfunction in Western diet-fed
P. copri
HIGH
subjects.
Conclusions
In summary, the data indicate diet to be the major influencer of gut bacterial diversity. However, diet and adiposity must be considered together when analyzing changes in abundance of specific bacterial taxa. Interestingly,
P. copri
appears to mediate metabolic dysfunction in Western diet-fed NHPs.
6J_wxx79_1pf52UFxoCxzk
Video abstract
Journal Article
Building geochemically based quantitative analogies from soil classification systems using different compositional datasets
Soil heterogeneity is a major contributor to the uncertainty in near-surface biogeochemical modeling. We sought to overcome this limitation by exploring the development of a new classification analogy concept for transcribing the largely qualitative criteria in the pedomorphologically based, soil taxonomic classification systems to quantitative physicochemical descriptions. We collected soil horizons classified under the Alfisols taxonomic Order in the U.S. National Resource Conservation Service (NRCS) soil classification system and quantified their properties via physical and chemical characterizations. Using multivariate statistical modeling modified for compositional data analysis (CoDA), we developed quantitative analogies by partitioning the characterization data up into three different compositions: Water-extracted (WE), Mehlich-III extracted (ME), and particle-size distribution (PSD) compositions. Afterwards, statistical tests were performed to determine the level of discrimination at different taxonomic and location-specific designations. The analogies showed different abilities to discriminate among the samples. Overall, analogies made up from the WE composition more accurately classified the samples than the other compositions, particularly at the Great Group and thermal regime designations. This work points to the potential to quantitatively discriminate taxonomically different soil types characterized by varying compositional datasets.
Journal Article