Chronic prenatal hypoxia sensitizes β-adrenoceptors in the embryonic heart but causes postnatal desensitization

2009 ◽  
Vol 297 (2) ◽  
pp. R258-R264 ◽  
Author(s):  
Isa Lindgren ◽  
Jordi Altimiras
Keyword(s):  
Adrenergic Receptors ◽  
Broiler Chickens ◽  
Cardiac Tissue ◽  
Cardiac Development ◽  
Cardiac Contractility ◽  
Prenatal Hypoxia ◽  
Response Curves ◽  
Cgp 12177 ◽  
Cardiac Enlargement ◽  
Fetal Cardiac Development

Prenatal hypoxia in mammals causes fetal growth restriction and catecholaminergic overstimulation that, in turn, alter signaling pathways associated with adrenergic receptors. β-Adrenoceptors (β-ARs) are essential for fetal cardiac development and regulation of cardiac contractility. We studied the effects of chronic prenatal hypoxia on cardiac β-AR signaling and the incidence of alterations in the juvenile β-AR system due to the embryonic treatment. We measured functional β-AR density (Bmax) through binding with [3H]CGP-12177 and the effect of agonists on β-AR-dependent contractility (pEC50) through concentration-response curves to epinephrine. Eggs from broiler chickens were incubated in normoxia (N, 21% O2) or chronic hypoxia (H, 14% O2). Cardiac tissue from embryos and juveniles was used (15 and 19 day of embryonic development and 14 and 35 days posthatching, E19, E15, P14, and P35, respectively). Relative cardiac enlargement was found in the hypoxic groups at E15, E19, and P14, but not P35. Bmax significantly decreased in E19H. Bmax more than doubled posthatching but decreased from P14 to P35. The sensitivity to epinephrine was lower in E19N compared with E15N, but hypoxia increased the sensitivity to agonist in both E15H and E19H. Despite maintained receptor density, the P35H juvenile displayed a decreased sensitivity to β-AR agonist, something that was not seen in P14H. The postnatal decrease in β-AR sensitivity as an effect of chronic prenatal hypoxia, without a concomitant change in β-AR density, leads us to conclude that the embryonic hypoxic challenge alters the future progression of β-AR signaling and may have important implications for cardiovascular function in the adult.

Binding of the hydrophilic β-adrenergic antagonist [3H]CGP-12177 to cardiac tissue slices: characterization and ontogenetic studies in dogs

1987 ◽  
Vol 65 (9) ◽  
pp. 1928-1933 ◽  
Author(s):  
C. Haddad ◽  
M. Wilkinson ◽  
L. M. Roeder ◽  
J. T. Tildon ◽  
J. A. Armour
Keyword(s):  
Adrenergic Receptors ◽  
Cardiac Tissue ◽  
Tissue Slices ◽  
Tissue Handling ◽  
Neonatal Life ◽  
Adrenergic Antagonist ◽  
Cgp 12177 ◽  
A New Technique ◽  
The Right ◽  
Β Adrenergic Receptors

A new technique was developed to characterize the binding of a hydrophilic β-adrenergic antagonist, [3H]CGP-12177, to 1-mm thick slices of canine cardiac tissue. This technique was used to quantify the density (Bmax) and the affinity (Kd) of these receptors in the right ventricular conus (RVC) and the left ventricle (LV) at day 1 to 6 weeks of age, and in the adult. Binding was found to be reversible, saturable, stereospecific, of high affinity, and thermolabile. There was an increase in the density of β-adrenergic receptors between day 1 (Bmax = 2.2 ± 0.3 fmol/mg tissue in RVC and 2.9 ± 0.8 fmol/mg tissue in the LV) and 2 weeks of age postnatally, after which it remained constant until 6 weeks of age (Bmax = 7.5 ± 0.4 and 6.8 ± 0.9 fmol/mg tissue in RVC and LV, respectively); however, by 6 weeks of age it had not reached adult levels (10.3 ± 1.0 fmol/mg tissue). The affinity of these receptors did not change between early neonatal life (Kd = 1.3 ± 0.4 nM) and adulthood (Kd = 1.4 ± 0.2 nM). The density of β-adrenergic receptors in the RVC was similar to that in the LV. This new method of quantifying β-adrenergic receptors in cardiac tissue is simple and fast, and requires minimal tissue handling. It proved to be useful in studying the development of cardiac β-adrenergic receptors with age.

scholarly journals Recapitulating Cardiac Structure and Function In Vitro from Simple to Complex Engineering

Micromachines ◽  
2021 ◽  
Vol 12 (4) ◽  
pp. 386
Author(s):  
Ana Santos ◽  
Yongjun Jang ◽  
Inwoo Son ◽  
Jongseong Kim ◽  
Yongdoo Park
Keyword(s):  
Tissue Engineering ◽  
Extracellular Matrix ◽  
Computational Modeling ◽  
Cardiac Tissue ◽  
Cardiac Development ◽  
Heart Tissue ◽  
Cardiac Tissue Engineering ◽  
Cardiac Cells

Cardiac tissue engineering aims to generate in vivo-like functional tissue for the study of cardiac development, homeostasis, and regeneration. Since the heart is composed of various types of cells and extracellular matrix with a specific microenvironment, the fabrication of cardiac tissue in vitro requires integrating technologies of cardiac cells, biomaterials, fabrication, and computational modeling to model the complexity of heart tissue. Here, we review the recent progress of engineering techniques from simple to complex for fabricating matured cardiac tissue in vitro. Advancements in cardiomyocytes, extracellular matrix, geometry, and computational modeling will be discussed based on a technology perspective and their use for preparation of functional cardiac tissue. Since the heart is a very complex system at multiscale levels, an understanding of each technique and their interactions would be highly beneficial to the development of a fully functional heart in cardiac tissue engineering.

scholarly journals Use of molecular biomarkers to estimate manganese requirements for broiler chickens from 22 to 42 d of age

2016 ◽  
Vol 116 (9) ◽  
pp. 1512-1518 ◽  
Author(s):  
Lin Lu ◽  
Bin Chang ◽  
Xiudong Liao ◽  
Runlian Wang ◽  
Liyang Zhang ◽  
...  
Keyword(s):  
Dna Binding ◽  
Protein Expression ◽  
Broiler Chickens ◽  
Mrna Level ◽  
Molecular Biomarkers ◽  
Expression Level ◽  
Response Curves ◽  
Expression Levels ◽  
Soyabean Meal ◽  
Mnsod Activity

AbstractThe present study was carried out to evaluate dietary Mn requirements of broilers from 22 to 42 d of age using molecular biomarkers. Chickens were fed a conventional basal maize–soyabean meal diet supplemented with Mn as Mn sulphate in graded concentrations of 20 mg Mn/kg from 0 to 140 mg Mn/kg of diet for 21 d (from 22 to 42 d of age). The Mn response curves were fitted for ten parameters including heart Mn-containing superoxide dismutase (MnSOD) mRNA and its protein expression levels and the DNA-binding activities of specificity protein 1 (Sp1) and activating protein-2 (AP-2). Heart MnSOD mRNA and protein expression levels showed significant quadratic responses (P<0·01), and heart MnSOD activity showed a broken-line response (P<0·01), whereas Mn content and DNA-binding activities of Sp1 and AP-2 in the heart displayed linear responses (P<0·01) to dietary Mn concentrations, respectively. The estimates of dietary Mn requirements were 101, 104 and 94 mg/kg for full expressions of MnSOD mRNA level, MnSOD protein level and MnSOD activity in the heart, respectively. Our findings indicate that heart MnSOD mRNA expression level is a more reliable indicator than heart MnSOD protein expression level and its activity for the evaluation of Mn requirement of broilers, and about 100 mg Mn/kg of diet is required for the full expression of heart MnSOD in broilers fed the conventional basal maize–soyabean meal diet from 22 to 42 d of age.

Abstract P499: Protein Kinase Cα Deletion Causes Hypotension Due to Decreased Vascular Contractility

Hypertension ◽  
2017 ◽  
Vol 70 (suppl_1) ◽  
Author(s):  
Brandi M Wynne ◽  
Cameron G McCarthy ◽  
Theodora Szasz ◽  
Janet D Klein ◽  
R. Clinton Webb ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Cardiac Contractility ◽  
Mesenteric Arteries ◽  
Response Curves ◽  
Smooth Muscle Contractility ◽  
Vascular Contractility ◽  
Cox Inhibitor ◽  
Protein Kinase Cα ◽  
Multiple Cell ◽  
Relaxation Responses

Protein kinase Cα (PKCα) regulates multiple cell signaling pathways, including those that impact blood pressure. PKCα activation increases vascular smooth muscle contractility, yet reduces cardiac contractility. PKCα has also been shown to modulate nephron ion transport. We have shown that PKCα deletion leads to hypotension, with compensatory increases in sodium retention. Here, we hypothesized that PKCα deficiency reduces vascular contractility, leading to decreased mean arterial pressure (MAP). MAP, measured by telemetry, was decreased in PKC KO (≈12 mmHg) compared to PKC control (PKC CTL) mice. Aorta and mesenteric arteries were isolated, and concentration response curves (CRCs) to phenylephrine (Phe), acetylcholine (ACh) or sodium nitroprusside (SNP) were performed in the presence of vehicle or the following inhibitors: L-NAME or indomethacin (NOS, COX inhibitor, resp. ). CRCs to KCL were performed to assess receptor-independent vascular responses. In aorta, we observed a striking reduction in KCl-mediated contraction (5.8±0.3mN vs. 10.4±1.1mN control, **p<0.01). PKC KO aorta and mesenteric arteries had decreased contractile responses to Phe, as compared to control (aorta, 12.7±0.5mN R max vs. 16.3±0.5mN R max , and mesenteric 9.9±0.3mN R max vs. 11.8±0.6mN R max ; n=4, **p<0.01), revealing a role for reduced vascular contractility. Endothelium-mediated relaxation responses to ACh were also increased in PKC KO mice, as compared to control (59.3±6.8% R max vs. 45.4±3.2% R max , n=4, *p<0.05). Interestingly, NOS inhibition increased contractility in mesenteric arteries from PKC KO mice (8.55±2.65mN R max vs. 6.95±0.39mN R max control, n=4, ***p<0.001). However, PKC KO aorta had an enhanced response to COX inhibition (12.2±0.7mN R max vs. 10.1±0.6mN R max control, n=4, *p<0.05) suggesting that PKCα may be negatively regulating NOS in mesenteric arteries, and COX-mediated prostaglandin production in the aorta. No differences were observed in the relaxation responses to SNP. These data suggest that global deletion of PKCα results in hypotension due to decreased vascular contractility, and loss of PKCα-mediated inhibition of endothelial relaxing factors. Thus, systemic targeting of PKCα may be beneficial for the reduction of MAP.

Abstract P477: A Novel SMYD1 Variant (c.302A>G) Leads To Dilated Cardiomyopathy And Biventricular Heart Failure.

2021 ◽  
Vol 129 (Suppl_1) ◽  
Author(s):  
Marta Szulik ◽  
Miguel Reyes-Mugica ◽  
Daniel F Marker ◽  
Lina Ghaloul-Gonzalez ◽  
Sarah Franklin
Keyword(s):  
Heart Failure ◽  
Skeletal Muscle ◽  
Cardiac Tissue ◽  
De Novo ◽  
Cardiac Development ◽  
Left Ventricular ◽  
Histopathological Analysis ◽  
Loss Of Function ◽  
Adult Mice ◽  
Heterozygous Variant

The lysine methyltransferase SMYD1 was first identified in mice and shown to be important for embryonic cardiac development. Subsequently, we reported the first analysis of SMYD1 in adult myocardium and demonstrated that cardiomyocyte-specific loss of SMYD1 lead to progressive cardiac hypertrophy and heart failure, and showed that this enzyme is necessary to maintain metabolic homeostasis through transcriptional regulation of mitochondrial energetics in adult mice. While SMYD1 has been the subject of several additional studies in zebrafish and mice, since it was first identified, only in the last few years have human patients been identified with variants in the SMYD1 gene thought to be responsible for their cardiomyopathies. Specifically, two patients have been identified to date, the first patient displaying hypertrophic cardiomyopathy had a de novo heterozygous variant (c.814T>C) and the second patient with left ventricular non-compaction cardiomyopathy and arrhythmias had a truncating heterozygous variant (c.675delA). Here we report a third patient with biventricular heart failure containing a homozygous variant (c.302A>G; p.Asn101S) in the SMYD1 gene which was identified by a whole exome sequencing. Our histopathological analysis of cardiac tissue and skeletal muscle from the proband showed abnormalities in myofibrillar organization in both cardiac and skeletal muscle suggesting that SMYD1 is necessary for sarcomere assembly and organization. In addition, we observe markedly abnormal myocardium with extensive fibrosis and multifocal calcification, and our ultrastructural (EM) analysis revealed presence of abnormal mitochondria with reduced and irregular or lost cristae. Lastly, we have performed structural modeling of SMYD1 containing the p.Asn101Ser variant (N101S) and report how this variant may affect the enzymatic activity of SMYD1 due to its proximity to the substrate binding site. The identification of this novel variant constitutes the third patient with a SMYD1 variant displaying cardiomyopathy and provides insights into the molecular functionality of this protein. In addition, this is the first analysis of tissue from a patient expressing a SMYD1 variant which provides critical insights into the role of SMYD1 in the heart and how loss of function mutations can effect cardiac physiology.

scholarly journals An assessment of the influence of macronutrients on growth performance and nutrient utilisation in broiler chickens by nutritional geometry

2016 ◽  
Vol 116 (12) ◽  
pp. 2129-2138 ◽  
Author(s):  
Sonia Y. Liu ◽  
Peter H. Selle ◽  
David Raubenheimer ◽  
David J. Cadogan ◽  
Stephen J. Simpson ◽  
...  
Keyword(s):  
Weight Gain ◽  
Growth Performance ◽  
Energy Intake ◽  
Feed Intake ◽  
Broiler Chickens ◽  
Muscle Protein ◽  
Feed Conversion ◽  
Response Curves ◽  
Protein Energy ◽  
Nutrient Utilisation

AbstractThe right-angled triangle mixture experiment was designed to include fourteen diets with different concentrations of starch, protein and lipid. Experimental diets were offered to male Ross 308 broiler chickens from 10 to 23 d after hatching, and response curves and surfaces were generated to illustrate the influence of macronutrients on growth performance and nutrient utilisations. Despite the primary function of macronutrients, especially protein, may not be providing energy, macronutrients were expressed as energy derived from starch, protein and fat for statistical purposes in the mixture design. Energy derived from lipid had a greater impact on feed intake than energy derived from starch and protein. When we compared the influence of starch and protein on feed intake, ‘equal distance rule’ was observed, which means the animal consumes feed to the point on its respective nutritional rails where the shortage of starch exactly equals the surplus of consumed protein. Increasing the protein-derived energy intake increased weight gain in broiler chickens, whereas energy intake derived from starch and lipid had little impact on weight gain. Feed conversion ratio (FCR) may be reduced by either increasing protein energy intake or decreasing starch energy intake. As the slope of the contours was less than 1, the influence of starch energy intakes on FCR exceeded that of protein energy intakes. In conclusion, energy derived from protein is more important than non-protein energy in terms of weight gain, and a balance between protein and energy supplies is required for efficient muscle protein deposition.

Modification of cardiac adrenergic receptors by oxygen free radicals

1991 ◽  
Vol 260 (3) ◽  
pp. H821-H826 ◽  
Author(s):  
M. Kaneko ◽  
D. C. Chapman ◽  
P. K. Ganguly ◽  
R. E. Beamish ◽  
N. S. Dhalla
Keyword(s):  
Free Radicals ◽  
Xanthine Oxidase ◽  
Binding Sites ◽  
Adrenergic Receptors ◽  
Oxygen Free Radicals ◽  
Beta Adrenergic Receptors ◽  
Beta Adrenergic ◽  
Alpha Adrenergic Receptors ◽  
Cgp 12177 ◽  
Number Of Binding Sites

To examine the effects of oxygen free radicals on alpha- and beta-adrenergic receptors, rat heart crude membranes were incubated with xanthine plus xanthine oxidase, H2O2, or H2O2 plus Fe2+. The assay of beta-adrenergic receptors involving [3H]dihydroalprenolol (DHA) binding revealed that the maximal number of binding sites (Bmax) and dissociation constant (Kd) were increased by xanthine plus xanthine oxidase. H2O2 increased the Kd value for [3H]DHA binding. When a hydrophilic ligand, [3H]CGP-12177, was used for the beta-adrenergic receptor assay, an increase in Kd value without any changes in Bmax value was evident on treating the membranes with xanthine plus xanthine oxidase. The assay of alpha-adrenergic receptors involving [3H]prazosin binding showed a decrease in the number of binding sites and an increase in Kd value only after a prolonged period of incubation. Both H2O2 and H2O2 plus Fe2+ increased the Kd value for [3H]prazosin without changes in Bmax. Changes in both alpha- and beta-adrenergic receptors similar to those with crude membranes were also seen by employing the purified heart sarcolemmal membranes. These data indicate that adrenergic receptors in the sarcolemmal membranes are modified by oxygen free radicals.

Effects of triiodothyronine administration on the adenylyl cyclase system in brown adipose tissue of rat

1997 ◽  
Vol 273 (2) ◽  
pp. E247-E253
Author(s):  
H. Adli ◽  
R. Bazin ◽  
R. Vassy ◽  
G. Y. Perret
Keyword(s):  
Adipose Tissue ◽  
Brown Adipose Tissue ◽  
Adenylyl Cyclase ◽  
Protein Concentration ◽  
Response Curves ◽  
Fourfold Increase ◽  
Brown Adipose ◽  
Cgp 12177 ◽  
Polymerase Chain ◽  
Gamma S

This study was undertaken to investigate the effect of triiodothyronine (T3) administration to euthyroid rats on beta 3-adrenoceptor (beta 3-AR) expression and on the different components of the adenylyl cyclase (AC) system in brown adipose tissue (BAT). In rats treated with T3, the beta 3-AR density (assessed by the binding of [3H]CGP-12177) showed a decrease of 50%, as did their mRNA, as analyzed by reverse transcriptase-polymerase chain reaction. In hyperthyroid rats, compared with control rats, there was a 40% increase in G alpha s activity (stimulated by NaF or GTP gamma S) and a fourfold increase in the protein concentration (Western blotting). In contrast, the level of the pertussis toxin substrate Gi declined by 35% in response to T3. Analysis of dose-response curves for isoproterenol and CGP-12177 revealed that neither basal nor stimulated AC activities nor 50% stimulatory concentration for these agonists was changed by T3 administration. In conclusion, these results suggest that downregulation of the beta 3-AR by T3 was counter-balanced by changes in other components of the AC cascade (i.e., Gs and Gi), so no change occurred in the capacity of BAT to generate adenosine 3',5'-cyclic monophosphate.

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