Initiation of cardiac hypertrophy in response to thyroxine is not limited by age

1993 ◽  
Vol 264 (4) ◽  
pp. H1041-H1047
Author(s):  
R. J. Tomanek ◽  
C. A. Butters ◽  
M. B. Zimmerman
Keyword(s):  
Young Adult ◽  
Cardiac Hypertrophy ◽  
Left Ventricular ◽  
Fischer 344 Rats ◽  
Tissue Levels ◽  
Fischer 344 ◽  
Lv Mass ◽  
Group A ◽  
And Control

We examined the role of age in the initiation of thyroxine-induced (T4) cardiac hypertrophy. T4 (0.4 mg/kg sc) was administered to prepubescent (2 mo), young adult (6 mo), and senescent (24 mo) Fischer 344 rats for 4 days. While significant increases in left ventricular (LV) mass and RNA/LV were evident at 4 days in all T4-treated groups, the elevation in RNA/LV occurred earlier (2 days) in the senescent group. A 0.2-mg/kg dose of T4 elevated RNA values within 24 h in senescent, but not in prepubescent, rats. LV norepinephrine levels were measured to determine whether it plays a role in this model of cardiac hypertrophy. When synthesis of this catecholamine was blocked with alpha-methyl-p-tyrosine, tissue levels fell significantly in all groups, and the decrement was similar in T4-treated and control rats in the two younger groups. We conclude that: 1) the initiation of T4-induced cardiac hypertrophy is not compromised in senescent rats, 2) hearts of senescent rats respond earlier and to a lower dose of T4 than young rats, and 3) the cardiac hypertrophy that occurs in hyperthyroidism is not due to enhanced levels of available cardiac norepinephrine.

Abstract 314: BRaf Plays a Major Role in Gene Expression in Cardiomyocytes in Mouse Hearts in vivo

2017 ◽  
Vol 121 (suppl_1) ◽  
Author(s):  
Michelle A Hardyman ◽  
Stephen J Fuller ◽  
Daniel N Meijles ◽  
Kerry A Rostron ◽  
Sam J Leonard ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cardiac Hypertrophy ◽  
Cardiac Function ◽  
Left Ventricular ◽  
Braf Mutations ◽  
Gene Markers ◽  
Lv Mass ◽  
Cardiac Volumes

Introduction: Raf kinases lie upstream of ERK1/2 with BRaf being the most highly expressed and having the highest basal activity. V600E BRaf mutations constitutively activate ERK1/2 and are common in cancer. The role of BRaf in the adult heart is yet to be established. ERK1/2 regulate cardiomyocyte gene expression, promoting cardiac hypertrophy and cardioprotection, but effects of ERK1/2 may depend on signal strength. Hypothesis: Our hypotheses are that BRaf is critical in regulating ERK1/2 signaling in cardiomyocytes and, whilst moderate ERK1/2 activity is beneficial, excessive ERK1/2 activity is detrimental to the heart. Methods: We generated heterozygote mice for tamoxifen- (Tam-) inducible cardiomyocyte-specific knockin of V600E in the endogenous BRaf gene. Mice (12 wks) received 2 injections of Tam or vehicle on consecutive days (n=4-10 per group). Kinase activities and mRNA expression were assessed by immunoblotting and qPCR. Echocardiography was performed (Vevo2100). M-mode images (short axis view) were analyzed; data for each mouse were normalized to the mean of 2 baseline controls. Results: V600E knockin did not affect overall BRaf or cRaf levels in mouse hearts, but significantly increased ERK1/2 activities within 48 h (1.51±0.05 fold). Concurrently, mRNAs for hypertrophic gene markers including BNP and immediate early genes (IEGs) increased signficantly. At 72 h, expression of BNP, Fosl1, Myc, Ereg and CTGF increased further, other IEGs (Jun, Fos, Egr1, Atf3) declined, and ANF was upregulated. In contrast, expression of α and β myosin heavy chain mRNAs was substantially downregulated (0.46/0.41±0.05 relative to controls). Within 72 h, left ventricular (LV) mass and diastolic LV wall thickness had increased (1.23±0.05 relative to controls), but cardiac function was severely compromised with significant decreases in ejection fraction and cardiac output (0.53/0.68±0.09 relative to controls) associated with increased LV internal diameters and cardiac volumes. Conclusions: Endogenous cardiomyocyte BRaf is sufficient to activate ERK1/2 in mouse hearts and induce cardiac hypertrophy associated with dynamic temporal changes in gene expression. However, excessive activation of ERK1/2 in isolation is detrimental to cardiac function.

The role of mitochondrial DNA large deletion for the development of presbycusis in Fischer 344 rats

2007 ◽  
Vol 27 (3) ◽  
pp. 370-377 ◽  
Author(s):  
Shankai Yin ◽  
Zhiping Yu ◽  
Ravi Sockalingam ◽  
Manohar Bance ◽  
Genlou Sun ◽  
...  
Keyword(s):  
Mitochondrial Dna ◽  
Large Deletion ◽  
Fischer 344 Rats ◽  
Fischer 344

Role of spontaneous interstitial cell testicular tumors on the mitogen reactivity of spleen cells from aged male fischer-344 rats

1984 ◽  
Vol 25 (3) ◽  
pp. 349-353 ◽  
Author(s):  
Richard J. Cross ◽  
Jean C. Jackson ◽  
Thomas L. Roszman ◽  
William H. Brooks ◽  
William R. Markesbery
Keyword(s):  
Interstitial Cell ◽  
Fischer 344 Rats ◽  
Spleen Cells ◽  
Testicular Tumors ◽  
Fischer 344

Abstract 2292: Torsional Deformation Delay: a Novel Echocardiographic Index of Left Ventricular Peak Rotation Sequence Between Basal and Apical Level.

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Lukasz Chrzanowski ◽  
Barbara Uznanska ◽  
Michal Plewka ◽  
Piotr Lipiec ◽  
Jaroslaw Drozdz ◽  
...  
Keyword(s):  
Systolic Function ◽  
Temporal Distribution ◽  
Left Ventricular ◽  
Torsional Deformation ◽  
Lv Mass ◽  
Echocardiographic Parameters ◽  
The Difference ◽  
Lv Systolic Function ◽  
Rotation Sequence

Purpose: left ventricular (LV) torsion (TOR) results from oppositely directed rotation (ROT) at the basal (BAS) and apical (AP) level. Speckle Tracking Echocardiography (STE) allows TOR assessment, but little is known of LV ROT temporal distribution. The aim was to evaluate the sequence of BAS and AP level ROT and to identify associated echocardiographic parameters. Methods: 48 patients (PTS) were studied (mean age 54±13 years, 23 men). LV systolic function was normal in 23 PTS (LVEF 60% or more), and various degrees of dysfunction were present in 25 PTS (mean LVEF 40±10%). Digital short axis loops at BAS and AP level were analyzed using STE algorithm to measure ROT in degrees (°). After adjustment for heart rate, Torsional Deformation Delay (TDD) was calculated as the difference between the time from the onset of QRS complex to the peak average systolic ROT at BAS and AP level (figure ). Results: mean TOR, BAS ROT and AP ROT was 14.3±7.3°, −6.8±4.7° and 7.5±6.1° respectively. Mean TDD was 19±107 ms (range from −285 to 248 ms); negative TDD indicated shorter time to BAS peak ROT. No difference of mean TDD was found between PTS with normal and decreased LVEF. TDD outside the range of −28 ms to 28 ms, derived by ROC analysis, was shown to have 96% specificity in detecting PTS with LVEF <60%. It was also associated with higher LV mass index as compared to TDD ranging from −28 to 28 ms (130 g/m2 vs 100 g/m2, p=0.025). Conclusions: a novel TDD index allows evaluation of LV ROT temporal distribution between BAS and AP level. TDD values outside the range of −28 ms to 28 ms are associated with decreased LVEF and presence of LV hypertrophy. Further studies are required to assess the role of TDD in cardiac imaging.

scholarly journals PKC-β is not necessary for cardiac hypertrophy

2001 ◽  
Vol 280 (5) ◽  
pp. H2264-H2270 ◽  
Author(s):  
Brian B. Roman ◽  
David L. Geenen ◽  
Michael Leitges ◽  
Peter M. Buttrick
Keyword(s):  
Cardiac Hypertrophy ◽  
Gene Knockout ◽  
Weight Ratio ◽  
Left Ventricular Pressure ◽  
Left Ventricular ◽  
Heart Weight ◽  
Hypertrophic Response ◽  
Pathological Hypertrophy ◽  
Pkc Β ◽  
And Control

Studies in human and rodent models have shown that activation of protein kinase C-β (PKC-β) is associated with the development of pathological hypertrophy, suggesting that ablation of the PKC-β pathway might prevent or reverse cardiac hypertrophy. To explore this, we studied mice with targeted disruption of the PKC-β gene (knockout, KO). There were no detectable differences in expression or distribution of other PKC isoforms between the KO and control hearts as determined by Western blot analysis. Baseline hemodynamics were measured using a closed-chest preparation and there were no differences in heart rate and arterial or left ventricular pressure. Mice were subjected to two independent hypertrophic stimuli: phenylephrine (Phe) at 20 mg · kg−1 · day−1 sq infusion for 3 days, and aortic banding (AoB) for 7 days. KO animals demonstrated an increase in heart weight-to-body weight ratio (Phe, 4.3 ± 0.6 to 6.1 ± 0.4; AoB, 4.0 ± 0.1 to 5.8 ± 0.7) as well as ventricular upregulation of atrial natriuretic factor mRNA analogous to those seen in control animals. These results demonstrate that PKC-β expression is not necessary for the development of cardiac hypertrophy nor does its absence attenuate the hypertrophic response.

Contractile function in chronic gradually developing subcoronary aortic stenosis

1981 ◽  
Vol 240 (1) ◽  
pp. H80-H84
Author(s):  
B. A. Carabello ◽  
R. Mee ◽  
J. J. Collins ◽  
R. A. Kloner ◽  
D. Levin ◽  
...  
Keyword(s):  
Aortic Stenosis ◽  
Cardiac Hypertrophy ◽  
Cardiac Muscle ◽  
Animal Studies ◽  
Contractile Function ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Stroke Work ◽  
Group A ◽  
Group B

Whether hypertrophied cardiac muscle functions normally or abnormally is a point of controversy in the literature. Most animal studies showing depressed performance of hypertrophied cardiac muscle have used experimental methods in which hypertrophy was produced by acutely imposing a pressure overload on the left or right ventricle, which may cause myocardial injury. To assess the possibility that chronic, slowly developing hypertrophy is associated with normal myocardial function, we developed an experimental model in which increased afterload is imposed gradually on the left ventricle in the dog. A snug band was placed around the aorta beneath the left coronary artery in puppies without producing a stenosis. As the puppies grew, relative aortic stenosis developed as increased cardiac output flowed across that fixed outflow area. One group (group A) of six puppies was banded early, whereas a second group (group B, five puppies) was banded late and served as controls. Left ventricular weight (g) to body weight (kg) ratio remained normal in group B animals (3.9 +/- 0.14), whereas this ratio was increased to 5.3 +/- 0.24 (P < 0.001) in group A animals indicating development of moderate cardiac hypertrophy. Ejection fraction, dP/dt, Vcf, and stroke work per gram of myocardium were virtually identical in both groups. We conclude that moderate, gradually developing cardiac hypertrophy as produced by this model is associated with normal myocardial contractile performance.

NAD(P)H oxidase-generated superoxide anion accounts for reduced control of myocardial O2 consumption by NO in old Fischer 344 rats

2003 ◽  
Vol 285 (3) ◽  
pp. H1015-H1022 ◽  
Author(s):  
Alexandra Adler ◽  
Eric Messina ◽  
Ben Sherman ◽  
Zipping Wang ◽  
Harer Huang ◽  
...  
Keyword(s):  
Oxidant Stress ◽  
Heart Weight ◽  
Fischer 344 Rats ◽  
No Donor ◽  
Fischer 344 ◽  
Old Rats ◽  
Fischer Rats ◽  
Enos Protein

We investigated the role of nitric oxide (NO) in the control of myocardial O2 consumption in Fischer 344 rats. In Fischer rats at 4, 14, and 23 mo of age, we examined cardiac function using echocardiography, the regulation of cardiac O2 consumption in vitro, endothelial NO synthase (eNOS) protein levels, and potential mechanisms that regulate superoxide. Aging was associated with a reduced ejection fraction [from 75 ± 2%at4moto66 ± 3% ( P < 0.05) at 23 mo] and an increased cardiac diastolic volume [from 0.60 ± 0.04 to 1.00 ± 0.10 ml ( P < 0.01)] and heart weight (from 0.70 ± 0.02 to 0.90 ± 0.02 g). The NO-mediated control of cardiac O2 consumption by bradykinin or enalaprilat was not different between 4 mo (36 ± 2 or 34 ± 3%) and 14 mo (29 ± 1 or 25 ± 3%) but markedly ( P < 0.05) reduced in 23-mo-old Fischer rats (15 ± 3 or 7 ± 2%). The response to the NO donor S-nitroso- N-acetyl penicillamine was not different across groups (35%, 35%, and 44%). Interestingly, the eNOS protein level was not different at 4, 14, and 23 mo. The addition of tempol (1 mmol/l) to the tissue bath eliminated the depression in the control of cardiac O2 consumption by bradykinin (25 ± 3%) or enalaprilat (28 ± 3%) in 23-mo-old Fischer rats. We next examined the levels of enzymes involved in the production and breakdown of superoxide. The expression of Mn SOD, Cu/Zn SOD, extracellular SOD, and p67phox, however, did not differ between 4- and 23-mo-old rats. Importantly, there was a marked increase in gp91phox, and apocynin restored the defect in NO-dependent control of cardiac O2 consumption at 23 mo to that seen in 4-mo-old rats, identifying the role of NADPH oxidase. Thus increased biological activity of superoxide and not decreases in the enzyme that produces NO are responsible for the altered control of cardiac O2 consumption by NO in 23-mo-old Fischer rats. Increased oxidant stress in aging, by decreasing NO bioavailability, may contribute not only to changes in myocardial function but also to altered regulation of vascular tone and the progression of cardiac or vascular disease.

An age-related difference in hyperoxia lethality: role of lung antioxidant defense mechanisms

1995 ◽  
Vol 268 (4) ◽  
pp. L539-L545 ◽  
Author(s):  
A. T. Canada ◽  
L. A. Herman ◽  
S. L. Young
Keyword(s):  
Defense Mechanisms ◽  
Antioxidant Defense ◽  
Fischer 344 Rats ◽  
Fischer 344 ◽  
Related Difference ◽  
Age Related ◽  
65 H ◽  
Old Rats ◽  
Gpx Activity

The role of animal age in the lethal response to > 98% oxygen has been extensively studied, with the observation that neonatal rats were resistant while mature animals were sensitive. Antioxidant enzymes increased during the oxygen exposure in neonatal but not in mature rats, suggesting they were important in the age-related toxicity difference. Because no studies had compared the response of mature and old rats to hyperoxia, we exposed Fischer 344 rats, aged 2 and 27 mo, to > 98% oxygen. Unexpectedly, the old rats lived significantly longer than young, 114 and 65 h, respectively. No histopathological differences were found to explain the results. Of the antioxidants, only glutathione peroxidase (GPx) activity was higher in the lungs of nonexposed old rats. Superoxide dismutase (SOD) was higher in the young, results opposite those expected if SOD was important in the lethality difference. No antioxidant induction occurred in the old oxygen-exposed rats. These results suggest that although there may be a role for GPx, mechanisms in addition to antioxidant protection and inflammation are likely responsible for the age-related difference in hyperoxia lethality.

scholarly journals Orai1 Channel Inhibition Preserves Left Ventricular Systolic Function and Normal Ca 2+ Handling After Pressure Overload

Circulation ◽  
2020 ◽  
Vol 141 (3) ◽  
pp. 199-216 ◽  
Author(s):  
Fiona Bartoli ◽  
Marc A. Bailey ◽  
Baptiste Rode ◽  
Philippe Mateo ◽  
Fabrice Antigny ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Systolic Function ◽  
Systolic Dysfunction ◽  
Pressure Overload ◽  
Left Ventricular Systolic Function ◽  
Left Ventricular ◽  
Specific Expression ◽  
Channel Inhibition

Background: Orai1 is a critical ion channel subunit, best recognized as a mediator of store-operated Ca 2+ entry (SOCE) in nonexcitable cells. SOCE has recently emerged as a key contributor of cardiac hypertrophy and heart failure but the relevance of Orai1 is still unclear. Methods: To test the role of these Orai1 channels in the cardiac pathophysiology, a transgenic mouse was generated with cardiomyocyte-specific expression of an ion pore-disruptive Orai1 R91W mutant (C-dnO1). Synthetic chemistry and channel screening strategies were used to develop 4-(2,5-dimethoxyphenyl)-N-[(pyridin-4-yl)methyl]aniline (hereafter referred to as JPIII), a small-molecule Orai1 channel inhibitor suitable for in vivo delivery. Results: Adult mice subjected to transverse aortic constriction (TAC) developed cardiac hypertrophy and reduced ventricular function associated with increased Orai1 expression and Orai1-dependent SOCE (assessed by Mn 2+ influx). C-dnO1 mice displayed normal cardiac electromechanical function and cellular excitation-contraction coupling despite reduced Orai1-dependent SOCE. Five weeks after TAC, C-dnO1 mice were protected from systolic dysfunction (assessed by preserved left ventricular fractional shortening and ejection fraction) even if increased cardiac mass and prohypertrophic markers induction were observed. This is correlated with a protection from TAC-induced cellular Ca 2+ signaling alterations (increased SOCE, decreased [Ca 2+ ] i transients amplitude and decay rate, lower SR Ca 2+ load and depressed cellular contractility) and SERCA2a downregulation in ventricular cardiomyocytes from C-dnO1 mice, associated with blunted Pyk2 signaling. There was also less fibrosis in heart sections from C-dnO1 mice after TAC. Moreover, 3 weeks treatment with JPIII following 5 weeks of TAC confirmed the translational relevance of an Orai1 inhibition strategy during hypertrophic insult. Conclusions: The findings suggest a key role of cardiac Orai1 channels and the potential for Orai1 channel inhibitors as inotropic therapies for maintaining contractility reserve after hypertrophic stress.

Inhibition of Urinary Bladder Carcinogenesis by Aqueous Extract of Sclerotia of Polyporus umbellatus Fries and Polyporus Polysaccharide

2011 ◽  
Vol 39 (01) ◽  
pp. 135-144 ◽  
Author(s):  
Guowei Zhang ◽  
Xing Zeng ◽  
Caixia Li ◽  
Jijun Li ◽  
Yu Huang ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Aqueous Extract ◽  
Low Dose ◽  
Control Group ◽  
Fischer 344 Rats ◽  
Glutathione S Transferase ◽  
Fischer 344 ◽  
Polyporus Umbellatus ◽  
Bladder Carcinogenesis ◽  
Group A

The study aimed to evaluate inhibition effect of sclerotia of Polyporus umbellatus Fries aqueous extract (SPUE) and polyporus polysaccharide (PPS) on bladder cancer, then to measure their effect on mRNA expression of glutathione S-transferase π (GSTPi) and NAD(P)H:quinone oxidoreductase 1 (NQO1) in female Fischer-344 rats model. The model rats were induced by N-butyl-N-(4-hydroxybutyl)-nitrosamine (BBN) for a period of 8 weeks and saccharin for 12 weeks. SPUE (50 mg/kg, 250 mg/kg, 500 mg/kg) and PPS (28 mg/kg) were orally administrated to the model rats during the whole study. Compared to the control group, a more preventive effect of SPUE and PPS treatment on bladder cancer was discovered, higher mRNA upregulation of GSTpi and NQO1 was seen in the treatment group. Furthermore, the GSTPi and NQO1 mRNA upregulated level in the low-dose group (SPUE 50 mg/kg) was at maximum. In brief, SPUE and PPS are highly effective in inhibiting bladder carcinogenesis in rats, which may be associated with upregulation of GSTPi and NQO1 in the bladder.

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