Ovariectomy augments pressure overload-induced hypertrophy associated with changes in Akt and nitric oxide synthase signaling pathways in female rats

2007 ◽  
Vol 293 (6) ◽  
pp. E1606-E1614 ◽  
Author(s):  
Md. Shenuarin Bhuiyan ◽  
Norifumi Shioda ◽  
Kohji Fukunaga
Keyword(s):  
Nitric Oxide ◽  
Body Weight ◽  
Diastolic Pressure ◽  
Heart Function ◽  
Weight Ratio ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Female Rats ◽  
Ovariectomized Rats ◽  
Body Weight Ratio

To elucidate the molecular mechanism underlying estrogen-mediated cardioprotection in left ventricular (LV) hypertrophy and remodeling, we analyzed myocardial hypertrophy as well as cardiac function and hypertrophy-related protein expression in ovariectomized, aortic-banded rats. Wistar rats subjected to bilateral ovariectomy (OVX) were further treated with abdominal aortic stenosis. Effects on LV morphology and function were assessed using echocardiography, and expression of protein levels was determined by Western blot analysis. The heart-to-body weight ratio was most significantly increased in the OVX-pressure overload (PO) group compared with the OVX group and in the PO group compared with sham. The LV weight-to-body weight ratio was also significantly increased in the OVX-PO group compared with the OVX group and in the PO group compared with sham. The most significant increases in LV end diastolic pressure, LV developed pressure, and ±dp/d tmax were observed in the OVX-PO group compared with the OVX group and represent compensatory phenotypes against hypertrophy. Both endothelial nitric oxide (eNOS) synthase expression and activity was markedly reduced in the OVX-PO group, and protein kinase B (Akt) activity was largely attenuated. Marked breakdown of dystrophin was also seen in hearts of OVX-PO groups. Finally, significantly increased mortality was observed in the OVX-PO group following chronic isoproterenol administration. Our results demonstrate that rats subjected to ovariectomy are unable to compensate for hypertrophy, showed deteriorated heart function, and demonstrated increased mortality. Simultaneous impairment of eNOS and Akt activities and reduced dystrophin by ovariectomy likely contribute to cardiac decompensation during PO-induced hypertrophy in ovariectomized rats.

Heart functional responses to pressure overload in exercised and sedentary rats

1976 ◽  
Vol 230 (1) ◽  
pp. 199-204 ◽  
Author(s):  
RT Dowell ◽  
AF Cutilletta ◽  
MA Rudnik ◽  
PC Sodt
Keyword(s):  
Cardiac Output ◽  
Diastolic Pressure ◽  
Heart Function ◽  
Pressure Overload ◽  
Normal Growth ◽  
Left Ventricular ◽  
Treadmill Running ◽  
Female Rats ◽  
Heart Weight ◽  
Functional Responses

Female rats that had been subjected to a moderate treadmill running program were compared with sedentary animals on the basis of heart weight, selected biochemical measurements, and heart function. Exercised animals maintained normal growth rate, and cardiac hypertrophy was not present. Left ventricular RNA, DNA, and cytochrome c levels were unchanged. Heart functional measurements obtained in situ were similar in sedentary and exercised animals under control conditions. When subjected to sustained (1-3 days) aortic constriction pressure overload, exercised animals maintained or increased myocardial contractility. Contractility was depressed in sedentary animals. Both sedentary and exercised animals increased left ventricular end diastolic pressure without changing contractility during acute (1-3 min) pressure overload. However, exercised animals were able to fully regain normal cardiac output when the acute overload was relieved. Cardiac output remained approximately 10% below control in sedentary animals. The improved ability of previously exercised animals to withstand pressure overload appears to be due to alterations in adaptation rather than preliminary augmentation of metabolism or function.

Diminished effect of cAMP on Ca2+ accumulation in skinned fibers of hypertrophied rat heart

1994 ◽  
Vol 266 (2) ◽  
pp. H749-H756
Author(s):  
F. Tomita ◽  
A. L. Bassett ◽  
R. J. Myerburg ◽  
S. Kimura
Keyword(s):  
Body Weight ◽  
Weight Ratio ◽  
Pressure Overload ◽  
Left Ventricular Pressure ◽  
Left Ventricular ◽  
Adrenergic Stimulation ◽  
Body Weight Ratio ◽  
The Right ◽  
Hypertrophied Ventricle ◽  
Concomitant Exposure

Sarcoplasmic reticulum (SR) Ca2+ uptake is reduced in the hypertrophied ventricle. To determine whether events initiated by beta-adrenergic stimulation are involved, we compared the effects of adenosine 3',5'-cyclic monophosphate (cAMP) on SR Ca2+ uptake between normal and pressure-overloaded hypertrophied hearts using saponin-skinned rat left ventricular muscles. Left ventricular pressure overload was induced by partial ligation of the abdominal aorta for 4–6 wk before study. Age-matched normal rats served as controls. Pressure overload increased the left ventricular weight-to-body weight ratio 60.8%. The SR was loaded by exposing the muscles to 10(-6) M Ca2+ solution; SR Ca2+ release was induced by 5 or 25 mM caffeine, and the amount of Ca2+ released from the SR was estimated by the area under the caffeine-induced transient contraction. Concomitant exposure to 10(-4) M cAMP did not influence caffeine-induced Ca2+ release in either normal or hypertrophied fibers. When 10(-4) M cAMP was applied during the Ca(2+)-loading periods, the amount of Ca2+ accumulated by the SR increased in both normal and hypertrophied fibers. However, the extent of increase was significantly smaller in hypertrophied fibers than in normal fibers [10.9 +/- 1.7 and 27.4 +/- 5.3% in 1 min of Ca2+ loading (P < 0.05), 12.2 +/- 3.2 and 24.7 +/- 3.8% in 4 min of Ca2+ loading (P < 0.05), respectively]. cAMP (10(-4) M) shifted the force-pCa relationship to the right similarly in normal and hypertrophied muscles, and there was no difference in the force-pCa relationship between the two groups either with or without cAMP.(ABSTRACT TRUNCATED AT 250 WORDS)

Abstract 1393: Inhibition of Cardiac Remodeling by Pravastatin is Associated with Amelioration of Endoplasmic Reticulum Stress

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Hui Zhao ◽  
Yulin Liao ◽  
Tetsuo Minamino ◽  
Yoshihiro Asano ◽  
Masanori Asakura ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Body Weight ◽  
Er Stress ◽  
Cardiac Remodeling ◽  
Weight Ratio ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Stress Signaling ◽  
Body Weight Ratio ◽  
Stress Signaling Pathway

Background We previously reported that prolonged endoplasmic reticulum (ER) stress contributes to progression from cardiac hypertrophy to heart failure. Statins have an inhibitory effect on cholesterol synthesis, oxidative stresses, protein synthesis and production of inflammatory cytokines, all of which could be associated with ER stress. However, it is unknown whether statins can ameliorate ER stress in heart disease. This study was designed to investigate whether pravastatin could inhibit cardiac remodeling and ameliorate ER stress caused by pressure overload or tumor necrosis factor α (TNF α ). Methods and Results Cardiac hypertrophy was induced by transverse aortic constriction (TAC) for four weeks in C57BL/6 male mice. Either pravastatin (5 mg/kg/d, n=20, TAC+prava group) or its vehicle (n=20) was orally administered to mice. The ER stress signaling pathway was also studied in pressure-overloaded mice hearts and in cultured cardiomyocytes treated with TNF α (10ng/ml) for 24 hours. Four weeks after TAC, both heart-to-body weight ratio (8.68 ± 1.23 in TAC group, 6.92 ± 1.11 in TAC+prava group) and lung-to-body weight ratio (11.08 ± 2.58 in TAC group, 7.92± 3.56 in TAC+prava group) became significantly lower in pravastatin-treated mice than in the TAC group. Left ventricular fractional shortening and left ventricular ejection fraction (LVFS and LVEF) were larger in TAC+prava group (48.0±1.9 % and 80±1.9% respectively) compared with TAC group (LVFS and LVEF, 34.8 ±1.4% and 65 ±3%; P<0.01 VS TAC group each). Markers of ER stress such as an increase in ER chaperones and CHOP expressions and enhanced phosphorylation of eIF2 α were observed in the hearts of TAC mice, while pravastatin treatment significantly blunted these changes. Pravastatin-treated TAC mice also showed a decrease of cardiac apoptosis. Cardiac expression of TNF α was increased in TAC mice, and TNF α induced ER stress in cultured neonatal rat cardiomyocytes, either of which was significantly inhibited by pravastatin. Conclusions These findings indicate that pravastatin inhibits cardiac remodeling in mice subjected to pressure overload, and this action is associated with inhibition of the ER stress signaling pathway.

Ventricular remodeling in a mouse model of myocardial infarction

1998 ◽  
Vol 274 (5) ◽  
pp. H1812-H1820 ◽  
Author(s):  
Richard D. Patten ◽  
Mark J. Aronovitz ◽  
Luz Deras-Mejia ◽  
Natesa G. Pandian ◽  
George G. Hanak ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Body Weight ◽  
Mouse Model ◽  
Sham Group ◽  
Ventricular Remodeling ◽  
Diastolic Pressure ◽  
Weight Ratio ◽  
Left Ventricular ◽  
Body Weight Ratio ◽  
Right Ventricular Mass

We investigated the suitability of studying ventricular remodeling in a mouse model of myocardial infarction (MI). We performed left coronary ligation ( n = 22) or a sham procedure ( n = 21) on normal C57BL/6J mice. Six weeks later, animals underwent echocardiography and hemodynamic evaluation. Left ventricular (LV) volume at a common distending pressure was calculated from passive pressure-volume curves. The MI group exhibited lower systolic blood pressure ( P < 0.05), higher LV end-diastolic pressure ( P < 0.05), and lower peak first derivative of LV pressure (dP/d t, P < 0.05) than the sham group. Mice with moderate (<40%, n = 11) and large (≥40%, n = 11) MIs displayed increased LV mass-to-body weight ratio ( P < 0.02 and P < 0.01, respectively, vs. sham group), whereas only the large-MI group exhibited increased right ventricular mass-to-body weight ratio ( P < 0.01). LV volumes were increased in the moderate-MI group ( P= 0.059 vs. sham group) and to a much greater extent in the large-MI group ( P < 0.0001 vs. sham group). The moderate- and large-MI groups also exhibited increases in LV end-diastolic diameter ( P < 0.03 and P < 0.0001, respectively, vs. sham group) and LV end-systolic diameter ( P< 0.01 and P < 0.0001, respectively, vs. sham group) with decreased fractional shortening ( P < 0.01 for both). These data demonstrate ventricular remodeling in a mouse model of MI and confirm the feasibility of quantifying indexes of remodeling in vivo and postmortem. This model will be of particular usefulness when applied to transgenic strains.

scholarly journals Progressive chronic heart failure slows the recovery of microvascular O2 pressures after contractions in the rat spinotrapezius muscle

2010 ◽  
Vol 299 (6) ◽  
pp. H1755-H1761 ◽  
Author(s):  
Steven W. Copp ◽  
Daniel M. Hirai ◽  
Leonardo F. Ferreira ◽  
David C. Poole ◽  
Timothy I. Musch
Keyword(s):  
Heart Failure ◽  
Skeletal Muscle ◽  
Body Weight ◽  
Chronic Heart Failure ◽  
Diastolic Pressure ◽  
Fiber Type ◽  
Weight Ratio ◽  
Left Ventricular ◽  
Type I ◽  
Body Weight Ratio

Chronic heart failure (CHF) induces muscle fiber-type specific alterations in skeletal muscle O2 delivery and utilization during metabolic transitions. As a result, the recovery of microvascular Po2 (PmvO2) is prolonged in slow-twitch skeletal muscle but not fast-twitch skeletal muscle in rats with CHF. We tested the hypothesis that CHF slows PmvO2 recovery in rat skeletal muscle of a mixed fiber-type analogous to human locomotory muscles and that the degree of slowing correlates with central indexes of heart failure. Healthy control [ n = 6, left ventricular end-diastolic pressure (LVEDP): 10 ± 1 mmHg], moderate CHF ( n = 6, LVEDP: 18 ± 2 mmHg), and severe CHF ( n = 4, LVEDP: 34 ± 2 mmHg) female Sprague-Dawley rats had their right spinotrapezius muscles (41% type I, 7% type IIa, and 52% type IIb and d/x) exposed, and PmvO2 was measured via phosphorescence quenching during 180 s of recovery from 180 s of electrically induced twitch contractions (1 Hz, 4–6 V). CHF progressively slowed the mean response time (MRT; the time to reach 63% of the overall dynamic response) of PmvO2 recovery (MRToff; control: 60.2 ± 6.9, moderate CHF: 72.8 ± 6.6, and severe CHF: 109.8 ± 6.6 s, P < 0.05 for all). MRToff correlated positively with central hemodynamic (LVEDP: r = 0.76, P < 0.01) and morphological (right ventricle-to-body weight ratio: r = 0.74, P < 0.01; and lung weight-to-body weight ratio: r = 0.79, P < 0.01) indexes of heart failure. The present investigation suggests that slowed PmvO2 kinetics during recovery in CHF constitutes a mechanistic link between impaired circulatory and metabolic recovery after contractions in CHF.

Downregulation of cyclin-dependent kinase inhibitors p21 and p27 in pressure-overload hypertrophy

1997 ◽  
Vol 273 (3) ◽  
pp. H1358-H1367 ◽  
Author(s):  
J. M. Li ◽  
G. Brooks
Keyword(s):  
Body Weight ◽  
Kinase Inhibitors ◽  
Weight Ratio ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Growth Potential ◽  
Cyclin Dependent Kinase ◽  
Body Weight Ratio ◽  
Adaptive Growth ◽  
Adult Rat

We postulated that the cyclin-dependent kinase inhibitors p21 and p27 could regulate the alterations in growth potential of cardiomyocytes during left ventricular hypertrophy (LVH). LVH was induced in adult rat hearts by aortic constriction (AC) and was monitored at days 0, 1, 3, 7, 14, 21, and 42 postoperation. Relative to sham-operated controls (SH), left ventricle (LV) weight-to-body weight ratio in AC increased progressively with time without significant differences in body weight or right ventricle weight-to-body weight ratio. Atrial natriuretic factor mRNA increased significantly in AC to 287% at day 42 compared with SH (P < 0.05), whereas p21 and p27 mRNA expression in AC rats decreased significantly by 58% (P < 0.03) and 40% (P < 0.05) at day 7, respectively. p21 and p27 protein expression decreased significantly from days 3 to 21 in AC versus SH, concomitant with LV adaptive growth. Immunocytochemistry showed p21 and p27 expression in cardiomyocyte nuclei. Thus downregulation of p21 and p27 may modulate the adaptive growth of cardiomyocytes during pressure overload-induced LVH.

scholarly journals Low-intensity aerobic interval training attenuates pathological left ventricular remodeling and mitochondrial dysfunction in aortic-banded miniature swine

2010 ◽  
Vol 299 (5) ◽  
pp. H1348-H1356 ◽  
Author(s):  
Craig A. Emter ◽  
Christopher P. Baines
Keyword(s):  
Body Weight ◽  
Exercise Training ◽  
Mitochondrial Dysfunction ◽  
Weight Ratio ◽  
Left Ventricular ◽  
Heart Weight ◽  
Lv Function ◽  
Body Weight Ratio ◽  
Miniature Swine ◽  
Low Intensity

Cardiac hypertrophy in response to hypertension or myocardial infarction is a pathological indicator associated with heart failure (HF). A central component of the remodeling process is the loss of cardiomyocytes via cell death pathways regulated by the mitochondrion. Recent evidence has indicated that exercise training can attenuate or reverse pathological remodeling, creating a physiological phenotype. The purpose of this study was to examine left ventricular (LV) function, remodeling, and cardiomyocyte mitochondrial function in aortic-banded (AB) sedentary (HFSED; n = 6), AB exercise-trained (HFTR, n = 5), and control sedentary ( n = 5) male Yucatan miniature swine. LV hypertrophy was present in both AB groups before the start of training, as indicated by increases in LV end-diastolic volume, LV end-systolic volume (LVESV), and LV end-systolic dimension (LVESD). Exercise training (15 wk) prevented further increases in LVESV and LVESD ( P < 0.05). The heart weight-to-body weight ratio, LV + septum-to-body weight ratio, LV + septum-to-right ventricle ratio, and cardiomyocyte cross-sectional area were increased in both AB groups postmortem regardless of training status. Preservation of LV function after exercise training, as indicated by the maintenance of fractional shortening, ejection fraction, and mean wall shortening and increased stroke volume, was associated with an attenuation of the increased LV fibrosis (23%) and collagen (36%) observed in HFSED animals. LV mitochondrial dysfunction, as measured by Ca2+-induced mitochondrial permeability transition, was increased in HFSED ( P < 0.05) but not HFTR animals. In conclusion, low-intensity interval exercise training preserved LV function as exemplified by an attenuation of fibrosis, maintenance of a positive inotropic state, and inhibition of mitochondrial dysfunction, providing further evidence of the therapeutic potential of exercise in a clinical setting.

Diverse regulation of IP3 and ryanodine receptors by pentazocine through σ1-receptor in cardiomyocytes

2013 ◽  
Vol 305 (8) ◽  
pp. H1201-H1212 ◽  
Author(s):  
Hideaki Tagashira ◽  
Md. Shenuarin Bhuiyan ◽  
Kohji Fukunaga
Keyword(s):  
Cardiac Hypertrophy ◽  
Diastolic Pressure ◽  
Ryanodine Receptors ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Female Rats ◽  
In Vivo Studies ◽  
Atp Production ◽  
Cultured Cardiomyocytes

Although pentazocine binds to σ1-receptor (σ1R) with high affinity, the physiological relevance of its binding remains unclear. We first confirmed that σ1R stimulation with pentazocine rescues contractile dysfunction following pressure overload (PO)-induced cardiac hypertrophy ovariectomized (OVX) female rats. In in vivo studies, vehicle, pentazocine (0.5–1.0 mg/kg ip), and NE-100 (1.0 mg/kg po), a σ1R antagonist, were administered for 4 wk (once daily) starting from the onset of aortic banding after OVX. We also examined antihypertrophic effects of pentazocine (0.5–1 μM) in cultured cardiomyocytes exposed to angiotensin II. Pentazocine administration significantly inhibited PO-induced cardiac hypertrophy and rescued hypertrophy-induced impairment of cardiac dysfunctions such as left ventricular end-diastolic pressure, left ventricular developed pressure, and left ventricular contraction and relaxation (±dp/dt) rates. Coadministration of NE-100 with pentazocine eliminated pentazocine-induced amelioration of heart dysfunction. Interestingly, pentazocine administration inhibited PO-induced σ1R reduction and inositol-1,4,5-trisphosphate (IP3) receptor type 2 (IP3R2) upregulation in heart. Therefore, the reduced mitochondrial ATP production following PO was restored by pentazocine administration. Furthermore, we found that σ1R binds to the ryanodine receptor (RyR) in addition to IP3 receptor (IP3R) in cardiomyocytes. The σ1R/RyR complexes were decreased following OVX-PO and restored by pentazocine administration. We noticed that pentazocine inhibits the ryanodine-induced Ca2+ release from sarcoplasmic reticulum (SR) in cultured cardiomyocytes. Taken together, the stimulation of σ1R by pentazocine rescues cardiac dysfunction by restoring IP3R-mediated mitochondrial ATP production and by suppressing RyR-mediated Ca2+ leak from SR in cardiomyocytes.

Sarcoplasmic reticulum-related changes in cytosolic calcium in pressure-overload-induced feline LV hypertrophy

1993 ◽  
Vol 265 (6) ◽  
pp. H2009-H2016 ◽  
Author(s):  
B. A. Bailey ◽  
S. R. Houser
Keyword(s):  
Sarcoplasmic Reticulum ◽  
Time Course ◽  
Weight Ratio ◽  
Pressure Overload ◽  
Cytosolic Calcium ◽  
Left Ventricular ◽  
Heart Weight ◽  
Body Weight Ratio ◽  
Rest Periods ◽  
Premature Beats

Alterations in Ca2+ homeostasis that involve the sarcoplasmic reticulum (SR) were studied in feline left ventricular (LV) myocytes isolated from hearts with LV hypertrophy induced by slow, progressive pressure overload. At death, severe hypertrophy was evidenced by increased heart weight-to-body weight ratio (8.4 +/- 0.6 vs. 4.2 +/- 0.2 g/kg in controls). Steady-state Ca2+ transients (measured as. indo 1 fluorescence at 410 nm/480 nm; I410/I480) in LV hypertrophy (LVH) myocytes had diminished peak amplitudes (I410/I480 2.28 +/- 0.07 vs. 2.53 +/- 0.07 in controls) and prolonged durations (0.75 +/- 0.03 vs. 0.59 +/- 0.02 s in controls). The magnitude of shortening was reduced and the contractile duration was prolonged in LVH myocytes. The idea that changes in SR function are responsible for these alterations in the Ca2+ transient was tested by studying two aspects of SR-related Ca2+ homeostasis. Restitution of releasable SR Ca2+ was studied by measuring indo 1 transients and contractions during premature beats. The time course of restitution of both the indo 1 transient and contraction of hypertrophy myocytes was significantly slower than in controls. These data suggest that restitution of releasable SR Ca2+ is slowed in hypertrophy myocytes. The reduction of the indo 1 transient and contraction in beats following long rest periods (rest decay) was measured to determine the rate of Ca2+ loss from the SR. Rest decay was significantly (P < 0.05) more pronounced in hypertrophy myocytes, suggesting that Ca2+ loss from the SR is accelerated in these myocytes. (ABSTRACT TRUNCATED AT 250 WORDS)

Hypertrophy alters effect of Ins(1,4,5)P3 on Ca2+ release in skinned rat heart muscle

1991 ◽  
Vol 260 (5) ◽  
pp. H1612-H1618 ◽  
Author(s):  
N. Furukawa ◽  
A. L. Bassett ◽  
T. Furukawa ◽  
R. J. Myerburg ◽  
S. Kimura
Keyword(s):  
Weight Ratio ◽  
Pressure Overload ◽  
Left Ventricular Pressure ◽  
Left Ventricular ◽  
Contractile Dysfunction ◽  
Body Weight Ratio ◽  
Rat Hearts ◽  
Inositol 1,4,5 Trisphosphate ◽  
Normal Rat ◽  
Skinned Cardiac Fibers

The effects of D-myo-inositol 1,4,5-trisphosphate [Ins(1,4,5)P3] on the ability of the sarcoplasmic reticulum (SR) to accumulate and release Ca2+ and on the Ca2+ sensitivity of the contractile proteins were investigated using chemically (saponin) skinned cardiac fibers (60–120 microns diam) obtained from normal and pressure-overloaded hypertrophied rat left ventricles. Left ventricular pressure overload was induced by partial ligation of the abdominal aorta 3-6 wk before study. Age- and weight-matched normal rats served as controls. Pressure overload increased the left ventricular weight-to-body weight ratio by 45%. Ins(1,4,5)P3 at a concentration of 10 microM did not change the Ca(2+)-tension relationship at Ca2+ concentrations of 10(-7) to 10(-5) M in either normal or hypertrophied fibers. Ins(1,4,5)P3 also did not influence Ca2+ uptake by the SR in either normal or hypertrophied fibers. Ins(1,4,5)P3 did not induce Ca2+ release from the SR directly in either group. However, pretreatment with Ins(1,4,5)P3 enhanced the 5 mM caffeine-induced Ca2+ release by 80.5 +/- 22.7% in normal fibers enhances, rather than directly induces, SR Ca2+ release in normal rat hearts and that sustained pressure overload diminishes the response of the SR Ca(2+)-release system to Ins(1,4,5)P3, an action that may be partly responsible for contractile dysfunction in cardiac hypertrophy.

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