NF-κB activation is required for the development of cardiac hypertrophy in vivo

2004 ◽  
Vol 287 (4) ◽  
pp. H1712-H1720 ◽  
Author(s):  
Yuehua Li ◽  
Tuanzhu Ha ◽  
Xiang Gao ◽  
Jim Kelley ◽  
David L. Williams ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Natriuretic Peptide ◽  
Weight Ratio ◽  
Dominant Negative ◽  
Heart Weight ◽  
Dominant Negative Mutant ◽  
Body Weight Ratio ◽  
Aortic Banding ◽  
Important Target

In the present study, we examined whether NF-κB activation is required for cardiac hypertrophy in vivo. Cardiac hypertrophy in rats was induced by aortic banding for 1, 3, and 5 days and 1–6 wk, and age-matched sham-operated rats served as controls. In a separate group of rats, an IκB-α dominant negative mutant (IκB-αM), a superrepressor of NF-κB activation, or pyrrolidinedithiocarbamate (PDTC), an antioxidant that can inhibit NF-κB activation, was administered to aortic-banded rats for 3 wk. The heart weight-to-body weight ratio was significantly increased at 5 days after aortic banding, peaked at 4 wk, and remained elevated at 6 wk compared with age-matched sham controls. Atrial natriuretic peptide and brain natriuretic peptide mRNA expressions were significantly increased after 1 wk of aortic banding, reached a maximum between 2 and 3 wk, and remained increased at 6 wk compared with age-matched sham controls. NF-κB activity was significantly increased at 1 day, reached a peak at 3 wk, and remained elevated at 6 wk, and IKK-β activity was significantly increased at 1 day, peaked at 5 days, and then decreased but remained elevated at 6 wk after aortic banding compared with age-matched sham controls. Inhibiting NF-κB activation in vivo by cardiac transfection of IκB-αM or by PDTC treatment significantly attenuated the development of cardiac hypertrophy in vivo with a concomitant decrease in NF-κB activity. Our results suggest that NF-κB activation is required for the development of cardiac hypertrophy in vivo and that NF-κB could be an important target for inhibiting the development of cardiac hypertrophy in vivo.

scholarly journals Cardioprotective Effects of the Novel Compound Vastiras in a Preclinical Model of End-Organ Damage

Hypertension ◽  
2020 ◽  
Vol 75 (5) ◽  
pp. 1195-1204
Author(s):  
Raffaele Altara ◽  
Gustavo J.J. da Silva ◽  
Michael Frisk ◽  
Francesco Spelta ◽  
Fouad A. Zouein ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Cardiac Hypertrophy ◽  
Natriuretic Peptide ◽  
Renal Damage ◽  
Weight Ratio ◽  
Hypertensive Heart Disease ◽  
Heart Weight ◽  
Preclinical Model ◽  
Continuous Administration ◽  
Positive Effects

Cardiac hypertrophy and renal damage associated with hypertension are independent predictors of morbidity and mortality. In a model of hypertensive heart disease and renal damage, we tested the actions of continuous administration of Vastiras, a novel compound derived from the linear fragment of ANP (atrial natriuretic peptide), namely pro-ANP 31–67 , on blood pressure and associated renal and cardiac function and remodeling. Of note, this peptide, unlike the ring structured forms, does not bind to the classic natriuretic peptide receptors. Dahl/Salt–Sensitive rats fed a 4% NaCl diet for 6 weeks developed hypertension, cardiac hypertrophy, and renal damage. Four weeks of treatment with 50 to 100 ng/kg per day of Vastiras exhibited positive effects on renal function, independent of blood pressure regulation. Treated rats had increased urine excretion, natriuresis, and enhanced glomerular filtration rate. Importantly, these favorable renal effects were accompanied by improved cardiac structure and function, including attenuated cardiac hypertrophy, as indicated by decreased heart weight to body weight ratio, relative wall thickness, and left atrial diameter, as well as reduced fibrosis and normalized ratio of the diastolic mitral inflow E wave to A wave. A renal subtherapeutic dose of Vastiras (25 ng/kg per day) induced similar protective effects on the heart. At the cellular level, cardiomyocyte size and t-tubule density were preserved in Vastiras-treated compared with untreated animals. In conclusion, these data demonstrate the cardiorenal protective actions of chronic supplementation of a first-in-class compound, Vastiras, in a preclinical model of maladaptive cardiac hypertrophy and renal damage induced by hypertension.

Blockade of MyD88 attenuates cardiac hypertrophy and decreases cardiac myocyte apoptosis in pressure overload-induced cardiac hypertrophy in vivo

2006 ◽  
Vol 290 (3) ◽  
pp. H985-H994 ◽  
Author(s):  
Tuanzhu Ha ◽  
Fang Hua ◽  
Yuehua Li ◽  
Jing Ma ◽  
Xiang Gao ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Cardiac Function ◽  
Cardiac Myocyte ◽  
Pressure Overload ◽  
Terminal Deoxynucleotidyl Transferase ◽  
Heart Weight ◽  
Aortic Banding ◽  
Myocyte Apoptosis ◽  
Cardiac Myocyte Apoptosis

In this study, we evaluated whether blocking myeloid differentiation factor-88 (MyD88) could decrease cardiac myocyte apoptosis following pressure overload. Adenovirus expressing dominant negative MyD88 (Ad5-dnMyD88) or Ad5-green fluorescent protein (GFP) (Ad5-GFP) was transfected into rat hearts ( n = 8/group) immediately followed by aortic banding for 3 wk. One group of rats ( n = 8) was subjected to aortic banding for 3 wk without transfection. Sham surgical operation ( n = 8) served as control. The ratios of heart weight to body weight (HW/BW) and heart weight to tibia length (HW/TL) were calculated. Cardiomyocyte size was examined by FITC-labeled wheat germ agglutinin staining of membranes. Cardiac myocyte apoptosis was determined by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling assay, and myocardial interstitial fibrosis was examined by Masson's Trichrome staining. Aortic banding significantly increased the HW/BW by 41.0% (0.44 ± 0.013 vs. 0.31 ± 0.008), HW/TL by 47.2% (42.7 ± 1.30 vs. 29.0 ± 0.69), cardiac myocyte size by 49.6%, and cardiac myocyte apoptosis by 11.5%, and myocardial fibrosis and decreased cardiac function compared with sham controls. Transfection of Ad5-dnMyD88 significantly reduced the HW/BW by 18.2% (0.36 ± 0.006 vs. 0.44 ± 0.013) and HW/TL by 22.3% (33.2 ± 0.95 vs. 42.7 ± 1.30) and decreased cardiomyocyte size by 56.8%, cardiac myocyte apoptosis by 76.2%, as well as fibrosis, and improved cardiac function compared with aortic-banded group. Our results suggest that MyD88 is an important component in the Toll-like receptor-4-mediated nuclear factor-κB activation pathway that contributes to the development of cardiac hypertrophy. Blockade of MyD88 significantly reduced cardiac hypertrophy, cardiac myocyte apoptosis, and improved cardiac function in vivo.

Regression of isoproterenol-induced cardiac hypertrophy

1984 ◽  
Vol 62 (9) ◽  
pp. 1141-1146 ◽  
Author(s):  
Qian Tang ◽  
Paul B. Taylor
Keyword(s):  
Cardiac Hypertrophy ◽  
Recovery Period ◽  
Control Level ◽  
Weight Ratio ◽  
Heart Weight ◽  
Half Time ◽  
Body Weight Ratio ◽  
Subcutaneous Injections ◽  
Rna Content ◽  
Female Wistar Rats

Cardiac hypertrophy was induced in adult female Wistar rats after 8 days of daily subcutaneous injections of isoproterenol (ISO). Regression from hypertrophy was studied following 1, 2, 4, 8, 12, and 20 days of ISO withdrawal. After 8 days of treatment cardiac mass increased 40%. Following ISO withdrawal, ventricular regression occurred during the first 8 days. After 12–20 days of recovery, a new steady-state heart weight to body weight ratio was established that was 12–13% above the controls. The half-time recovery for heart weight was 3.8 days. Ventricular RNA content was stimulated 76% after 8 days of ISO-induced hypertrophy. During regression RNA content decreased rapidly during the first 8 days with a half-time of 3.4 days. Following 20 days of recovery ventricular RNA was still 31% above the controls. However, myocyte RNA was stimulated 86% following 8 days of ISO treatment and returned to control level after 12 days of regression. Myocardial DNA was increased 23% in the hypertrophied hearts and did not change during the recovery period. Hydroxyproline was increased in the ISO-treated hearts and decreased only slightly during the recovery interval. These data indicate that ISO-induced hypertrophy was reversible while ventricular RNA content only partially recovered. Nevertheless, myocyte RNA showed a large stimulation that was completely reversible at least after 12 days of recovery.

scholarly journals Bawei Chenxiang Wan Ameliorates Cardiac Hypertrophy by Activating AMPK/PPAR-α Signaling Pathway Improving Energy Metabolism

2021 ◽  
Vol 12 ◽  
Author(s):  
Xiaoying Zhang ◽  
Zhiying Zhang ◽  
Pengxiang Wang ◽  
Yiwei Han ◽  
Lijun Liu ◽  
...  
Keyword(s):  
Body Weight ◽  
Energy Metabolism ◽  
Cardiac Hypertrophy ◽  
Heart Function ◽  
Weight Ratio ◽  
Tibetan Medicine ◽  
Heart Weight ◽  
Cardiomyocyte Hypertrophy ◽  
Body Weight Ratio ◽  
Cross Sectional

Bawei Chenxiang Wan (BCW), a well-known traditional Chinese Tibetan medicine formula, is effective for the treatment of acute and chronic cardiovascular diseases. In the present study, we investigated the effect of BCW in cardiac hypertrophy and underlying mechanisms. The dose of 0.2, 0.4, and 0.8 g/kg BCW treated cardiac hypertrophy in SD rat model induced by isoprenaline (ISO). Our results showed that BCW (0.4 g/kg) could repress cardiac hypertrophy, indicated by macro morphology, heart weight to body weight ratio (HW/BW), left ventricle heart weight to body weight ratio (LVW/BW), hypertrophy markers, heart function, pathological structure, cross-sectional area (CSA) of myocardial cells, and the myocardial enzymes. Furthermore, we declared the mechanism of BCW anti-hypertrophy effect was associated with activating adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK)/peroxisome proliferator–activated receptor-α (PPAR-α) signals, which regulate carnitine palmitoyltransferase1β (CPT-1β) and glucose transport-4 (GLUT-4) to ameliorate glycolipid metabolism. Moreover, BCW also elevated mitochondrial DNA-encoded genes of NADH dehydrogenase subunit 1(ND1), cytochrome b (Cytb), and mitochondrially encoded cytochrome coxidase I (mt-co1) expression, which was associated with mitochondria function and oxidative phosphorylation. Subsequently, knocking down AMPK by siRNA significantly can reverse the anti-hypertrophy effect of BCW indicated by hypertrophy markers and cell surface of cardiomyocytes. In conclusion, BCW prevents ISO-induced cardiomyocyte hypertrophy by activating AMPK/PPAR-α to alleviate the disturbance in energy metabolism. Therefore, BCW can be used as an alternative drug for the treatment of cardiac hypertrophy.

Abstract 153: Inhibition of the 5-a-reductase Reduces Cardiac Hypertrophy and Improves Cardiac Function

2013 ◽  
Vol 113 (suppl_1) ◽  
Author(s):  
Carolin Zwadlo ◽  
Natali Froese ◽  
Johann Bauersachs ◽  
Joerg Heineke
Keyword(s):  
Cardiac Hypertrophy ◽  
Weight Ratio ◽  
Capillary Density ◽  
Left Ventricular ◽  
Heart Weight ◽  
Rat Cardiomyocytes ◽  
Male And Female ◽  
Female Mice

Objectives: Left ventricular hypertrophy (LVH) is an independent risk factor for increased cardiovascular mortality and a precursor of heart failure. Gender-specific differences point to a pivotal role of androgens in the development of pathological LVH. Dihydrotestosterone (DHT) is metabolized from testosterone via the enzyme 5-α-reductase. The 5-α-reductase is upregulated in the hypertrophied myocardium, leading to our assumption that DHT rather than testosterone is the crucial component in the development of LVH and might therefore constitute a potential therapeutic target. Methods: One week after transverse aortic constriction (TAC) or sham surgery male wild-type mice were treated for 2 weeks via an oralgastric tube with the 5-α-reductase inhibitor finasteride (daily dose 25mg/kg BW) or were left untreated (controls). Male and female transgenic Gαq (TG, a model of dilative cardiomyopathy) or non-transgenic mice were treated with finasteride for 6 weeks. Results: Cardiac hypertrophy after TAC was dramatically reduced by finasteride in male mice (heart weight/ body weight ratio, HW/BW in mg/g: control 6.65±0.35 versus finasteride treated 5.23±0.3; p<0.01). The reduced hypertrophy in these mice was accompanied by a reduction in cardiomyocyte diameter, ANP expression and fibrosis, but increased capillary density and Serca2a expression. Accordingly, finasteride also markedly reduced hypertrophy in isolated primary rat cardiomyocytes in vitro . Amelioration of hypertrophy by finasteride was associated with blunted activation of the prohypertrophic kinase mTOR in vitro and in vivo . Left ventricular dilation in male Gαq TG mice was markedly reduced by treatment with finasteride, which also led to an improvement in left ventricular function (determined as fractional area change in % by echocardiography: finasteride 44.72±1.71 vs. control 32.8±3.84, p<0.05) and a similar trend was observed in female mice. Interestingly, finasteride reduced pulmonary congestion in male and female mice alike. Conclusion: Finasteride treatment reduces hypertrophy and eccentric cardiac remodelling in mice, indicating a possible involvement of DHT in these processes as well as a potential benefit of 5-α-reductase inhibition in cardiac disease.

Lansoprazole alleviates pressure overload-induced cardiac hypertrophy and heart failure in mice by blocking the activation of β-catenin

2019 ◽  
Vol 116 (1) ◽  
pp. 101-113 ◽  
Author(s):  
Hairuo Lin ◽  
Yang Li ◽  
Hailin Zhu ◽  
Qiancheng Wang ◽  
Zhenhuan Chen ◽  
...  
Keyword(s):  
Heart Failure ◽  
Body Weight ◽  
Angiotensin Ii ◽  
Cardiac Hypertrophy ◽  
Weight Ratio ◽  
Left Ventricular ◽  
Neonatal Rat ◽  
Cardiac Remodelling ◽  
Heart Weight ◽  
Body Weight Ratio

Abstract Aims Proton pump inhibitors (PPIs) are widely used in patients receiving percutaneous coronary intervention to prevent gastric bleeding, but whether PPIs are beneficial for the heart is controversial. Here, we investigated the effects of lansoprazole on cardiac hypertrophy and heart failure, as well as the underlying mechanisms. Methods and results Adult male C57 mice were subjected to transverse aortic constriction (TAC) or sham surgery and then were treated with lansoprazole or vehicle for 5 weeks. In addition, cultured neonatal rat ventricular cardiomyocytes and fibroblasts were exposed to angiotensin II in the presence or absence of lansoprazole. At 5 weeks after TAC, the heart weight/body weight ratio was lower in lansoprazole-treated mice than in untreated mice, as was the lung weight/body weight ratio, while left ventricular (LV) fractional shortening and the maximum and minimum rates of change of the LV pressure were higher in lansoprazole-treated mice, along with less cardiac fibrosis. In cultured cardiomyocytes, lansoprazole inhibited angiotensin II-induced protein synthesis and hypertrophy, as well as inhibiting proliferation of fibroblasts. Lansoprazole decreased myocardial levels of phosphorylated Akt, phosphorylated glycogen synthase kinase 3β, and active β-catenin in TAC mice and in angiotensin II-stimulated cardiomyocytes. After overexpression of active β-catenin or knockdown of H+/K+-ATPase α-subunit, lansoprazole still significantly attenuated myocyte hypertrophy. Conclusion Lansoprazole inhibits cardiac remodelling by suppressing activation of the Akt/GSK3β/β-catenin pathway independent of H+/K+-ATPase inhibition, and these findings may provide a novel insight into the pharmacological effects of PPIs with regard to alleviation of cardiac remodelling.

scholarly journals PO-148 Effect of Aerobic Exercise on the Expression of CaMKIIδ/MEF2 in Hypertensive and Physiological Cardiac Hypertrophy

2018 ◽  
Vol 1 (4) ◽  
Author(s):  
Man Zhu ◽  
Lijun Shi
Keyword(s):  
Body Weight ◽  
Cardiac Hypertrophy ◽  
Aerobic Exercise ◽  
Weight Ratio ◽  
Exercise Group ◽  
The Body ◽  
Expression Level ◽  
Heart Weight ◽  
Control Group ◽  
Body Weight Ratio

Objective The type II calcium/calmodulin-dependent protein kinase IIδ (CaMKIIδ) signal plays a key role in the development of cardiac hypertrophy. This study used CaMKIIδ as an entry point to investigate the mechanism of moderate-intensity aerobic exercise affecting myocardial function. Methods Male spontaneously hypertensive rats (SHRs) and Wistar-Kyoto rats (WKYs), 12 weeks age, were randomly divided into aerobic exercise group (SHR-EX/WKY-EX) and sedentary control group (SHR-SED/WKY-SED), with 12 rats in each group. The aerobic exercise group conducted an 8-week treadmill exercise training with a slope of 0°, 20m/min (about 55-65% of maximal aerobic velocity), 60min/day, and 5d/wk. The control group did not exercise. The body weight of each group of rats was measured weekly and the blood pressure of the rats was measured non-invasively. After 8 weeks, the hearts of SHR-EX group, WKY-EX group, SHR-SED group and WKY-SED group were weighed, and then myocardial tissue sections were taken for HE staining to observe the thickness of the ventricular wall and the morphology of myocardial cells. The expression of CaMKIIδ and MEF2 in each group was determined by Western blotting. Results (1) The body weight of SHR-SED group was significantly higher than that of SHR-EX group (p<0.01), and the heart weight of rats in exercise group changed significantly. The WKY-EX group had greater heart weight than the WKY-SED group, and the SHR-SED group was heavier than the SHR-EX group (p<0.05). The heart weight/body weight ratio of the WKY-EX group was significantly higher than that of the WKY-SED group (p<0.01). The heart weight/body weight ratio of SHR-EX group and SHR-SED group was higher than that of WKY-EX group and WKY-SED group (p<0.01). (2) Compared with the WKY-SED group, the SHR-SED group had loose interstitial cells and increased single cell area. The SHR-EX group is more compact than the SHR-SED group, and the cell cross-sectional area is reduced. (3) The expression of CaMKIIδ protein in SHR-EX group was significantly lower than that in SHR-SED group (p<0.01), but the expression level of CaMKIIδ in WKY-EX group was significantly higher than that in WKY-SED group (p<0.01). The expression level of CaMKIIδ was significantly higher in the SHR-SED group than in the WKY-SED group. In addition, the expression of MEF2 protein in SHR-EX group and WKY-SED group was significantly lower than that in SHR-SED group (p<0.01), while the MEF2 expression level in WKY-EX group was higher than WKY-SED group and SHR-EX group (p<0.05). Conclusions There is an interaction between aerobic exercise and hypertension. Aerobic exercise can effectively delay the development of hypertensive cardiac hypertrophy by regulating the expression of CaMKIIδ and MEF2 protein in the myocardium, but it can also cause cardiac hypertrophy in normal heart. It is one of the important mechanisms affecting the myocardial morphology and function.    

ANG II receptor blockade prevents ventricular hypertrophy and ANF gene expression with pressure overload in mice

1994 ◽  
Vol 266 (6) ◽  
pp. H2468-H2475 ◽  
Author(s):  
H. A. Rockman ◽  
S. P. Wachhorst ◽  
L. Mao ◽  
J. Ross
Keyword(s):  
Body Weight ◽  
Angiotensin Ii ◽  
Cardiac Hypertrophy ◽  
Ventricular Hypertrophy ◽  
Systolic Pressure ◽  
Weight Ratio ◽  
Pressure Overload ◽  
Heart Weight ◽  
Receptor Blockade ◽  
Body Weight Ratio

There is increasing evidence that the renin-angiotensin system may play a important role in cardiac hypertrophy. To assess the role of angiotensin II in the induction of cardiac hypertrophy, three groups of adult mice were subjected to left ventricular pressure overload by transverse aortic constriction (TAC). For the next 7 days the groups received either the specific angiotensin II subtype 1 receptor (AT1) antagonist (losartan, 1.05 g/l; n = 17), an angiotensin enzyme inhibitor (captopril, 2 g/l; n = 17), or no treatment (n = 22) administered in the drinking water and compared with three similarly treated sham-operated groups (n = 7 each). TAC resulted in a significant increase in heart weight-to-body weight ratio (0.634 +/- 0.087 vs. 0.525 +/- 0.039, g/g x 100, P < 0.05), which was prevented by losartan (0.506 +/- 0.069, g/g x 100, P < 0.0001) despite similar hemodynamic load (proximal systolic pressure 146 +/- 31 vs. 136 +/- 32 mmHg, untreated vs. losartan, P = NS). Proximal systolic pressure was positively correlated with the development of ventricular hypertrophy. In the presence of AT1-receptor blockade, the increase in heart weight-to-body weight ratio at any given systolic pressure was significantly attenuated compared with untreated TAC mice. The increase in heart weight-to-body weight ratio was also significantly attenuated by captopril compared with untreated banded controls (0.542 +/- 0.091, g/g x 100, P = 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

scholarly journals Cardiac hypertrophy associated with impaired regulation of cardiac ryanodine receptor by calmodulin and S100A1

2013 ◽  
Vol 305 (1) ◽  
pp. H86-H94 ◽  
Author(s):  
Naohiro Yamaguchi ◽  
Asima Chakraborty ◽  
Tai-Qin Huang ◽  
Le Xu ◽  
Angela C. Gomez ◽  
...  
Keyword(s):  
Body Weight ◽  
Amino Acid ◽  
Atrial Natriuretic Peptide ◽  
Cardiac Hypertrophy ◽  
Cardiac Function ◽  
Ryanodine Receptor ◽  
Weight Ratio ◽  
Heart Weight ◽  
Mrna Levels ◽  
Body Weight Ratio

The cardiac ryanodine receptor (RyR2) is inhibited by calmodulin (CaM) and S100A1. Simultaneous substitution of three amino acid residues (W3587A, L3591D, F3603A; RyR2ADA) in the CaM binding domain of RyR2 results in loss of CaM inhibition at submicromolar (diastolic) and micromolar (systolic) Ca2+, cardiac hypertrophy, and heart failure in Ryr2 ADA/ADA mice. To address whether cardiac hypertrophy results from the elimination of CaM and S100A1 inhibition at diastolic or systolic Ca2+, a mutant mouse was generated with a single RyR2 amino acid substitution (L3591D; RyR2D). Here we report that in single-channel measurements RyR2-L3591D isolated from Ryr2 D/D hearts lost CaM inhibition at diastolic Ca2+ only, whereas S100A1 regulation was eliminated at both diastolic and systolic Ca2+. In contrast to the ∼2-wk life span of Ryr2 ADA/ADA mice, Ryr2 D/D mice lived longer than 1 yr. Six-month-old Ryr2 D/D mice showed a 9% increase in heart weight-to-body weight ratio, modest changes in cardiac morphology, and a twofold increase in atrial natriuretic peptide mRNA levels compared with wild type. After 4-wk pressure overload with transverse aortic constriction, heart weight-to-body weight ratio and atrial natriuretic peptide mRNA levels increased and echocardiography showed changes in heart morphology of Ryr2 D/D mice compared with sham-operated mice. Collectively, the findings indicate that the single RyR2-L3591D mutation, which distinguishes the effects of diastolic and systolic Ca2+, alters heart size and cardiac function to a lesser extent in Ryr2 D/D mice than the triple mutation in Ryr2 ADA/ADA mice. They further suggest that CaM inhibition of RyR2 at systolic Ca2+ is important for maintaining normal cardiac function.

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