Inhibition of IκB phosphorylation prevents load-induced cardiac dysfunction in mice

2012 ◽  
Vol 303 (12) ◽  
pp. H1435-H1445 ◽  
Author(s):  
Tetsu Tanaka ◽  
Masahito Ogawa ◽  
Jun-ichi Suzuki ◽  
Asuka Sekinishi ◽  
Akiko Itai ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Cardiac Dysfunction ◽  
Cardiac Fibrosis ◽  
Nuclear Translocation ◽  
Pressure Overload ◽  
Treated Group ◽  
Left Ventricular ◽  
Matrix Metalloproteinase 2 ◽  
Cardiomyocyte Hypertrophy ◽  
Iκb Kinase

Pressure overload is known to be a cause of cardiac hypertrophy that often transits to heart failure. Although nuclear factor (NF)-κB is a key factor in the progression of cardiac hypertrophy, its pathophysiology is yet to be elucidated. Thus, we aimed to show that inhibition of NF-κB activation improves pressure overload-induced cardiac dysfunction. To assess the effect of inhibition on NF-κB activation in pressure overload cardiac hypertrophy, we used IMD-1041 in a murine thoracic aortic constriction (TAC) model. IMD-1041 inhibits the phosphorylation of IκB via inhibition of IκB kinase-β. IMD-1041 (100 mg·kg−1·day−1) or vehicle was administered orally into mice once a day, and mice were euthanized on day 42 after TAC. TAC resulted in left ventricular wall thickening, cardiac dysfunction, and increases of heart and lung weight, whereas IMD-1041 significantly suppressed the development of cardiac hypertropy 6 wk after TAC. Histologically, developed cardiac fibrosis and cardiomyocyte hypertrophy occurred in the vehicle-treated group, whereas IMD-1041 significantly attenuated these changes. IMD-1041 suppressed the expression of p65-positive cells and nuclear translocation of p65 induced by TAC compared with vehicle. Matrix metalloproteinase-2 activity increased in the vehicle + TAC-treated group; however, it was suppressed in the IMD-1041 + TAC-treated group. IMD-1041 treatment from day 28 to day 42 after TAC significantly attenuated the decrease in the percentage of fractional shortening and cardiac fibrosis without an antihypertrophic effect. In conclusion, IMD-1041 may be useful for preventing pressure overload-induced cardiac dysfunction and the transition of cardiac hypertrophy to contraction failure via suppression of NF-κB activation.

Cacao Bean Polyphenols Inhibit Cardiac Hypertrophy and Systolic Dysfunction in Pressure Overload-induced Heart Failure Model Mice

Planta Medica ◽  
2020 ◽  
Vol 86 (17) ◽  
pp. 1304-1312
Author(s):  
Nurmila Sari ◽  
Yasufumi Katanasaka ◽  
Hiroki Honda ◽  
Yusuke Miyazaki ◽  
Yoichi Sunagawa ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Hypertrophy ◽  
Gene Transcription ◽  
Binding Protein ◽  
Systolic Dysfunction ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Cardiomyocyte Hypertrophy ◽  
Extracellular Signal Regulated Kinase ◽  
Extracellular Signal

AbstractPathological stresses such as pressure overload and myocardial infarction induce cardiac hypertrophy, which increases the risk of heart failure. Cacao bean polyphenols have recently gained considerable attention for their beneficial effects on cardiovascular diseases. This study investigated the effect of cacao bean polyphenols on the development of cardiac hypertrophy and heart failure. Cardiomyocytes from neonatal rats were pre-treated with cacao bean polyphenols and then stimulated with 30 µM phenylephrine. C57BL/6j male mice were subjected to sham or transverse aortic constriction surgery and then orally administered with vehicle or cacao bean polyphenols. Cardiac hypertrophy and function were examined by echocardiography. In cardiomyocytes, cacao bean polyphenols significantly suppressed phenylephrine-induced cardiomyocyte hypertrophy and hypertrophic gene transcription. Extracellular signal-regulated kinase 1/2 and GATA binding protein 4 phosphorylation induced by phenylephrine was inhibited by cacao bean polyphenols treatment in the cardiomyocytes. Cacao bean polyphenols treatment at 1200 mg/kg significantly ameliorated left ventricular posterior wall thickness, fractional shortening, hypertrophic gene transcription, cardiac hypertrophy, cardiac fibrosis, and extracellular signal-regulated kinase 1/2 phosphorylation induced by pressure overload. In conclusion, these findings suggest that cacao bean polyphenols prevent pressure overload-induced cardiac hypertrophy and systolic dysfunction by inhibiting the extracellular signal-regulated kinase 1/2-GATA binding protein 4 pathway in cardiomyocytes. Thus, cacao bean polyphenols may be useful for heart failure therapy in humans.

scholarly journals Osteopontin RNA aptamer can prevent and reverse pressure overload-induced heart failure

2017 ◽  
Vol 113 (6) ◽  
pp. 633-643 ◽  
Author(s):  
Jihe Li ◽  
Keyvan Yousefi ◽  
Wen Ding ◽  
Jayanti Singh ◽  
Lina A. Shehadeh
Keyword(s):  
Heart Failure ◽  
Cardiac Function ◽  
Cardiac Dysfunction ◽  
Cardiac Fibrosis ◽  
Cardiac Myocyte ◽  
Pressure Overload ◽  
Cardiomyocyte Hypertrophy ◽  
Therapeutic Effects ◽  
Rna Aptamer ◽  
Myocyte Hypertrophy

Aims Cardiac myocyte hypertrophy, the main compensatory response to chronic stress in the heart often progresses to a state of decompensation that can lead to heart failure. Osteopontin (OPN) is an effector for extracellular signalling that induces myocyte growth and fibrosis. Although increased OPN activity has been observed in stressed myocytes and fibroblasts, the detailed and long term effects of blocking OPN signalling on the heart remain poorly defined. Targeting cardiac OPN protein by an RNA aptamer may be beneficial for tuning down OPN pathologic signalling. We aimed to demonstrate the therapeutic effects of an OPN RNA aptamer on cardiac dysfunction. Methods and results In vivo, we show that in a mouse model of pressure overload, treating at the time of surgeries with an OPN aptamer prevented cardiomyocyte hypertrophy and cardiac fibrosis, blocked OPN downstream signalling (PI3K and Akt phosphorylation), reduced expression of extracellular matrix (Lum, Col3a1, Fn1) and hypertrophy (Nppa, Nppb) genes, and prevented cardiac dysfunction. Treating at two months post-surgeries with the OPN aptamer reversed cardiac dysfunction and fibrosis and myocyte hypertrophy. While genetic homozygous deletion of OPN reduced myocardial wall thickness, surprisingly cardiac function and myocardial fibrosis, specifically collagen deposition and myofibroblast infiltration, were worse compared with wild type mice at three months of pressure overload. Conclusion Taken together, these data demonstrate that tuning down cardiac OPN signalling by an OPN RNA aptamer is a novel and effective approach for preventing cardiac hypertrophy and fibrosis, improving cardiac function, and reversing pressure overload-induced heart failure.

scholarly journals Distinct Phenotypes Induced by Different Degrees of Transverse Aortic Constriction in C57BL/6N Mice

2021 ◽  
Vol 8 ◽  
Author(s):  
Haiyan Deng ◽  
Lei-Lei Ma ◽  
Fei-Juan Kong ◽  
Zengyong Qiao
Keyword(s):  
Heart Failure ◽  
Cardiac Hypertrophy ◽  
Cardiac Dysfunction ◽  
Cardiac Fibrosis ◽  
Disease Model ◽  
Pressure Overload ◽  
Mouse Strains ◽  
Transverse Aortic Constriction ◽  
Aortic Constriction ◽  
The Difference

The transverse aortic constriction (TAC) model surgery is a widely used disease model to study pressure overload–induced cardiac hypertrophy and heart failure in mice. The severity of adverse cardiac remodeling of the TAC model is largely dependent on the degree of constriction around the aorta, and the phenotypes of TAC are also different in different mouse strains. Few studies focus on directly comparing phenotypes of the TAC model with different degrees of constriction around the aorta, and no study compares the difference in C57BL/6N mice. In the present study, C57BL/6N mice aged 10 weeks were subjected to sham, 25G TAC, 26G TAC, and 27G TAC surgery for 4 weeks. We then analyzed the different phenotypes induced by 25G TAC, 26G TAC, and 27G TAC in c57BL/6N mice in terms of pressure gradient, cardiac hypertrophy, cardiac function, heart failure situation, survival condition, and cardiac fibrosis. All C57BL/6N mice subjected to TAC surgery developed significantly hypertrophy. Mice subjected to 27G TAC had severe cardiac dysfunction, severe cardiac fibrosis, and exhibited characteristics of heart failure at 4 weeks post-TAC. Compared with 27G TAC mice, 26G TAC mice showed a much milder response in cardiac dysfunction and cardiac fibrosis compared to 27G TAC, and a very small fraction of the 26G TAC group exhibited characteristics of heart failure. There was no obvious cardiac dysfunction, cardiac fibrosis, and characteristics of heart failure observed in 25G TAC mice. Based on our results, we conclude that the 25G TAC, 26G TAC, and 27G TAC induced distinct phenotypes in C57BL/6N mice.

Activation of SIRT1 by Resveratrol Alleviates Pressure Overload-Induced Cardiac Hypertrophy via Suppression of TGF-β1 Signaling

Pharmacology ◽  
2021 ◽  
pp. 1-15
Author(s):  
Yong Chen ◽  
Ting He ◽  
Zhongjun Zhang ◽  
Junzhi Zhang
Keyword(s):  
Cardiac Hypertrophy ◽  
Protective Effect ◽  
Signaling Pathway ◽  
Cardiac Fibrosis ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Neonatal Rat ◽  
Ang Ii ◽  
Tgf Β1

<b><i>Introduction:</i></b> Silent information regulator 1 (SIRT1) has been extensively investigated in the cardiovascular system and has been shown to play a pivotal role in mediating cell death/survival, energy production, and oxidative stress. However, the functional role of SIRT1 in pressure overload-induced cardiac hypertrophy and dysfunction remains unclear. Resveratrol (Rsv), a widely used activator of SIRT1, has been reported to protect against cardiovascular disease. We here examine whether activation of SIRT1 by Rsv attenuate pressure overload-induced cardiac hypertrophy and to identify the underlying molecular mechanisms. <b><i>Methods:</i></b> In vivo, rat model of pressure overload-induced myocardial hypertrophy was established by abdominal aorta constriction (AAC) procedure. In vitro, Angiotensin II (Ang II) was applied to induce hypertrophy in cultured neonatal rat cardiomyocytes (NCMs). Hemodynamics and histological analyses of the heart were evaluated. The expression of SIRT1, transforming growth factor-β1 (TGF-β1)/phosphorylated (p)-small mother against decapentaplegic (Smad)3 and hypertrophic markers were determined by immunofluorescence, real-time PCR, and Western blotting techniques. <b><i>Results:</i></b> In the current study, Rsv treatment improved left ventricular function and reduced left ventricular hypertrophy and cardiac fibrosis significantly in the pressure overload rats. The expression of SIRT1 was significantly reduced, while the expression of TGF-β1/p-Smad3 was significantly enhanced in AAC afflicted rat heart. Strikingly, treatment with Rsv restored the expressions of SIRT1 and TGF-β1/p-Smad3 under AAC influence. However, SIRT1 inhibitor Sirtinol (Snl) markedly prevented the effects of Rsv, which suggest that SIRT1 signaling pathway was involved in the cardiac protective effect of Rsv. In vitro studies performed in Ang II-induced hypertrophy in NCMs confirmed the cardiac protective effect of Rsv. Furthermore, the study presented that SIRT1 negatively correlated with the cardiac hypertrophy, cardiac fibrosis, and the TGF-β1/p-Smad3 expression. <b><i>Conclusions:</i></b> Taken together, these results indicated that activation of SIRT1 by Rsv attenuates cardiac hypertrophy, cardiac fibrosis, and improves cardiac function possibly via regulation of the TGF-β1/p-Smad3 signaling pathway. Our study may provide a potential therapeutic strategy for cardiac hypertrophy.

Abstract 1224: Rock1 Deletion Prevents Cardiac Dilation And Improves Contractile Function In Pathological Cardiac Hypertrophy

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Jianjian Shi ◽  
Yi-Wei Zhang ◽  
Gerald W Dorn ◽  
Lei Wei
Keyword(s):  
Heart Failure ◽  
Cardiac Hypertrophy ◽  
Cardiac Fibrosis ◽  
Contractile Function ◽  
Left Ventricular ◽  
Cardiomyocyte Hypertrophy ◽  
Molecular Defect ◽  
Contractile Dysfunction ◽  
Adrenergic Stimulation ◽  
Compensatory Response

The development of left ventricular cardiomyocyte hypertrophy in response to increased hemodynamic load and neurohormonal stress is initially a compensatory response. However, persistent stress eventually leads to dilated heart failure, which is a common cause of heart failure in human hypertensive and valvular heart disease. We have recently reported that ROCK1 homozygous knockout mice exhibited reduced cardiac fibrosis and cardiomyocyte apoptosis, while displayed a preserved compensatory hypertrophic response to pressure overload. Here, we tested effects of ROCK1 deficiency on cardiac hypertrophy, dilation, and dysfunction by using the transgenic Gαq mice which represent a well-characterized and highly relevant genetic mouse model of pathological hypertrophy and heart failure. We have shown that ROCK1 deletion prevented left ventricular dilation and contractile dysfunction in Gαq mice under basal condition. ROCK1 deletion also partially rescued bradycardia and improved contractile response to β-adrenergic stimulation in Gαq mice. Although the development of cardiomyocyte hypertrophy was not affected, ROCK1 deletion in Gαq mice resulted in a concentric hypertrophic phenotype associated with reduced induction of hypertrophic markers. Finally, ROCK1 deletion prevented down-regulation of type V adenylyl cyclase expression, which is a critical molecular defect contributing to the impaired β-adrenergic signaling in Gαq mice. The present study establishes for the first time a role for ROCK1 in cardiac dilation and contractile dysfunction.

scholarly journals Mixed lineage kinase-3 prevents cardiac dysfunction and structural remodeling with pressure overload

2019 ◽  
Vol 316 (1) ◽  
pp. H145-H159 ◽  
Author(s):  
Timothy D. Calamaras ◽  
Robert A. Baumgartner ◽  
Mark J. Aronovitz ◽  
Angela L. McLaughlin ◽  
Kelly Tam ◽  
...  
Keyword(s):  
Cardiac Remodeling ◽  
Cardiac Dysfunction ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Cardiomyocyte Hypertrophy ◽  
Rat Cardiomyocytes ◽  
Jnk Signaling ◽  
Mixed Lineage Kinase ◽  
Adult Rat ◽  
Mixed Lineage Kinase 3

Myocardial hypertrophy is an independent risk factor for heart failure (HF), yet the mechanisms underlying pathological cardiomyocyte growth are incompletely understood. The c-Jun NH2-terminal kinase (JNK) signaling cascade modulates cardiac hypertrophic remodeling, but the upstream factors regulating myocardial JNK activity remain unclear. In this study, we sought to identify JNK-activating molecules as novel regulators of cardiac remodeling in HF. We investigated mixed lineage kinase-3 (MLK3), a master regulator of upstream JNK-activating kinases, whose role in the remodeling process had not previously been studied. We observed increased MLK3 protein expression in myocardium from patients with nonischemic and hypertrophic cardiomyopathy and in hearts of mice subjected to transverse aortic constriction (TAC). Mice with genetic deletion of MLK3 (MLK3−/−) exhibited baseline cardiac hypertrophy with preserved cardiac function. MLK3−/− mice subjected to chronic left ventricular (LV) pressure overload (TAC, 4 wk) developed worsened cardiac dysfunction and increased LV chamber size compared with MLK3+/+ littermates ( n = 8). LV mass, pathological markers of hypertrophy ( Nppa, Nppb), and cardiomyocyte size were elevated in MLK3−/− TAC hearts. Phosphorylation of JNK, but not other MAPK pathways, was selectively impaired in MLK3−/− TAC hearts. In adult rat cardiomyocytes, pharmacological MLK3 kinase inhibition using URMC-099 blocked JNK phosphorylation induced by neurohormonal agents and oxidants. Sustained URMC-099 exposure induced cardiomyocyte hypertrophy. These data demonstrate that MLK3 prevents adverse cardiac remodeling in the setting of pressure overload. Mechanistically, MLK3 activates JNK, which in turn opposes cardiomyocyte hypertrophy. These results support modulation of MLK3 as a potential therapeutic approach in HF. NEW & NOTEWORTHY Here, we identified a role for mixed lineage kinase-3 (MLK3) as a novel antihypertrophic and antiremodeling molecule in response to cardiac pressure overload. MLK3 regulates phosphorylation of the stress-responsive JNK kinase in response to pressure overload and in cultured cardiomyocytes stimulated with hypertrophic agonists and oxidants. This study reveals MLK3-JNK signaling as a novel cardioprotective signaling axis in the setting of pressure overload.

scholarly journals Baicalin Attenuates Cardiac Dysfunction and Myocardial Remodeling in a Chronic Pressure-Overload Mice Model

2017 ◽  
Vol 41 (3) ◽  
pp. 849-864 ◽  
Author(s):  
Yanqing Zhang ◽  
Pingping Liao ◽  
Meng’en Zhu ◽  
Wei Li ◽  
Dan Hu ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Cardiac Dysfunction ◽  
Cardiac Fibrosis ◽  
Ventricular Remodeling ◽  
Pressure Overload ◽  
Protective Effects ◽  
Mice Model ◽  
Ischaemic Injury

Background/Aims: Baicalin has been shown to be effective for various animal models of cardiovascular diseases, such as pulmonary hypertension, atherosclerosis and myocardial ischaemic injury. However, whether baicalin plays a role in cardiac hypertrophy remains unknown. Here we investigated the protective effects of baicalin on cardiac hypertrophy induced by pressure overload and explored the potential mechanisms involved. Methods: C57BL/6J-mice were treated with baicalin or vehicle following transverse aortic constriction or Sham surgery for up to 8 weeks, and at different time points, cardiac function and heart size measurement and histological and biochemical examination were performed. Results: Mice under pressure overload exhibited cardiac dysfunction, high mortality, myocardial hypertrophy, increased apoptosis and fibrosis markers, and suppressed cardiac expression of PPARα and PPARβ/δ. However, oral administration of baicalin improved cardiac dysfunction, decreased mortality, and attenuated histological and biochemical changes described above. These protective effects of baicalin were associated with reduced heart and cardiomyocyte size, lower fetal genes expression, attenuated cardiac fibrosis, lower expression of profibrotic markers, and decreased apoptosis signals in heart tissue. Moreover, we found that baicalin induced PPARα and PPARβ/δ expression in vivo and in vitro. Subsequent experiments demonstrated that long-term baicalin treatment presented no obvious cardiac lipotoxicity. Conclusions: The present results demonstrated that baicalin attenuates pressure overload induced cardiac dysfunction and ventricular remodeling, which would be due to suppressed cardiac hypertrophy, fibrosis, apoptosis and metabolic abnormality.

Effect of Berberine on Regression of Pressure-Overload Induced Cardiac Hypertrophy in Rats

2002 ◽  
Vol 30 (04) ◽  
pp. 589-599 ◽  
Author(s):  
Ying Hong ◽  
Siu-Chun Hui ◽  
Tak-Yuen Chan ◽  
Jia-Yu Hou
Keyword(s):  
Cardiac Hypertrophy ◽  
Matched Control ◽  
Pressure Overload ◽  
Ventricular Myocardium ◽  
Treated Group ◽  
Left Ventricular ◽  
Left Ventricular Myocardium ◽  
Left Ventricular Tissue ◽  
Ventricular Tissue ◽  
Contraction And Relaxation

Berberine is the basic chemical component of a Chinese herb, Coptis chinensis Franch (coptis), considered to be useful in treating some diseases of the cardiovascular system, such as hypertension and chronic heart failure (CHF). In this study, we investigate the inhibitory effect of berberine on experimental cardiac hypertrophy, which is regarded as a risk factor of CHF and other heart diseases. Forty-two male SD rats were divided into four groups: age-matched control, aortic banding model, berberine-treated group and captopril-treated group. Cardiac hypertrophy was induced by suprarenal abdominal aorta constriction (banding). The drugs were orally administered for 8 weeks starting from 4 weeks after surgery at dosage of berberine 10 mg/kg and captopril 50 mg/kg. Blood pressure (BP) was measured four times during the period of the experiment, and hemodynamic parameters, cardiac index, cell size of left ventricular myocardium and total protein of left ventricular tissue were detected 8 weeks after treatment with drugs. The data from the present study showed that: (1) The BP of the aorta banded rats was increased compared with those of the normal ( p < 0.001) and the age-matched control rats ( p < 0.001), and berberine showed no significant effect on it. (2) After 8 weeks of treatment with berberine, the elevated left ventricular end diastolic pressure (LVEDP) was slightly decreased compared with the aortic banded rats. Meanwhile, the maximum rates of contraction and relaxation (± dp/dt max) was increased ( p < 0.05) and the time to reach the point of maximum rate from beginning of contraction (t-dp/dt) was shortened ( p < 0.01), indicating that the functions of heart, both contraction and relaxation, were improved. (3) Cardiac growth was inhibited by treatment with berberine. Both whole heart and left ventricular weight were notably decreased compared with the banded rats ( p < 0.05 and p < 0.01). (4) The cell size of left ventricular myocardium was significantly reduced ( p < 0.001) and the total protein of left ventricular tissue was slightly down-regulated by treatment with berberine. These data suggest that berberine can improve abnormal cardiac function and can prevent the development of left ventricular hypertrophy induced by pressure overload. This indicates that it may have therapeutic potential in the treatment of CHF.

scholarly journals Endogenous Relaxin Does Not Affect Chronic Pressure Overload-Induced Cardiac Hypertrophy and Fibrosis

Endocrinology ◽  
2007 ◽  
Vol 149 (2) ◽  
pp. 476-482 ◽  
Author(s):  
Qi Xu ◽  
Edna D. Lekgabe ◽  
Xiao-Ming Gao ◽  
Ziqiu Ming ◽  
Geoffrey W. Tregear ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Cardiac Fibrosis ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Wild Type ◽  
Gene Profile ◽  
Aortic Constriction ◽  
Littermate Control ◽  
Lv Remodeling ◽  
Hypertrophic Myocardium

The effect of endogenous relaxin on the development of cardiac hypertrophy, dysfunction, and fibrosis remains completely unknown. We addressed this question by subjecting relaxin-1 deficient (Rln1−/−) and littermate control (Rln1+/+) mice of both genders to chronic transverse aortic constriction (TAC). The extent of left ventricular (LV) remodeling and dysfunction were studied by serial echocardiography over an 8-wk period and by micromanometry. The degree of hypertrophy was estimated by LV weight, cardiomyocyte size, and expression of relevant genes. Cardiac fibrosis was determined by hydroxyproline assay and quantitative histology. Expression of endogenous relaxin during the course of TAC was also examined. In response to an 8-wk period of pressure overload, TAC mice of both genotypes developed significant LV hypertrophy, fibrosis, hypertrophy related gene profile, and signs indicating congestive heart failure when compared with respective sham controls. The severity of these alterations was not statistically different between the two genotypes of either gender. Relaxin mRNA expression was up-regulated, whereas that of its receptor was unchanged in the hypertrophic myocardium of wild-type mice. Collectively, the extent of pressure overload-induced LV hypertrophy, fibrosis, and dysfunction were comparable between Rln1+/+ and Rln1−/− mice. Thus, although up-regulated in its expression, endogenous relaxin had no significant effect on the progression of cardiac maladaptation and dysfunction in the setting of chronic pressure overload.

Abstract 289: Retinoblastoma Gene Deletion Promotes Cardiac Dysfunction, Fibrosis and Apoptosis in Response to Pressure Overload

2014 ◽  
Vol 115 (suppl_1) ◽  
Author(s):  
Paul B Ammann ◽  
Takanobu Yamamoto ◽  
Peiyong Zhai ◽  
Junichi Sadoshima
Keyword(s):  
Cardiac Hypertrophy ◽  
Cardiac Dysfunction ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Heart Weight ◽  
Tunel Staining ◽  
Pressure Gradients ◽  
Lung Weight ◽  
Rb Protein

The retinoblastoma (Rb) protein is a universal cell cycle regulator in mammals. When the Rb protein is phosphorylated by Cyclins/Cdks, it dissociates from E2F, and Rb-dependent E2F repression is subsequently inactivated. Furthermore, the Rb protein has also been implicated in the regulation of cardiac hypertrophy and apoptosis in cardiomyocytes (CMs). To elucidate the role of Rb in response to mechanical stress, we conducted transverse aortic constriction (TAC) in cardiac-specific Rb knockout mice (cRb-KO) in vivo (C57BL/6J). Cardiac-specific deletion of Rb was achieved by crossing Rb flox/flox mice with αMHC-Cre mice. Under basal conditions, 3- to 5-month-old cRb-KO mice showed increased heart weight (HW) (left ventricular weight/ tibial length (TL): 5.93 ± 029 vs. 4.76 ± 0.14, p< 0.01), increased apoptosis as determined by TUNEL staining (0.12% vs. 0.02%, p< 0.05) and a trend towards cardiac dysfunction (-dP/dt: 4320 ± 388 vs. 5933 ± 489 mmHg/sec, p < 0.05) compared to control mice (Rb flox/flox) Following 2 weeks of TAC, cRb-KO mice showed increased heart weight (HW/TL: 8.58 ± 0.35 vs. 7.50 ± 0.24, p < 0.05), cardiac dysfunction (ejection fraction (EF): 51.1% ± 4.0 vs. 74.3% ± 0.9, p < 0.01) , increased apoptosis as determined by TUNEL staining (0.48% vs. 0.05%, p < 0.01) and increased fibrosis as determined by Masson’s Trichrome staining (1.84% vs. 1.03%, p < 0.05) compared to Rb flox/flox mice after TAC. In response to 4 weeks of TAC, cRb-KO mice showed increased heart weight (HW/TL: 12.93 ± 085 vs. 9.32 ± 0.34, p < 0.01), lung weight (LW) (LW/TL: 18.35 ± 2.66 vs. 10.21 ± 1.93, p < 0.01), cardiac dysfunction (EF: 34.5% ± 8.3 vs. 64.3% ± 8.9, p < 0.01), increased apoptosis as determined by TUNEL staining (0,42% vs. 0,18%, p < 0.05) and increased fibrosis as determined by Masson’s Trichrome staining (4.2 % vs. 1.1 %, p < 0.05) compared to Rb flox/flox mice after TAC. Pressure gradients were similar between the cRb-KO mice submitted to 2 and 4 weeks of TAC and their respective controls. In conclusion, our results suggest that endogenous Rb plays an important role in mediating cell survival in CMs and negatively regulates cardiac hypertrophy at baseline. Furthermore, we showed that the Rb protein is important for the maintenance of cardiac function in response to pressure overload.

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