scholarly journals O-ring-induced transverse aortic constriction (OTAC) is a new simple method to develop cardiac hypertrophy and heart failure in mice

2022 ◽  
Vol 12 (1) ◽  
Author(s):  
Yasuhisa Nakao ◽  
Jun Aono ◽  
Mika Hamaguchi ◽  
Kayo Takahashi ◽  
Tomohisa Sakaue ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Hypertrophy ◽  
Pressure Overload ◽  
Experimental Models ◽  
Left Ventricular ◽  
Transverse Aortic Constriction ◽  
Aortic Constriction ◽  
Lung Weight ◽  
Simple Method ◽  
Fractional Shortening

AbstractSuture-based transverse aortic constriction (TAC) in mice is one of the most frequently used experimental models for cardiac pressure overload-induced heart failure. However, the incidence of heart failure in the conventional TAC depends on the operator’s skill. To optimize and simplify this method, we proposed O-ring-induced transverse aortic constriction (OTAC) in mice. C57BL/6J mice were subjected to OTAC, in which an o-ring was applied to the transverse aorta (between the brachiocephalic artery and the left common carotid artery) and tied with a triple knot. We used different inner diameters of o-rings were 0.50 and 0.45 mm. Pressure overload by OTAC promoted left ventricular (LV) hypertrophy. OTAC also increased lung weight, indicating severe pulmonary congestion. Echocardiographic findings revealed that both OTAC groups developed LV hypertrophy within one week after the procedure and gradually reduced LV fractional shortening. In addition, significant elevations in gene expression related to heart failure, LV hypertrophy, and LV fibrosis were observed in the LV of OTAC mice. We demonstrated the OTAC method, which is a simple and effective cardiac pressure overload method in mice. This method will efficiently help us understand heart failure (HF) mechanisms with reduced LV ejection fraction (HFrEF) and cardiac hypertrophy.

scholarly journals CX3CR1 is a prerequisite for the development of cardiac hypertrophy and left ventricular dysfunction in mice upon transverse aortic constriction

PLoS ONE ◽  
2021 ◽  
Vol 16 (1) ◽  
pp. e0243788
Author(s):  
Christina Katharina Weisheit ◽  
Jan Lukas Kleiner ◽  
Maria Belen Rodrigo ◽  
Sven Thomas Niepmann ◽  
Sebastian Zimmer ◽  
...  
Keyword(s):  
Heart Failure ◽  
Immune Response ◽  
Cardiac Hypertrophy ◽  
Left Ventricular Dysfunction ◽  
Ventricular Dysfunction ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Transverse Aortic Constriction ◽  
Aortic Constriction ◽  
Deficient Mice

The CX3CL1/CX3CR1 axis mediates recruitment and extravasation of CX3CR1-expressing subsets of leukocytes and plays a pivotal role in the inflammation-driven pathology of cardiovascular disease. The cardiac immune response differs depending on the underlying causes. This suggests that for the development of successful immunomodulatory therapy in heart failure due to chronic pressure overload induced left ventricular (LV) hypertrophy, the underlying immune patterns must be examined. Here, the authors demonstrate that Fraktalkine-receptor CX3CR1 is a prerequisite for the development of cardiac hypertrophy and left ventricular dysfunction in a mouse model of transverse aortic constriction (TAC). The comparison of C57BL/6 mice with CX3CR1 deficient mice displayed reduced LV hypertrophy and preserved cardiac function in response to pressure overload in mice lacking CX3CR1. Moreover, the normal immune response following TAC induced pressure overload which is dominated by Ly6Clow macrophages changed to an early pro-inflammatory immune response driven by neutrophils, Ly6Chigh macrophages and altered cytokine expression pattern in CX3CR1 deficient mice. In this early inflammatory phase of LV hypertrophy Ly6Chigh monocytes infiltrated the heart in response to a C-C chemokine ligand 2 burst. CX3CR1 expression impacts the immune response in the development of LV hypertrophy and its absence has clear cardioprotective effects. Hence, suppression of CX3CR1 may be an important immunomodulatory therapeutic target to ameliorate pressure-overload induced heart failure.

Minoxidil accelerates heart failure development in rats with ascending aortic constriction

1998 ◽  
Vol 76 (6) ◽  
pp. 613-620 ◽  
Author(s):  
Marian Turcani ◽  
Ruthard Jacob
Keyword(s):  
Heart Failure ◽  
Myocardial Contractility ◽  
Pressure Overload ◽  
Volume Overload ◽  
Left Ventricular Pressure ◽  
Left Ventricular ◽  
Aortic Constriction ◽  
Lung Weight ◽  
Eccentric Hypertrophy ◽  
Hemodynamic Overload

To test the ability of the heart to express characteristic geometric features of concentric and eccentric hypertrophy concurrently, constriction of the ascending aorta was performed in 4-week-old rats. Simultaneously, these rats were treated with an arteriolar dilator minoxidil. An examination 6 weeks after induction of the hemodynamic overload revealed no signs of congestion in systemic or pulmonary circulation in rats with aortic constriction or minoxidil-treated sham-operated rats. The magnitude of hemodynamic overload caused by aortic constriction or minoxidil treatment could be considered as equivalent, because the same enlargement of left ventricular pressure-volume area was necessary to compensate for either pressure or volume overload. Myocardial contractility decreased in rats with aortic constriction, and the compensation was achieved wholly by the marked concentric hypertrophy. Volume overload in minoxidil-treated rats was compensated partially by the eccentric hypertrophy and partially by the increased myocardial contractility. In contrast, increased lung weight and pleural effusion were found in all minoxidil-treated rats with aortic constriction. Unfavorable changes in left ventricular mass and geometry, relatively high chamber stiffness, and depressed ventricular and myocardial function were responsible for the massive pulmonary congestion.Key words: cardiac hypertrophy, heart failure, pressure overload, volume overload, minoxidil.

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.

scholarly journals Inhibition of Uncoupling Protein 2 Attenuates Cardiac Hypertrophy Induced by Transverse Aortic Constriction in Mice

2015 ◽  
Vol 36 (5) ◽  
pp. 1688-1698 ◽  
Author(s):  
Xiao-Bing Ji ◽  
Xiu-Rong Li ◽  
Hao-Ding ◽  
Qi Sun ◽  
Yang Zhou ◽  
...  
Keyword(s):  
Energy Metabolism ◽  
Cardiac Hypertrophy ◽  
Uncoupling Protein ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Uncoupling Protein 2 ◽  
Transverse Aortic Constriction ◽  
Aortic Constriction ◽  
Atp Concentration ◽  
Ucp2 Expression

Background: Uncoupling protein 2 (UCP2) is critical in regulating energy metabolism. Due to the significant change in energy metabolism of myocardium upon pressure overload, we hypothesize that UCP2 could contribute to the etiology of cardiac hypertrophy. Methods: Adult male C57BL/6J mice were subjected to pressure overload by using transverse aortic constriction (TAC), and then received genipin (a UCP2 selective inhibitor; 25 mg/kg/d, ip) or vehicle for three weeks prior to histologic assessment of myocardial hypertrophy. ATP concentration, ROS level, and myocardial apoptosis were also examined. A parallel set of experiments was also conducted in UCP2-/- mice. Results: TAC induced left ventricular hypertrophy, as reflected by increased ventricular weight/thickness and increased size of myocardial cell (vs. sham controls). ATP concentration was decreased; ROS level was increased. Apoptosis and fibrosis markers were increased. TAC increased mitochondrial UCP2 expression in the myocardium at both mRNA and protein levels. Genipin treatment attenuated cardiac hypertrophy and the histologic/biochemical changes described above. Hypertrophy and associated changes induced by TAC in UCP2-/- mice were much less pronounced than in WT mice. Conclusions: Blocking UCP2 expression attenuates cardiac hypertrophy induced by pressure overload.

scholarly journals Pressure Overload by Transverse Aortic Constriction Induces Maladaptive Hypertrophy in a Titin-Truncated Mouse Model

2015 ◽  
Vol 2015 ◽  
pp. 1-6 ◽  
Author(s):  
Qifeng Zhou ◽  
Scott Kesteven ◽  
Jianxin Wu ◽  
Parwez Aidery ◽  
Meinrad Gawaz ◽  
...  
Keyword(s):  
Heart Failure ◽  
Mouse Model ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Transverse Aortic Constriction ◽  
Aortic Constriction ◽  
Ventricular Ejection Fraction ◽  
Human Phenotype ◽  
Large Pedigree

Mutations in the giant sarcomeric protein titin (TTN) are a major cause for inherited forms of dilated cardiomyopathy (DCM). We have previously developed a mouse model that imitates a TTN truncation mutation we found in a large pedigree with DCM. While heterozygousTtnknock-in mice do not display signs of heart failure under sedentary conditions, they recapitulate the human phenotype when exposed to the pharmacological stressor angiotensin II or isoproterenol. In this study we investigated the effects of pressure overload by transverse aortic constriction (TAC) in heterozygous (Het)Ttnknock-in mice. Two weeks after TAC, Het mice developed marked impairment of left ventricular ejection fraction(p<0.05), while wild-type (WT) TAC mice did not. Het mice also trended toward increased ventricular end diastolic pressure and volume compared to WT littermates. We found an increase in histologically diffuse cardiac fibrosis in Het compared to WT in TAC mice. This study shows that a pattern of DCM can be induced by TAC-mediated pressure overload in a TTN-truncated mouse model. This model enlarges our arsenal of cardiac disease models, adding a valuable tool to understand cardiac pathophysiological remodeling processes and to develop therapeutic approaches to combat heart failure.

Abstract 17583: Autophagy Protects the Heart Against Pressure Overload Induced Heart Failure

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Akihiro Shirakabe ◽  
Yoshiyuki Ikeda ◽  
Peiyong Zai ◽  
Toshiro Saito ◽  
Junichi Sadoshima
Keyword(s):  
Heart Failure ◽  
Cardiac Dysfunction ◽  
Sham Group ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Autophagic Flux ◽  
Aortic Constriction ◽  
Double Positive ◽  
Lung Weight ◽  
Transient Activation

Autophagy is an important mechanism for the degradation of cytosolic proteins and organelles. We investigated how autophagy is regulated in the heart in response to pressure overload (PO). Mice were subjected to transverse aortic constriction (TAC) for multiple durations ranging from 1 hour to 30 days. Left ventricular (LV) weight/tibial length (TL) was significantly elevated at Day 5 (6.21 ± 0.10 vs 4.59 ± 0.10, p<0.05) and thereafter. Ejection fraction (EF) was maintained at Day 7 (82.1±3.4 vs 78.4±3.2%), but gradually decreased thereafter (at Day 30, 51.0±4.5, p<0.05). The level of LC3II increased rapidly, peaking at 3 hours (2.4 fold, p<0.05), returned to normal by 24 hours, and then was significantly decreased at Day 5 (-40.0%, p<0.05) and thereafter. Autophagic flux was evaluated with tandem fluorescent LC3. At 6 hours, both GFP/RFP double positive (yellow) dots and RFP dots were significantly increased in the TAC group compared to the sham group, with or without chloroquine (CQ) (yellow 12±2 vs 4±0 CQ(-), 23±3 vs 9±1 CQ(+); RFP 13±2 vs 5±1 CQ(-), 19±1 vs 13±1 CQ(+)). However, both yellow and RFP dots were significantly decreased at Day 7 and thereafter in the TAC group compared to the sham group, with or without CQ. These data suggest that autophagic flux is activated only transiently after TAC, but is inactivated after Day 5. To examine the functional significance of autophagy during PO, beclin1 heterozygous knockout (beclin1-hetKO) mice, atg7 cardiac-specific knockout (Atg7-CKO) mice, and cardiac-specific U6-shRNA beclin1 (U6shRNAbeclin1) mice were subjected to TAC. At Day 7 and 14 of TAC, decreases in EF (60.7 ± 4.8%, 53.8 ± 2.1% and 46.7 ± 5.9%, p<0.05) and increases in lung weight/TL (8.43 ± 0.87, 11.04 ± 4.16 and 18.76 ± 3.77, p<0.05) were exacerbated in beclin1-hetKO, atg7-CKO and U6shRNAbeclin1 mice compared to in control mice. These results suggest that, after transient activation during the initial 24 hours, PO inhibits autophagy below control levels after Day 5, which coincides with the development of cardiac dysfunction. Since heart failure is exacerbated by further suppression of autophagy, autophagy during PO protects the heart from cardiac dysfunction and PO-induced downregulation of autophagy exacerbates heart failure.

scholarly journals CRD-733, a Novel PDE9 (Phosphodiesterase 9) Inhibitor, Reverses Pressure Overload–Induced Heart Failure

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Daniel A. Richards ◽  
Mark J. Aronovitz ◽  
Peiwen Liu ◽  
Gregory L. Martin ◽  
Kelly Tam ◽  
...  
Keyword(s):  
Heart Failure ◽  
Pulmonary Edema ◽  
Left Atrial ◽  
Phosphorylation Site ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Guanosine Monophosphate ◽  
Transverse Aortic Constriction ◽  
Aortic Constriction ◽  
Cgmp Signaling

Background: Augmentation of NP (natriuretic peptide) receptor and cyclic guanosine monophosphate (cGMP) signaling has emerged as a therapeutic strategy in heart failure (HF). cGMP-specific PDE9 (phosphodiesterase 9) inhibition increases cGMP signaling and attenuates stress-induced hypertrophic heart disease in preclinical studies. A novel cGMP-specific PDE9 inhibitor, CRD-733, is currently being advanced in human clinical studies. Here, we explore the effects of chronic PDE9 inhibition with CRD-733 in the mouse transverse aortic constriction pressure overload HF model. Methods: Adult male C57BL/6J mice were subjected to transverse aortic constriction and developed significant left ventricular (LV) hypertrophy after 7 days ( P <0.001). Mice then received daily treatment with CRD-733 (600 mg/kg per day; n=10) or vehicle (n=17), alongside sham-operated controls (n=10). Results: CRD-733 treatment reversed existing LV hypertrophy compared with vehicle ( P <0.001), significantly improved LV ejection fraction ( P =0.009), and attenuated left atrial dilation ( P <0.001), as assessed by serial echocardiography. CRD-733 prevented elevations in LV end diastolic pressures ( P =0.037) compared with vehicle, while lung weights, a surrogate for pulmonary edema, were reduced to sham levels. Chronic CRD-733 treatment increased plasma cGMP levels compared with vehicle ( P <0.001), alongside increased phosphorylation of Ser 273 of cardiac myosin binding protein-C, a cGMP-dependent protein kinase I phosphorylation site. Conclusions: The PDE9 inhibitor, CRD-733, improves key hallmarks of HF including LV hypertrophy, LV dysfunction, left atrial dilation, and pulmonary edema after pressure overload in the mouse transverse aortic constriction HF model. Additionally, elevated plasma cGMP may be used as a biomarker of target engagement. These findings support future investigation into the therapeutic potential of CRD-733 in human HF.

scholarly journals Leonurine Attenuates Pressure-Overload Cardiac Hypertrophy Induced By Abdominal Aortic Constriction In Rats

2021 ◽  
Author(s):  
Ding Xiaoli ◽  
Yuan Qingqing ◽  
Qian Haibing
Keyword(s):  
Angiotensin Ii ◽  
Cardiac Hypertrophy ◽  
Pressure Overload ◽  
Ventricular Myocardium ◽  
Left Ventricular ◽  
Left Ventricular Myocardium ◽  
Ang Ii ◽  
Aortic Constriction ◽  
Qrt Pcr ◽  
Abdominal Aortic

Abstract Background: Myocardial hypertrophy occurs in many cardiovascular diseases. Leonurine (Leo) is commonly used for cardiovascular and cerebrovascular diseases. However, whether it can prevent cardiac hypertrophy is not known. The aim of this study was to investigate the effect and mechanism of Leonurine (Leo) against pressure-overload cardiac hypertrophy induced by abdominal aortic constriction (AAC) in rats. Methods: To answer this question, we prove it in the following way: Cardiac function was evaluated by hemodynamic; the left ventricle enlargement was measured by heart weight index (HWI) and left ventricular mass index (LVWI); myocardial tissue changes and myocardial cell diameter (MD) were determined by Hematoxylin and eosin (HE) staining; theβ-myosin heavy chain(β-MHC)and atrial natriuretic factor (ANF), which are recognized as a marker of cardiac hypertrophy, were determined by Real-time quantitative PCR (qRT-PCR), then another gene phospholipase C (PLC), inositol triphosphate (IP3), which associated with RAS were determined by Western blot(WB). angiotensin II (Ang II), angiotensin II type 1 receptor (AT1R) were determined by ELISA, WB and qRT-PCR methods. Finally, we measured the level of Ca2+ by microplate method and the protooncogene c-fos and c-myc mRNA in left ventricular myocardium by qRT-PCR.Results: Compare with control group, Leonurine can improve systolic dysfunction; inhibit the increase of left cardiac; inhibit myocardial cells were abnormally large and restrain the changes of cardiac histopathology; decrease the expression of β-MHC, ANF, Ang II, AT1R, c-fos and c-myc mRNA and the protein levels of PLC, IP3, AngII and AT1R in left ventricular myocardium, in addition, the content of Ca2+ also decrease. Conclusion: Therefore, Leonurine can inhibit cardiac hypertrophy induced by AAC and its effects may be associated with RAS.

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.

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