Pressure overload-induced hypertrophy in transgenic mice selectively overexpressing AT2 receptors in ventricular myocytes

2008 ◽  
Vol 294 (3) ◽  
pp. H1274-H1281 ◽  
Author(s):  
Xinhua Yan ◽  
Adam J. T. Schuldt ◽  
Robert L. Price ◽  
Ivo Amende ◽  
Fen-Fen Liu ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Cardiac Hypertrophy ◽  
Ventricular Myocytes ◽  
Diastolic Pressure ◽  
Tyrosine Phosphatase ◽  
Systolic Pressure ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Lv Function ◽  
Aortic Banding

The role of the angiotensin II type 2 (AT2) receptor in cardiac hypertrophy remains controversial. We studied the effects of AT2 receptors on chronic pressure overload-induced cardiac hypertrophy in transgenic mice selectively overexpressing AT2 receptors in ventricular myocytes. Left ventricular (LV) hypertrophy was induced by ascending aorta banding (AS). Transgenic mice overexpressing AT2 (AT2TG-AS) and nontransgenic mice (NTG-AS) were studied after 70 days of aortic banding. Nonbanded NTG mice were used as controls. LV function was determined by catheterization via LV puncture and cardiac magnetic resonance imaging. LV myocyte diameter and interstitial collagen were determined by confocal microscopy. Atrial natriuretic polypeptide (ANP) and brain natriuretic peptide (BNP) were analyzed by Northern blot. Sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA)2, inducible nitric oxide synthase (iNOS), endothelial NOS, ERK1/2, p70S6K, Src-homology 2 domain-containing protein tyrosine phosphatase-1, and protein serine/threonine phosphatase 2A were analyzed by Western blot. LV myocyte diameter and collagen were significantly reduced in AT2TG-AS compared with NTG-AS mice. LV anterior and posterior wall thickness were not different between AT2TG-AS and NTG-AS mice. LV systolic and diastolic dimensions were significantly higher in AT2TG-AS than in NTG-AS mice. LV systolic pressure and end-diastolic pressure were lower in AT2TG-AS than in NTG-AS mice. ANP, BNP, and SERCA2 were not different between AT2TG-AS and NTG-AS mice. Phospholamban (PLB) and the PLB-to-SERCA2 ratio were significantly higher in AT2TG-AS than in NTG-AS mice. iNOS was higher in AT2TG-AS than in NTG-AS mice but not significantly different. Our results indicate that AT2 receptor overexpression modified the pathological hypertrophic response to aortic banding in transgenic mice.

Colchicine attenuates left ventricular hypertrophy but preserves cardiac function of aortic-constricted rats

2003 ◽  
Vol 94 (4) ◽  
pp. 1627-1633 ◽  
Author(s):  
Beatriz S. Scopacasa ◽  
Vicente P. A. Teixeira ◽  
Kleber G. Franchini
Keyword(s):  
Diastolic Pressure ◽  
Systolic Pressure ◽  
Pressure Overload ◽  
Colchicine Treatment ◽  
Average Diameter ◽  
Left Ventricular ◽  
Lv Function ◽  
Right Ventricular Mass ◽  
Lv Mass ◽  
Phenylephrine Infusion

To investigate the effects of colchicine on left ventricular (LV) function and hypertrophy (LVH) of rats subjected to constriction of transverse aorta (TAoC), we evaluated SO (sham operated, vehicle; n = 25), SO-T (sham operated, colchicine 0.4 mg/kg body wt ip daily; n = 38), TAoC (vehicle; n = 37), and TAoC-T (TAoC, colchicine; n = 34) on the 2nd, 6th, and 15th day after surgery. Colchicine attenuated LVH of TAoC-T compared with TAoC rats, as evaluated by ratio between LV mass (LVM) and right ventricular mass, LV wall thickness, and average diameter of cardiac myocytes. Systolic gradient across TAoC (∼45 mmHg), LV systolic pressure, LV end-diastolic pressure, and rate of LV pressure increase (+dP/d t) were comparable in TAoC-T and TAoC rats. However, the baseline and increases of LV systolic pressure-to-LVM and +dP/d t-to-LVMratios induced by phenylephrine infusion were greater in TAoC-T and SO-T compared with SO rats. Baseline and increases of +dP/d t-to-LVM ratio were reduced in TAoC compared with SO rats. TAoC rats increased polymerized fraction of tubulin compared with SO, SO-T, and TAoC-T rats. Our results indicate that colchicine treatment reduced LVH to pressure overload but preserved LV function.

Abstract 17904: Deficiency of Yes-associated Protein Promotes Cardiac Dysfunction in Response to Pressure Overload in the Mouse Heart

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Jaemin Byun ◽  
Dominic P Del Re ◽  
Peiyong Zhai ◽  
Akihiro Shirakabe ◽  
Junichi Sadoshima
Keyword(s):  
Cardiac Hypertrophy ◽  
Mammalian Cells ◽  
Diastolic Pressure ◽  
Systolic Function ◽  
Pressure Overload ◽  
Wall Stress ◽  
Left Ventricular ◽  
Lv Function ◽  
Mouse Heart ◽  
And Control

Yes-Associated Protein (YAP), a downstream effector of the Hippo pathway, plays an important role in regulating cell proliferation and survival in mammalian cells. We have shown that cardiac-specific loss of YAP leads to increased cardiomyocyte (CM) apoptosis and impaired hypertrophy during chronic myocardial infarction in the mouse heart. However, it remains unclear whether YAP mediates hypertrophy of individual CMs under stress conditions in vivo. We hypothesized that endogenous YAP plays an essential role in mediating hypertrophy and survival of CMs in response to pressure overload (PO). Three-month-old YAP+/fl;α-MHC-Cre (YAP-cKO) and YAP+/fl (control) mice were subjected to transverse aortic constriction (TAC). Two weeks later, YAP-cKO and control mice developed similar levels of cardiac hypertrophy (left ventricular (LV) weight/tibia length: 7.27±0.38, 6.93±0.29) compared to sham (5.08±0.14, 4.07±0.33). LV CM cross sectional area was similarly increased by TAC in YAP-cKO and control mice compared to their respective shams. Induction of fetal-type genes, such as Anf and Myh7, was also similar in YAP-cKO and control mice. YAP-cKO and control mice exhibited similar baseline LV systolic function (ejection fraction (EF): 75, 76%). YAP-cKO mice had significantly decreased LV function after TAC compared to Sham-control mice (EF: 51%, 76%, p<0.05) and TAC-control mice (75%, p<0.05). LV end diastolic pressure (LVEDP, mmHg) was significantly increased (19.3 ±3.2, 9.8±1.6, p<0.05), and LV +dP/dt (mmHg/s, 7250±588, 9500±453, p<0.01) and -dP/dt (mmHg/s, 6000±433, 7781± 314, p<0.05) were significantly decreased in YAP-cKO compared to in control mice after TAC. LV end diastolic diameter (mm) was significantly greater in YAP-cKO than in control mice after TAC (3.95±0.11, 3.35±0.15, p<0.05), whereas LV pressure was similar, suggesting that LV wall stress was elevated in YAP-cKO compared to in control mice. Since cardiac hypertrophy in YAP-cKO mice is similar to that in control mice despite elevated wall stress, the lack of YAP appears to limit the extent of cardiac hypertrophy in response to increased wall stress. These data suggest that endogenous YAP plays an important role in mediating adaptive hypertrophy and protecting the heart against PO.

GH-releasing peptides improve cardiac dysfunction and cachexia and suppress stress-related hormones and cardiomyocyte apoptosis in rats with heart failure

2005 ◽  
Vol 289 (4) ◽  
pp. H1643-H1651 ◽  
Author(s):  
Xiang-Bin Xu ◽  
Jin-Jiang Pang ◽  
Ji-Min Cao ◽  
Chao Ni ◽  
Rong-Kun Xu ◽  
...  
Keyword(s):  
Heart Failure ◽  
Diastolic Pressure ◽  
Systolic Pressure ◽  
Pressure Overload ◽  
Chronic Administration ◽  
Posterior Wall ◽  
Left Ventricular ◽  
Cardiomyocyte Apoptosis ◽  
Lv Function ◽  
Cardiac Cachexia

Growth hormone (GH)-releasing peptides (GHRP), a class of synthetic peptidyl GH secretagogues, have been reported to exert a cardioprotective effect on cardiac ischemia. However, whether GHRP have a beneficial effect on chronic heart failure (CHF) is unclear, and the present work aims to clarify this issue. At 9 wk after pressure-overload CHF was created by abdominal aortic banding in rats, one of four variants of GHRP (GHRP-1, -2, and -6 and hexarelin, 100 μg/kg) or saline was injected subcutaneously twice a day for 3 wk. Echocardiography and cardiac catheterization were performed to monitor cardiac function and obtain blood samples for hormone assay. GHRP treatment significantly improved left ventricular (LV) function and remodeling in CHF rats, as indicated by increased LV ejection fraction, LV end-systolic pressure, and diastolic posterior wall thickness and decreased LV end-diastolic pressure and LV end-diastolic dimension. GHRP also significantly alleviated development of cardiac cachexia, as shown by increases in body weight and tibial length in CHF rats. Plasma CA, renin, ANG II, aldosterone, endothelin-1, and atrial natriuretic peptide were significantly elevated in CHF rats but were significantly decreased in GHRP-treated CHF rats. GHRP suppressed cardiomyocyte apoptosis and increased cardiac GH secretagogue receptor mRNA expression in CHF rats. GHRP also decreased myocardial creatine kinase release in hypophysectomized rats subjected to acute myocardial ischemia. We conclude that chronic administration of GHRP alleviates LV dysfunction, pathological remodeling, and cardiac cachexia in CHF rats, at least in part by suppressing stress-induced neurohormonal activations and cardiomyocyte apoptosis.

Abstract 1226: Augmentation Of Cardiac Function In Response To Pressure Overload In Transgenic Mice With A Cardiac-Specific Expression Of Adenylyl Cyclase Type 2

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Che-Lin Hu ◽  
Shumin Gao ◽  
Chull Hong ◽  
Huasheng Liu ◽  
Yimin Tian ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Adenylyl Cyclase ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Pathological Examination ◽  
Lv Function ◽  
Aortic Banding ◽  
Specific Expression ◽  
Ventricular Ejection Fraction

The results from studies examining the effects of transgenic (TG) mice with overexpression of the major adenylyl cyclase (AC) isoforms in the heart, AC5 and 6, has been controversial. Accordingly, we examined the effects of a non-calcium regulated AC isoform, AC2, by overexpressing it in the heart. This resulted in a 3 fold increase in overall cardiac AC activity. Baseline left ventricular ejection fraction (LVEF), measured by echocardiography, was higher (P<0.05) in TG mice when compared to WT (75±1% vs 72±1%) while heart rate was similar (P<0.05). The extent of increased LVEF stimulated by isoproterenol (ISO) was also higher in TG suggesting an increase in functional response of beta-AR signaling in these transgenic mice. Aortic banding for 1 wk induced significantly greater (P<0.05) LV hypertrophy in TG compared to WT as indicated by LV weight (LVW)/tibial length (TL) ratio (7.1±0.4 vs 6.0±0.3 mg/mm, P<0.05). Aortic banding resulted in no change of LVEF in the AC2TG (76±3%) or in WT (70±3%), i.e., LV function was maintained. Pathological examination of the 1wk banded hearts demonstrated fewer TUNEL positive myocytes in the AC2TG (0.16±0.08 cells/microm2) vs WT (1.00±0013 cell/microm2) (P<0.05). Cross-sectional myocyte area in AC2TG was also larger (316±16microm2) than WT (289±20microm2) which confirmed the increased in LV/TL. Thus, a moderate level of AC2 overexpression in the heart increases the amount of cardiac hypertrophy, in response to pressure overload, but exerts a beneficial effect on apoptosis and LV function.

Minimally invasive aortic banding in mice: effects of altered cardiomyocyte insulin signaling during pressure overload

2003 ◽  
Vol 285 (3) ◽  
pp. H1261-H1269 ◽  
Author(s):  
Ping Hu ◽  
Dongfang Zhang ◽  
LeAnne Swenson ◽  
Gopa Chakrabarti ◽  
E. Dale Abel ◽  
...  
Keyword(s):  
Minimally Invasive ◽  
Insulin Signaling ◽  
Systolic Pressure ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Tissue Growth ◽  
Cardiac Response ◽  
Heart Weight ◽  
Surgical Morbidity ◽  
Aortic Banding

We developed a minimally invasive method for producing left ventricular (LV) pressure overload in mice. With the use of this technique, we quickly and reproducibly banded the transverse aorta with low surgical morbidity and mortality. Minimally invasive transverse aortic banding (MTAB) acutely and chronically increased LV systolic pressure, increased heart weight-to-body weight ratio, and induced myocardial fibrosis. We used this technique to determine whether reduced insulin signaling in the heart altered the cardiac response to pressure overload. Mice with cardiac myocyte-restricted knockout of the insulin receptor (CIRKO) have smaller hearts than wild-type (WT) controls. Four weeks after MTAB, WT and CIRKO mice had comparably increased LV systolic pressure, increased cardiac mass, and induction of mRNA for β-myosin heavy chain and atrial natriuretic factor. However, CIRKO hearts were more dilated, had depressed LV systolic function by echocardiography, and had greater interstitial fibrosis than WT mice. Expression of connective tissue growth factor was increased in banded CIRKO hearts compared with WT hearts. Thus lack of insulin signaling in the heart accelerates the transition to a more decompensated state during cardiac pressure overload. The use of the MTAB approach should facilitate the study of the pathophysiology and treatment of pressure-overload hypertrophy.

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.

scholarly journals TANK Promotes Pressure Overload Induced Cardiac Hypertrophy via Activating AKT Signaling Pathway

2021 ◽  
Vol 8 ◽  
Author(s):  
Yanan Pang ◽  
Minglu Ma ◽  
Dong Wang ◽  
Xun Li ◽  
Li Jiang
Keyword(s):  
Transgenic Mice ◽  
Cardiac Hypertrophy ◽  
Knockout Mice ◽  
Pressure Overload ◽  
Akt Signaling ◽  
Control Group ◽  
Akt Inhibitor ◽  
Aortic Banding ◽  
Pathological Cardiac Hypertrophy

Background: TANK (TRAF family member associated NF-κB activator) acts as a member of scaffold proteins participated in the development of multiple diseases. However, its function in process of cardiac hypertrophy is still unknown.Methods and Results: In this study, we observed an increased expression of TANK in murine hypertrophic hearts after aortic banding, suggesting that TANK may be involved in the pathogenesis of cardiac hypertrophy. We generated cardiac-specific TANK knockout mice, and subsequently subjected to aortic banding for 4–8 weeks. TANK knockout mice showed attenuated cardiac hypertrophy and dysfunction compared to the control group. In contrast, cardiac-specific TANK transgenic mice showed opposite signs. Consistently, in vitro experiments revealed that TANK knockdown decreased the cell size and expression of hypertrophic markers. Mechanistically, AKT signaling was inhibited in TANK knockout mice, but activated in TANK transgenic mice after aortic banding. Blocking AKT signaling with a pharmacological AKT inhibitor alleviated the cardiac hypertrophy and dysfunction in TANK transgenic mice.Conclusions: Collectively, we identified TANK accelerates the progression of pathological cardiac hypertrophy and is a potential therapeutic target.

Temporal sequence of endotoxin-induced systolic and diastolic myocardial depression in rabbits

1993 ◽  
Vol 265 (3) ◽  
pp. H810-H819 ◽  
Author(s):  
J. Hung ◽  
W. Y. Lew
Keyword(s):  
Time Course ◽  
Diastolic Pressure ◽  
Systolic Pressure ◽  
Progressive Increase ◽  
Left Ventricular ◽  
Temporal Sequence ◽  
Lv Function ◽  
Myocardial Depression ◽  
Systolic Volume ◽  
End Systolic Volume

Twelve anesthetized rabbits received endotoxin (175 +/- 38 micrograms/kg i.v., mean +/- SD) to evaluate the temporal sequence of alterations in left ventricular (LV) function. LV volume was calculated from LV minor- and long-axis diameters, and wall thickness was measured with sonomicrometers. Hypotension, acidosis, and hypoxia were immediately corrected to eliminate these causes of myocardial depression. LV dilation developed early (1.2 +/- 0.5 h) with a significant (21 +/- 23%) increase in end-diastolic volume measured at a LV end-diastolic pressure of 5 +/- 6 mmHg. The LV stiffness did not change, and the LV dilation did not progressively worsen. Significant systolic depression developed later (2.8 +/- 1.0 h) with a 32 +/- 22% increase in end-systolic volume measured at a LV end-systolic pressure of 69 +/- 9 mmHg. The late preterminal phase (4.1 +/- 0.8 h) was characterized by a progressive increase in end-systolic volume (73 +/- 41% above control) and a significant (53 +/- 34%) increase in tau, the time constant of LV pressure fall. Diastolic abnormalities (LV dilation and increased tau) were not attributable to depressed contractility or altered hemodynamics. We conclude that endotoxin impairs systolic and diastolic LV function with distinct differences in time course. This suggests that contractility, relaxation, and passive LV properties are impaired by different endotoxin-mediated pathways and/or have different sensitivities to endotoxin.

Reversible effects of isoproterenol-induced hypertrophy on in situ left ventricular function in rat hearts

2004 ◽  
Vol 287 (1) ◽  
pp. H277-H285 ◽  
Author(s):  
Yutaka Kitagawa ◽  
Daisuke Yamashita ◽  
Haruo Ito ◽  
Miyako Takaki
Keyword(s):  
Cardiac Hypertrophy ◽  
Systolic Pressure ◽  
Left Ventricular ◽  
Lv Function ◽  
Osmotic Minipump ◽  
Good Index ◽  
Rat Hearts ◽  
Lv Volume ◽  
Work Capability

The aim of the present study was to evaluate specifically left ventricular (LV) function in rat hearts as they transition from the normal to hypertrophic state and back to normal. Either isoproterenol (1.2 and 2.4 mg·kg−1·day−1 for 3 days; Iso group) or vehicle (saline 24 μl·day−1 for 3 days; Sa group) was infused by subcutaneous implantation of an osmotic minipump. After verifying the development of cardiac hypertrophy, we recorded continuous LV pressure-volume (P-V) loops of in situ ejecting hypertrophied rat hearts. The curved LV end-systolic P-V relation (ESPVR) and systolic P-V area (PVA) were obtained from a series of LV P-V loops in the Sa and Iso groups 1 h or 2 days after the removal of the osmotic minipump. PVA at midrange LV volume (PVAmLVV) was taken as a good index for LV work capability ( 13 , 15 , 20 , 21 ). However, in rat hearts during remodeling, whether PVAmLVV is a good index for LV work capability has not been determined yet. In the present study, in contrast to unchanged end-systolic pressure at midrange LV volume, PVAmLVV was significantly decreased by isoproterenol treatment relative to saline; however, these measurements were the same 2 days after pump removal. Simultaneous treatment with a β1-blocker, metoprolol (24 mg·kg−1·day−1), blocked the formation of cardiac hypertrophy and thus PVAmLVV did not decrease. The reversible changes in PVAmLVV reflect precisely the changes in LV work capability in isoproterenol-induced hypertrophied rat hearts mediated by β1-receptors. These results indicate that the present approach may be an appropriate strategy for evaluating the effects of antihypertrophic and antifibrotic modalities.

Abstract 88: Cardiac-specific Deletion of Protein Tyrosine Phosphatase 1B Exacerbates Pressure Overload-induced Hypertrophy and Heart Failure in Mice

2016 ◽  
Vol 119 (suppl_1) ◽  
Author(s):  
Gerald Coulis ◽  
Alexandre Bergeron ◽  
Yanfen Shi ◽  
David Labbe ◽  
Michel Tremblay ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Hypertrophy ◽  
Cardiac Function ◽  
Tyrosine Phosphatase ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Compensatory Hypertrophy ◽  
Mrna Levels ◽  
Compensatory Response ◽  
Left Ventricular Dilation

Cardiac hypertrophy involves the re-expression of a foetal gene program that occurs when cardiomyocytes are continuously exposed to stresses. The enlargement initially improves cardiac function, however, this compensatory hypertrophy predisposes individuals to arrhythmias, pathological hypertrophy and heart failure. Given the importance of reactive oxygen species (ROS) in the transition from cardiac hypertrophy to heart failure and the documented inhibition of PTPs by ROS, we hypothesized and explored whether specific PTPs could act as checkpoints in this process. We have identified PTP1B as a target of ROS in hearts undergoing hypertrophy. To better understand the role of PTP1B inhibition in cardiac hypertrophy, we generated cardiomyocyte-specific PTP1B knockout (PTP1B cKO) mice. Subjecting PTP1B cKO mice to pressure overload (PO) caused a dramatic left ventricular dilation and several distinctive features of heart failure when compared to control mice subjected to PO for the same period. Characterization of the mRNAs expressed in the hypertrophy-associated foetal gene program revealed that although PO led to increased mRNA levels of ANF and BNP, the increased expression of β-MHC observed in control mice subjected to PO was compromised in PTP1B cKO-PO mice. Since PTP1B inactivation can lead to the inactivation of AGO2 and compromise miRNA-mediated mRNAs repression, we investigated whether PTP1B regulated AGO2 phosphorylation and association with mRNAs in this context. We observed that AGO2 phosphotyrosine-393 levels were elevated and that AGO2 was a substrate of PTP1B in myocytes and in hearts undergoing hypertrophy. We also found changes in AGO2-mRNA associations between control- and PTP1B cKO-PO hearts and identified MED13 as a regulator of β-MHC expression that was differentially regulated by AGO2 in PTP1B cKO-PO hearts. Since increased expression of β-MHC contributes to the compensatory response that initially improves cardiac function, we will propose a model in which PTP1B inhibition regulates AGO2 activity and contributes to heart failure.

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