The ability of phosphodiesterase-5 inhibitors sildenafil and ordonafil to reverse L-NAME induced cardiac hypertrophy in the rabbit: possible role of calcineurin and p38

2012 ◽  
Vol 90 (9) ◽  
pp. 1247-1255 ◽  
Author(s):  
Asad Zeidan ◽  
Aiad Siam ◽  
Abdulaziz Al Kaabba ◽  
Mukhallad Mohammad ◽  
Said Khatib
Keyword(s):  
Cell Surface ◽  
Cardiac Hypertrophy ◽  
Surface Area ◽  
Left Ventricular ◽  
Neonatal Rat ◽  
Cell Surface Area ◽  
Control Value ◽  
Phosphodiesterase 5 Inhibitors ◽  
Phosphodiesterase 5 ◽  
Calcineurin Activity

Phosphodiesterase 5 inhibitors (PDE-5Is) can suppress and (or) reverse pressure overload induced myocardial hypertrophy. This study investigated the suppressive effect of 2 PDE-5Is (sildenafil and ordonafil) on N-nitro-l-arginine methyl ester (L-NAME)-induced cardiac hypertrophy in rabbit heart, and examined their possible mechanism of action. L-NAME increased left ventricular thickness to 6.1± 0.18 mm from 4.6 ± 0.13 mm (p < 0.05), which regressed after treatment with either sildenafil or ordonafil to 5.1 ± 0.1 mm and 4.8 ± 0.2 mm, respectively (p < 0.05). Phenylephrine increased neonatal rat ventricular myocyte cell surface area to 131% ± 3% of the control value, which was associated with significant increment in ERK1/2 to 143% ± 5% of the control value (p < 0.05). Ordonafil and sildenafil decreased cell surface area to 95% ± 3% and 90% ± 1% of the control value, respectively. Both drugs decreased ERK1/2 to 88% ± 4% of the control value. Calcineurin activity was significantly decreased after 1 h of treatment with 0.1 mg·L–1 ordonafil (1.15 ± 0.05, p < 0.05). For sildenafil (0.1 mg·L–1), calcineurin activity significantly decreased only after 24 h of incubation (22%). Also p38 activation was attenuated by ordonafil and sildenafil (0.1 mg·L–1). It is suggested that both drugs have the ability to reverse L-NAME-induced cardiac hypertrophy and suppress phenylphrine-induced myocyte hypertrophy, and that these effects may be mediated through the attenuation of calcineurin and its downstream signaling pathways (p38) in neonatal rat ventricular myocytes.

Abstract 143: Caveolae Regulate PI3K/Akt/RhoA-Mediated p38 MAPK Nuclear Translocation in Leptin-Induced Cardiomyocyte Hypertrophy

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Asad Zeidan ◽  
Sabzali Javadov ◽  
Subrata Chakrabarti ◽  
Morris Karmazyn
Keyword(s):  
Cell Surface ◽  
Cardiac Hypertrophy ◽  
Surface Area ◽  
P38 Mapk ◽  
Nuclear Translocation ◽  
Neonatal Rat ◽  
Cardiomyocyte Hypertrophy ◽  
Leucine Incorporation ◽  
Cell Surface Area ◽  
C3 Exoenzyme

Background : Obesity is associated with increased leptin production which may contribute to cardiac hypertrophy. However, the mechanism of leptin-induced cardiac hypertrophy remains incompletely understood. Previous studies have shown that the RhoA/ROCK/cofilin pathway and p38 MAPK but not ERK1/2 activation are major contributors to leptin-induced cardiac hypertrophy. In this study we explored the roles of caveolae and the PI3K/Akt pathway in regulating RhoA and p38 MAPK activation during leptin-induced cardiomyocyte hypertrophy. Methods and Results : Neonatal rat ventricular myocytes were cultured with 3.1 nmol/L leptin for 24 hours. Caveolae number and expression of caveolin-3 were significantly increased after leptin treatment (2 and 3 fold, respectively; p<0.01). These effects were associated with a 29% (p<0.05) increase in cell surface area and a 40% (p<0.05) increase in leucine incorporation, indicating cardiomyocyte hypertrophy. Disruption of cardiomyocyte caveolae with 5 mM methyl-beta-cyclodextrin (MβCD) significantly inhibited leptin-induced hypertrophy. RhoA was detected in caveolae fractions of a sucrose gradient after cardiomyocytes were treated with leptin for 5 min, demonstrating subcellular translocation of RhoA. Treatment with MβCD, 50 ng/ml C3 exoenzyme (a RhoA inhibitor) or 50 nM latrunculin B (actin filaments depolymerization agent) significantly attenuated leptin-induced RhoA translocation into caveolae fractions. Moreover, Western blot analysis showed that leptin-dependent activation of PI3K (116%; p<0.05), Akt (115%; p<0.05) and RhoA (330%; p<0.05) were significantly inhibited by 50 μM LY294002, a specific PI3K inhibitor. In addition, LY294002 significantly attenuated leptin-induced increases in cell surface area and in leucine incorporation. Furthermore, we found that leptin-induced activation of p38 (189%; p<0.05) and ERK1/2 (220%; p<0.05) was associated with p38 MAPK but not ERK1/2 nuclear translocation. MβCD, C3 exoenzyme and LY294002 potently attenuated leptin-induced p38 MAPK nuclear translocation. Conclusions : Our results demonstrate that caveolae, the PI3K/Akt/RhoA pathway and p38 MAPK nuclear translocation play a pivotal role in leptin-induced cardiomyocyte hypertrophy.

scholarly journals MiR-26a-5p inhibits GSK3β expression and promotes cardiac hypertrophy in vitro

PeerJ ◽  
2020 ◽  
Vol 8 ◽  
pp. e10371
Author(s):  
Liqun Tang ◽  
Jianhong Xie ◽  
Xiaoqin Yu ◽  
Yangyang Zheng
Keyword(s):  
Cell Surface ◽  
Cardiac Hypertrophy ◽  
Surface Area ◽  
Myocardial Cell ◽  
Immunofluorescence Staining ◽  
Cell Surface Area ◽  
Direct Target

Background The role of miR-26a-5p expression in cardiac hypertrophy remains unclear. Herein, the effect of miR-26a-5p on cardiac hypertrophy was investigated using phenylephrine (PE)-induced cardiac hypertrophy in vitro and in a rat model of hypertension-induced hypertrophy in vivo. Methods The PE-induced cardiac hypertrophy models in vitro and vivo were established. To investigate the effect of miR-26a-5p activation on autophagy, the protein expression of autophagosome marker (LC3) and p62 was detected by western blot analysis. To explore the effect of miR-26a-5p activation on cardiac hypertrophy, the relative mRNA expression of cardiac hypertrophy related mark GSK3β was detected by qRT-PCR in vitro and vivo. In addition, immunofluorescence staining was used to detect cardiac hypertrophy related mark α-actinin. The cell surface area was measured by immunofluorescence staining. The direct target relationship between miR-26a-5p and GSK3β was confirmed by dual luciferase report. Results MiR-26a-5p was highly expressed in PE-induced cardiac hypertrophy. MiR-26a-5p promoted LC3II and decreased p62 expression in PE-induced cardiac hypertrophy in the presence or absence of lysosomal inhibitor. Furthermore, miR-26a-5p significantly inhibited GSK3β expression in vitro and in vivo. Dual luciferase report results confirmed that miR-26a-5p could directly target GSK3β. GSK3β overexpression significantly reversed the expression of cardiac hypertrophy-related markers including ANP, ACTA1 and MYH7. Immunofluorescence staining results demonstrated that miR-26a-5p promoted cardiac hypertrophy related protein α-actinin expression, and increased cell surface area in vitro and in vivo. Conclusion Our study revealed that miR-26a-5p promotes myocardial cell autophagy activation and cardiac hypertrophy by regulating GSK3β, which needs further research.

Abstract 3770: Concentration-dependent Divergent Hypertrophic Effects of Estrogen in Adult Ventricular Myocytes

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Ana Kilic ◽  
Sabzali A Javadov ◽  
Morris Karmazyn
Keyword(s):  
Cell Surface ◽  
Surface Area ◽  
Ventricular Remodeling ◽  
Specific Inhibitor ◽  
Left Ventricular ◽  
Synthetic Analog ◽  
Gene Markers ◽  
Low Concentration ◽  
Cell Surface Area ◽  
High Concentrations

High concentrations of estrogen have been shown to attenuate myocardial hypertrophy and left ventricular remodeling. However, the effects of low concentration of estrogen observed in postmenopausal women on cardiac hypertrophy have not been studied. In the present study we examined the effects of high (0.1 and 1 nM) and low (1 and 10 pM) concentration of the synthetic analog of estradiol, 17β-estradiol (E2) on adult cardiomyocytes (CMs). CMs were isolated from adult male and female Sprague-Dawley rats. The cells were used immediately after isolation to measure pH i or cultured to assess hypertrophic phenotype (cell surface area), gene markers (atrial natriuretic peptide, ANP), and protein activation. Low concentration of E2 (1 and 10 pM) increased cell surface area (females: 20%, P <0.05; males: 28%, P <0.05) and ANP expression (females: 394%, P <0.05; males: 497%, P <0.05) after 24 h. However, high concentrations (0.1 and 1 nM) of E2 did not induce cell hypertrophy but instead blocked the hypertrophic effect of the α 1 -agonist phenylephrinerophy. The pro-hypertrophic effect of low concentration of E2 was prevented by the sodium-hydrogen exchange isoform 1 (NHE-1) specific inhibitor AVE-4890 (AVE, 5 μM) suggesting involvement of NHE-1 in mediating the E2-induced hypertrophy. Fluorometric measurements with the pH i -sensitive dye BCECF demonstrated that a 1 pM E2 increased the pH i (females: +0.05 pH units; males +0.12 pH units, P <0.05) by a rapid non-genomic mechanism that was blocked by AVE. On the other hand, 1 nM E2 decreased the pH i (females: −0.24 pH units, P <0.05; males: −0.07 pH units, P <0.05) and this effect was also prevented by AVE. The NHE-1-mediated pro-hypertrophic effect of 1 pM E2 was dependent on phosphorylation of ERK1/2 MAPK since the effect was blocked with the ERK1/2 inhibitor PD98059 (10 μM) and there was no gender difference on ERK1/2 activation. E2 has a dual concentration-dependent role in adult CMs as manifested by a pro-hypertrophic effect at low concentrations (1 and 10 pM), and conversely, an anti-hypertrophic effect at high concentrations (0.1 and 1 nM). The pro-hypertrophic effect of E2 is mediated, at least in part, through ERK1/2/NHE-1 activation.

Polydatin attenuates cardiac hypertrophy through modulation of cardiac Ca2+ handling and calcineurin-NFAT signaling pathway

2014 ◽  
Vol 307 (5) ◽  
pp. H792-H802 ◽  
Author(s):  
Wenwen Ding ◽  
Ming Dong ◽  
Jianxin Deng ◽  
Dewen Yan ◽  
Yun Liu ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Hypertrophy ◽  
Cardiac Function ◽  
Cardiac Contractility ◽  
Weight Ratio ◽  
Left Ventricular ◽  
Neonatal Rat ◽  
Therapeutic Effects ◽  
Calcineurin Activity ◽  
Calcineurin Pathway

Polydatin (PD), a resveratrol glucoside extracted from the perennial herbage Polygonum cuspidatum, has been suggested to have wide cardioprotective effects. This study aimed to explore the direct antihypertrophic role of PD in cultured neonatal rat ventricular myocytes (NRVMs) and its therapeutic effects against pressure overload (PO)-induced hypertrophic remodeling and heart failure. Furthermore, we investigated the mechanisms underlying the actions of PD. Treatment of NRVMs with phenylephrine for 72 h induced myocyte hypertrophy, where the cell surface area and protein levels of atrial natriuretic peptide and β-myosin heavy chain (β-MHC) were significantly increased. The amplitude of systolic Ca2+ transient was increased, and sarcoplasmic reticulum Ca2+ recycling was prolonged. Concomitantly, calcineurin activity was increased and NFAT protein was imported into the nucleus. PD treatment restored Ca2+ handling and inhibited calcineurin-NFAT signaling, thus attenuating the hypertrophic remodeling in NRVMs. PO-induced cardiac hypertrophy was produced by transverse aortic constriction (TAC) in C57BL/6 mice, where the left ventricular posterior wall thickness and heart-to-body weight ratio were significantly increased. The cardiac function was increased at 5 wk of TAC, but significantly decreased at 13 wk of TAC. The amplitude of Ca2+ transient and calcineurin activity were increased at 5 wk of TAC. PD treatment largely abolished TAC-induced hypertrophic remodeling by inhibiting the Ca2+-calcineurin pathway. Surprisingly, PD did not inhibit myocyte contractility despite that the amplitude of Ca2+ transient was decreased. The cardiac function remained intact at 13 wk of TAC. In conclusion, PD is beneficial against PO-induced cardiac hypertrophy and heart failure largely through inhibiting the Ca2+-calcineurin pathway without compromising cardiac contractility.

scholarly journals Role of protein kinase C-ε in hypertrophy of cultured neonatal rat ventricular myocytes

2001 ◽  
Vol 280 (2) ◽  
pp. H756-H766 ◽  
Author(s):  
James B. Strait ◽  
Jody L. Martin ◽  
Allison Bayer ◽  
Ruben Mestril ◽  
Diane M. Eble ◽  
...  
Keyword(s):  
Cell Surface ◽  
Surface Area ◽  
Total Protein ◽  
Ventricular Myocytes ◽  
Dominant Negative ◽  
Neonatal Rat ◽  
Protein Accumulation ◽  
Cell Surface Area ◽  
Kinase C ◽  
Neonatal Rat Ventricular Myocytes

Using adenovirus (Adv)-mediated overexpression of constitutively active (ca) and dominant-negative (dn) mutants, we examined whether protein kinase C (PKC)-ε, the major novel PKC isoenzyme expressed in the adult heart, was necessary and/or sufficient to induce specific aspects of the hypertrophic phenotype in low-density, neonatal rat ventricular myocytes (NRVM) in serum-free culture. Adv-caPKC-ε did not increase cell surface area or the total protein-to-DNA ratio. However, cell shape was markedly affected, as evidenced by a 67% increase in the cell length-to-width ratio and a 17% increase in the perimeter-to-area ratio. Adv-caPKC-ε also increased atrial natriuretic factor (ANF) and β-myosin heavy chain (MHC) mRNA levels 2.5 ± 0.3- and 2.1 ± 0.2-fold, respectively, compared with NRVM infected with an empty, parent vector ( P < 0.05 for both). Conversely, Adv-dnPKC-ε did not block endothelin-induced increases in cell surface area, the total protein-to-DNA ratio, or upregulation of β-MHC and ANF gene expression. However, the dominant-negative inhibitor markedly suppressed endothelin-induced extracellular signal-regulated kinase (ERK) 1/2 activation. Taken together, these results indicate that caPKC-ε overexpression alters cell geometry, producing cellular elongation and remodeling without a significant, overall increase in cell surface area or total protein accumulation. Furthermore, PKC-ε activation and downstream signaling via the ERK cascade may not be necessary for cell growth, protein accumulation, and gene expression changes induced by endothelin.

Oleanolic Acid, a Novel Endothelin A Receptor Antagonist, Alleviated High Glucose-Induced Cardiomyocytes Injury

2018 ◽  
Vol 46 (06) ◽  
pp. 1187-1201 ◽  
Author(s):  
Dewei Wu ◽  
Qiao Zhang ◽  
Yangyang Yu ◽  
Yuxin Zhang ◽  
Minyu Zhang ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Cell Surface ◽  
Surface Area ◽  
Oleanolic Acid ◽  
High Glucose ◽  
Neonatal Rat ◽  
Antagonistic Effects ◽  
Cell Surface Area ◽  
Endothelin A Receptor ◽  
Endothelin A

Endothelin-1 (ET-1) and its receptor endothelin A receptor (ET[Formula: see text] have been shown to be upregulated in a high glucose environment, which increase the incidence of diabetes-related heart failure. Our previous study demonstrated that oleanolic acid (OA), a natural compound found in Chinese herbs had ET-1 antagonistic effects. We aimed to verify whether OA could ameliorate diabetes mellitus (DM)-induced injury in cardiomyocytes by reducing the antagonistic effects of the ET-1 pathway. For the induction of high glucose-related injury in cardiomyocytes, neonatal rat ventricular cardiomyocytes (NRVMs) were subjected to culture medium containing 25[Formula: see text]mM of glucose. Natriuretic peptide B (BNP), mitochondrial membrane potential (MMP) and cell surface area were measured to evaluate the severity of NRVMs injury. mRNA expression of ET-1 and ETA was determined using quantitative PCR. Moreover, a Ca[Formula: see text] influx assay was used to evaluate potential ETA antagonistic effects. Molecular docking of OA and ETA was performed using the Sulflex-Dock program. Human induced pluripotent stem cell (iPS-C)-derived cardiomyocytes and real time cell analysis system (RTCA) were used to verify the effect of OA on the ET-1 pathway. High glucose levels increased the expression of BNP at both mRNA and protein levels in cardiomyocytes. Moreover, cell surface area and MMP were also elevated in a high glucose environment. High glucose-induced injury in NRVMs was not reversible by hypoglycemic therapy. In addition, ETA was upregulated by high glucose treatment and levels could not be reduced by hypoglycemic treatment. The Ca[Formula: see text] influx assay on ETA/HEK293 cells showed that OA had a partial ETA antagonistic effect. Molecular docking approaches showed that OA was docked into the active site of ETA. Furthermore, functionality tests based on iPS-C and RTCA demonstrated that treatment with OA could reverse ET-1-induced alternation of beating rates and amplitude. Thus, OA could reverse high glucose-induced BNP upregulation, and increased both the cell area and MMP in NRVMs. High glucose-induced irreversible ETA upregulation is a major reason of continuous diabetes-related injury in cardiomyocytes. Treatment with OA had a protective effect on high glucose-induced injury in cardiomyocytes through a partial ETA antagonistic role.

Differential AMPK phosphorylation sites associated with phenylephrine vs. antihypertrophic effects of adenosine agonists in neonatal rat ventricular myocytes

2010 ◽  
Vol 298 (5) ◽  
pp. H1382-H1390 ◽  
Author(s):  
Theresa Pang ◽  
Venkatesh Rajapurohitam ◽  
Michael A. Cook ◽  
Morris Karmazyn
Keyword(s):  
Gene Expression ◽  
Protein Synthesis ◽  
Cell Surface ◽  
Surface Area ◽  
Adenosine Receptor ◽  
Neonatal Rat ◽  
Adenosine Receptor Agonists ◽  
Cell Surface Area ◽  
Receptor Agonists ◽  
Ampk Phosphorylation

Stimulation of cardiac AMP-activated protein kinase (AMPK) has been demonstrated in both prohypertrophic and antihypertrophic settings, although the reasons for such discrepant results are not well understood. We determined how AMPK is regulated in response to phenylephrine-induced cardiomyocyte hypertrophy and assessed whether AMPK activity may be a factor underlying the antihypertrophic effect of adenosine receptor agonists. The role of AMPK in hypertrophic responses was determined by assessing the effect of the AMPK activator 5-aminoimidazole-4-carboxyamide ribonucleoside on three hypertrophic indexes, including protein synthesis, cell surface area, and fetal gene expression. The changes in phosphorylation of the catalytic α-subunit of AMPK at two different sites, Thr172 and Ser485/491, in response to phenylephrine and adenosine receptor agonists were also examined. 5-Aminoimidazole-4-carboxyamide ribonucleoside completely abolished phenylephrine-induced increases in protein synthesis, cell surface area, and fetal gene expression. AMPK phosphorylation time course studies revealed that phenylephrine induced a time-dependent activation at site Ser485/491, in contrast to adenosine receptor agonists, which demonstrated rapid AMPK phosphorylation at Thr172. Furthermore, the phosphorylation at Ser485/491 by phenylephrine was not affected by the addition of adenosine receptor agonists, although, conversely, phosphorylation of AMPK at Thr172 by adenosine receptor agonists was abrogated by the addition of phenylephrine. We propose from these results that cardiomyocyte hypertrophic and antihypertrophic responses, at least with respect to inhibition of phenylephrine-induced hypertrophy by adenosine receptor agonists, are mediated by multisite AMPK regulation. The latter are reflected by increased phosphorylation at Ser485/491 and at Thr172, associated with prohypertrophic and antihypertrophic responses, respectively.

scholarly journals Qiliqiangxin Attenuates Phenylephrine-Induced Cardiac Hypertrophy through Downregulation of MiR-199a-5p

2016 ◽  
Vol 38 (5) ◽  
pp. 1743-1751 ◽  
Author(s):  
Haifeng Zhang ◽  
Shanshan Li ◽  
Qiulian Zhou ◽  
Qi Sun ◽  
Shutong Shen ◽  
...  
Keyword(s):  
Cell Surface ◽  
Cardiac Hypertrophy ◽  
Natriuretic Peptide ◽  
Neonatal Rat ◽  
Immunofluorescent Staining ◽  
Mouse Heart ◽  
Mrna Levels ◽  
Elevated Protein ◽  
Ischemic Stress

Background/Aims: Qiliqiangxin (QL), a traditional Chinese medicine, has long been used to treat chronic heart failure. Previous studies demonstrated that QL could prevent cardiac remodeling and hypertrophy in response to hypertensive or ischemic stress. However, little is known about whether QL could modulate cardiac hypertrophy in vitro, and (if so) whether it is through modulation of specific hypertrophy-related microRNA. Methods: The primary neonatal rat ventricular cardiomyocytes were isolated, cultured, and treated with phenylephrine (PE, 50 µmol/L, 48 h) to induce hypertrophy in vitro, in the presence or absence of pretreatment with QL (0.5 µg/ml, 48 h). The cell surface area was determined by immunofluorescent staining for α-actinin. The mRNA levels of hypertrophic markers including atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and β-myosin heavy chain (MYH7) were assayed by qRT-PCRs. The protein synthesis of cardiomyocytes was determined by the protein/DNA ratio. The miR-199a-5p expression level was quantified in PE-treated cardiomyocytes and heart samples from acute myocardial infarction (AMI) mouse model. MiR-199a-5p overexpression was used to determine its role in the anti-hypertrophic effect of QL on cardiomyocytes. Results: PE induced obvious enlargement of cell surface in cardiomyocytes, paralleling with increased ANP, BNP, and MYH7 mRNA levels and elevated protein/DNA ratio. All these changes were reversed by the treatment with QL. Meanwhile, miR-199a-5p was increased in AMI mouse heart tissues. Of note, the increase of miR-199a-5p in PE-treated cardiomyocytes was reversed by the treatment with QL. Moreover, overexpression of miR-199a-5p abolished the anti-hypertrophic effect of QL on cardiomyocytes. Conclusion: QL prevents PE-induced cardiac hypertrophy. MiR-199a-5p is increased in cardiac hypertrophy, while reduced by treatment with QL. miR-199a-5p suppression is essential for the anti-hypertrophic effect of QL on cardiomyocytes.

Abstract 133: A Systems Genetics Approach to Identify Genetic Pathways and Key Drivers of Isoproterenol-induced Cardiac Hypertrophy and Cardiomyopathy in Mice

2016 ◽  
Vol 119 (suppl_1) ◽  
Author(s):  
Christoph D Rau ◽  
Milagros Romay ◽  
Jessica Wang ◽  
Aldons J Lusis ◽  
Yibin Wang
Keyword(s):  
Heart Failure ◽  
Cardiac Hypertrophy ◽  
Gene Networks ◽  
Complex Disease ◽  
Left Ventricular ◽  
Causal Modeling ◽  
Neonatal Rat ◽  
Mouse Strains ◽  
Phenotypic Traits ◽  
Systems Genetics

Heart Failure (HF) is a complex disease involving numerous environmental and genetic factors. We previously reported a genetic analysis of HF traits in a population of inbred mouse strains treated with isoproterenol, a β-adrenergic agonist used to mimic catecholamine-driven cardiac hypertrophy. We now present a systems genetics analysis in which we have used left ventricular transcript levels from these mice to perform co-expression network modeling. We constructed gene networks composed of 8,126 genes and 20 modules using the wMICA algorithm. In the wMICA network generated from treated hearts, we identified a module with significant correlations to several HF-related phenotypic traits. Further analysis of this module showed significant over-representation of genes known to contribute to the development of HF. Using the causal modeling algorithm NEO, we identified the gene Adamts2 as a putative master regulator of the module. We then validated the role of this gene through siRNA-mediated knockdown in neonatal rat ventricular myocytes (NRVM). Consistent with our model, Adamts2 silencing was able to regulate the expression of the genes residing within the module as well as impairing isoproterenol-induced cell size changes . Our results provide a view of higher order interactions in heart failure with potential to facilitate diagnostic and therapeutic approaches.

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