scholarly journals Adapter molecule DOC-2 is differentially expressed in pressure and volume overload hypertrophy and inhibits collagen synthesis in cardiac fibroblasts

2007 ◽  
Vol 102 (5) ◽  
pp. 2024-2032 ◽  
Author(s):  
Deepa H. Kumbar ◽  
Andrew VanBergen ◽  
Catherina Ocampo ◽  
Sunthorn Muangmingsuk ◽  
Andrew J. Griffin ◽  
...  
Keyword(s):  
Cardiac Fibroblasts ◽  
Pressure Overload ◽  
Volume Overload ◽  
Ang Ii ◽  
In Vivo Models ◽  
Erk Activation ◽  
Collagen Mrna ◽  
Collagen Expression

DOC-2 (differentially expressed in ovarian carcinoma) is involved in Ras-, β-integrin-, PKC-, and transforming growth factor-β-mediated cell signaling. These pathways are implicated in the accumulation of extracellular matrix proteins during progression of hypertrophy to heart failure; however, the role of DOC-2 in cardiac pathophysiology has never been examined. This study was undertaken to 1) analyze DOC-2 expression in primary cultures of cardiac fibroblasts and cardiac myocytes and in the heart following different types of hemodynamic overloads and 2) examine its role in growth factor-mediated ERK activation and collagen production. Pressure overload and volume overload were induced for 10 wk in Sprague-Dawley rats by aortic constriction and by aortocaval shunt, respectively. ANG II (0.3 mg·kg−1·day−1) was infused for 2 wk. Results showed that, compared with myocytes, DOC-2 was found abundantly expressed in cardiac fibroblasts. Treatment of cardiac fibroblasts with ANG II and TPA resulted in increased expression of DOC-2. Overexpression of DOC-2 in cardiac fibroblasts led to inhibition of hypertrophy agonist-stimulated ERK activation and collagen expression. An inverse correlation between collagen and DOC-2 was observed in in vivo models of cardiac hypertrophy; in pressure overload and after ANG II infusion, increased collagen mRNA correlated with reduced DOC-2 levels, whereas in volume overload increased DOC-2 levels were accompanied by unchanged collagen mRNA. These data for the first time describe expression of DOC-2 in the heart and demonstrate its modulation by growth-promoting agents in cultured cardiac fibroblasts and in in vivo models of heart hypertrophy. Results suggest a role of DOC-2 in cardiac remodeling involving collagen expression during chronic hemodynamic overload.

scholarly journals Sex-specific regulation of collagen I and III expression by 17β-Estradiol in cardiac fibroblasts: role of estrogen receptors

2018 ◽  
Vol 115 (2) ◽  
pp. 315-327 ◽  
Author(s):  
Elke Dworatzek ◽  
Shokoufeh Mahmoodzadeh ◽  
Cindy Schriever ◽  
Kana Kusumoto ◽  
Lisa Kramer ◽  
...  
Keyword(s):  
Estrogen Receptor Alpha ◽  
Cardiac Fibrosis ◽  
Cardiac Fibroblasts ◽  
Pressure Overload ◽  
Collagen I ◽  
Female Rat ◽  
17Β Estradiol ◽  
Specific Regulation

Abstract Aims Sex differences in cardiac fibrosis point to the regulatory role of 17β-Estradiol (E2) in cardiac fibroblasts (CF). We, therefore, asked whether male and female CF in rodent and human models are differentially susceptible to E2, and whether this is related to sex-specific activation of estrogen receptor alpha (ERα) and beta (ERβ). Methods and results In female rat CF (rCF), 24 h E2-treatment (10−8  M) led to a significant down-regulation of collagen I and III expression, whereas both collagens were up-regulated in male rCF. E2-induced sex-specific collagen regulation was also detected in human CF, indicating that this regulation is conserved across species. Using specific ERα- and ERβ-agonists (10−7 M) for 24 h, we identified ERα as repressive and ERβ as inducing factor in female and male rCF, respectively. In addition, E2-induced ERα phosphorylation at Ser118 only in female rCF, whereas Ser105 phosphorylation of ERβ was exclusively found in male rCF. Further, in female rCF we found both ER bound to the collagen I and III promoters using chromatin immunoprecipitation assays. In contrast, in male rCF only ERβ bound to both promoters. In engineered connective tissues (ECT) from rCF, collagen I and III mRNA were down-regulated in female ECT and up-regulated in male ECT by E2. This was accompanied by an impaired condensation of female ECT, whereas male ECT showed an increased condensation and stiffness upon E2-treatment, analysed by rheological measurements. Finally, we confirmed the E2-effect on both collagens in an in vivo mouse model with ovariectomy for E2 depletion, E2 substitution, and pressure overload by transverse aortic constriction. Conclusion The mechanism underlying the sex-specific regulation of collagen I and III in the heart appears to involve E2-mediated differential ERα and ERβ signaling in CFs.

Abstract 423: Kinase Independent Signaling of PI3Kγ Mediates Cardiac Fibrosis

2016 ◽  
Vol 119 (suppl_1) ◽  
Author(s):  
Maradumane L Mohan ◽  
Lisa M Grove ◽  
Mitchell A Olman ◽  
Sathyamangla V Naga Prasad
Keyword(s):  
Cardiac Fibrosis ◽  
Cardiac Tissue ◽  
Cardiac Fibroblasts ◽  
Pressure Overload ◽  
Stress Fibers ◽  
Independent Function ◽  
Specific Expression ◽  
Myofibroblast Phenotype

Phosphoinositide 3 Kinase γ (PI3Kγ) belongs to a family of lipid kinases genetic deletion of which leads to pressure overload induced cardiac fibrosis in mice. However, the mechanism by which PI3Kγ mediates cardiac fibrosis is unknown. Cardiac fibrosis is a key underlying cause of fatal heart failure. A well-known fibrogenic mechanism is the generation of myofibroblasts, which are characterized by overexpression of smooth muscle α-actin (αSMA). Myofibroblast is a fibrosis-effector cell that produces pro-fibrotic cytokines and exuberant extracellular matrix that leads to cardiac fibrosis. To evaluate the role of PI3Kγ in fibrotic phenotype, cardiac tissue lysates from 3 months old WT and PI3Kγ null (PI3Kγ -/- ) mice were assessed for the expression of αSMA. Interestingly, there is significant up-regulation of αSMA in PI3Kγ -/- in comparison to littermate controls (WT) even at baseline suggesting that loss of PI3Kγ predisposes the hearts towards fibrosis. To directly confirm that PI3Kγ -/- cardiac fibroblasts (CF) exhibit a myofibroblast phenotype even at baseline, CF were isolated from hearts of WT and PI3Kγ -/- mice and assessed for myofibroblast phenotype by immunostaining for αSMA in stress fibers. Fluorescence microscopy on the CF from PI3Kγ -/- mice showed intense immunostaining for αSMA with greater number of cells exhibiting αSMA in stress fibers when compared to CF from WT mice. Consistently, immunoblotting showed significantly higher αSMA protein levels in PI3Kγ -/- CF compared to WT CF suggesting that PI3Kγ -/- fibroblasts are “primed” to undergo myofibroblast differentiation. To determine the role of kinase-independent function of PI3Kγ in vivo, we generated unique mice lines with cardiomyocyte-specific expression of either kinase-dead PI3Kγ (PI3Kγ inact ) or constitutively active PI3Kγ ( Myr PI3Kγ) in the global PI3Kγ -/- (PI3Kγ inact /PI3Kγ -/- or Myr PI3Kγ/PI3Kγ -/- ) and measured αSMA. Surprisingly, abundance of αSMA protein is significantly reduced in PI3Kγ inact /PI3Kγ -/- when compared to WT and PI3Kγ -/- mice. These data reveal that kinase-independent function of PI3Kγ is a key component in the myocyte-initiated pathway that ultimately drives CF to become myofibroblasts uncovering a novel mechanism of regulating pro-fibrotic signals.

Abstract 16434: IL-6 Signaling is Crucial for Cardiomyocyte Hypertrophy and Left Ventricular Dysfunction Induced by Pressure Overload

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Lin Zhao ◽  
Guangming Cheng ◽  
Yanjuan Yang ◽  
Anweshan Samanta ◽  
Rizwan R Afzal ◽  
...  
Keyword(s):  
Therapeutic Potential ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Cardiomyocyte Hypertrophy ◽  
Lv Function ◽  
Ang Ii ◽  
Adult Cardiomyocytes

Introduction: Interleukin-6 (IL-6), a proinflammatory cytokine, has been implicated in ischemic cardiac pathologies. Very little is currently known regarding the role of IL-6 signaling in pathological cardiomyocyte hypertrophy and LV dysfunction. Hypothesis: We hypothesized that IL-6 signaling plays a central role in cardiomyocyte hypertrophy and exerts a deleterious impact on LV remodeling induced by pressure overload. Methods: In vitro, adult cardiomyocytes from C57BL/6 (WT, control) and IL-6 knockout (KO) mice were stimulated by IL-6 and pro-hypertrophic agent angiotensin II (Ang II). The expression of hypertrophy markers and related signaling molecules were examined by real-time quantitative RT-PCR. In vivo, weight-matched male WT and IL-6 KO mice underwent transverse aortic constriction (TAC) or a sham procedure. Serial echocardiograms and a terminal hemodynamic study were performed. Results: After exposure to IL-6 and hypertrophic agonists, the expression of hypertrophy related genes, BNP, GATA-4, αSK actin, and β-MHC increased significantly in WT cardiomyocytes (Fig). These effects were significantly attenuated in IL-6 knockout cardiomyocytes (Fig), indicating an essential role of IL-6 in cardiomyocyte hypertrophy. In vivo, the worsening in LV contraction as well as relaxation after TAC was significantly attenuated in IL-6 KO mice, indicating superior preservation of LV function in the setting of pressure overload in the absence of IL-6 signaling. Conclusions: The protection against Ang II-induced hypertrophy observed in IL-6 KO adult cardiomyocytes in vitro, and in hearts of IL-6 KO mice after TAC in vivo illustrates a crucial role played by IL-6 in pathogenesis of pressure overload-induced LV hypertrophy. Modulation of IL-6 signaling may have preventive therapeutic potential for countless hypertensive patients at risk for LV hypertrophy and failure.

scholarly journals Mitochondrion-Dependent Cell Death in TDP-43 Proteinopathies

Biomedicines ◽  
2021 ◽  
Vol 9 (4) ◽  
pp. 376
Author(s):  
Chantal B. Lucini ◽  
Ralf J. Braun
Keyword(s):  
Cell Death ◽  
Oxygen Species ◽  
In Vivo Models ◽  
Dependent Cell ◽  
Cell Death Mechanisms ◽  
Sting Pathway ◽  
Mitochondrial Membrane Permeabilization

In the last decade, pieces of evidence for TDP-43-mediated mitochondrial dysfunction in neurodegenerative diseases have accumulated. In patient samples, in vitro and in vivo models have shown mitochondrial accumulation of TDP-43, concomitantly with hallmarks of mitochondrial destabilization, such as increased production of reactive oxygen species (ROS), reduced level of oxidative phosphorylation (OXPHOS), and mitochondrial membrane permeabilization. Incidences of TDP-43-dependent cell death, which depends on mitochondrial DNA (mtDNA) content, is increased upon ageing. However, the molecular pathways behind mitochondrion-dependent cell death in TDP-43 proteinopathies remained unclear. In this review, we discuss the role of TDP-43 in mitochondria, as well as in mitochondrion-dependent cell death. This review includes the recent discovery of the TDP-43-dependent activation of the innate immunity cyclic GMP-AMP synthase/stimulator of interferon genes (cGAS/STING) pathway. Unravelling cell death mechanisms upon TDP-43 accumulation in mitochondria may open up new opportunities in TDP-43 proteinopathy research.

Abstract 277: Microrna-33 Promotes Cardiac Fibrosis by Maintaining Cellular Lipid Homeostasis

2016 ◽  
Vol 119 (suppl_1) ◽  
Author(s):  
Masataka Nishiga ◽  
Takahiro Horie ◽  
Yasuhide Kuwabara ◽  
Osamu Baba ◽  
Tetsushi Nakao ◽  
...  
Keyword(s):  
Cardiac Fibrosis ◽  
Cardiac Fibroblasts ◽  
Pressure Overload ◽  
Cholesterol Content ◽  
Atp Binding Cassette Transporter ◽  
Primary Fibroblasts ◽  
Proliferation In Vitro ◽  
Altered Lipid

Background: A highly conserved microRNA, miR-33 is considered as a potential therapeutic target for atherosclerosis, because recent reports, including ours, indicated miR-33 has atherogenic effects by reducing HDL-C. However, the functions of miR-33 in heart failure remain to be elucidated. Methods and results: To clarify the functions of miR-33 involved in cardiac hypertrophy and fibrosis in vivo, we investigated the responses to pressure overload by transverse aortic constriction (TAC) in miR-33 deficient (KO) mice. When subjected to TAC, miR-33 expression level was significantly up-regulated in wild-type (WT) left ventricles, whereas miR-33 KO hearts displayed no less hypertrophic responses than WT hearts. However, interestingly, histological and gene expression analyses showed ameliorated cardiac fibrosis in miR-33 KO hearts compared to WT hearts. Furthermore, we generated cardiac fibroblast specific miR-33 deficient mice, which also showed ameliorated cardiac fibrosis when they were subjected to TAC. We also found that cardiac fibroblasts were mainly responsible for miR-33 expression in the heart, because its expression was about 4-folds higher in isolated primary cardiac fibroblasts than cardiomyocytes. Deficiency of miR-33 impaired cell proliferation in primary fibroblasts, which was considered due to altered lipid raft cholesterol content by up-regulated ATP-binding cassette transporter A1/G1. Conclusion: Deficiency of miR-33 impaired fibroblast proliferation in vitro, and ameliorated cardiac fibrosis induced by pressure overload in vivo.

Abstract 313: STIM1 Silencing Reverses Pressure-overload Induced Cardiac Hypertrophy In Mice

2013 ◽  
Vol 113 (suppl_1) ◽  
Author(s):  
Ludovic O Bénard ◽  
Daniel S Matasic ◽  
Mathilde Keck ◽  
Anne-Marie Lompré ◽  
Roger J Hajjar ◽  
...  
Keyword(s):  
Ventricular Hypertrophy ◽  
Contractile Function ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Aortic Banding ◽  
Cross Section Area ◽  
Abdominal Aortic ◽  
Section Area

STromal Interaction Molecule 1 (STIM1), a membrane protein of the sarcoplasmic reticulum, has recently been proposed as a positive regulator of cardiomyocyte growth by promoting Ca2+ entry through the plasma membrane and the activation of Ca2+-mediated signaling pathways. We demonstrated that STIM1 silencing prevented the development of left ventricular hypertrophy (LVH) in rats after abdominal aortic banding. Our aim was to study the role of STIM1 during the transition from LVH to heart failure (HF). For experimental timeline, see figure. Transverse Aortic Constriction (TAC) was performed in C57Bl/6 mice. In vivo gene silencing was performed using recombinant Associated AdenoVirus 9 (AAV9). Mice were injected with saline or with AAV9 expressing shRNA control or against STIM1 (shSTIM1) (dose: 1e+11 viral genome), which decreased STIM1 cardiac expression by 70% compared to control. While cardiac parameters were similar between the TAC groups at weeks 3 and 6, shSTIM1 animals displayed a progressive and total reversion of LVH with LV walls thickness returning to values observed in sham mice at week 8. This reversion was associated with the development of significant LV dilation and severe contractile dysfunction, as assessed by echography. Hemodynamic analysis confirmed the altered contractile function and dilation of shSTIM1 animals. Immunohistochemistry showed a trend to more fibrosis. Despite hypertrophic stimuli, there was a significant reduction in cardiac myocytes cross-section area in shSTIM1-treated animals as compared to other TAC mice. This study showed that STIM1 is essential to maintain compensatory LVH and that its silencing accelerates the transition to HF.

Abstract 791: A Critical Role for Bmper (BMP-binding Endothelial cell precursor-derived Regulator) in Cardiac Muscle Mass Regulation during Development and Pressure Overload Induced Hypertrophy

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Monte Willis ◽  
Rongqin Ren ◽  
Cam Patterson
Keyword(s):  
Cardiac Function ◽  
Cardiac Muscle ◽  
Muscle Mass ◽  
Cardiac Development ◽  
Critical Role ◽  
Pressure Overload ◽  
Posterior Wall ◽  
Fractional Shortening

Bone morphogenetic proteins (BMPs) of the TGF-beta superfamily, have been implicated in multiple processes during cardiac development. Our laboratory recently described an unprecedented role for Bmper in antagonizing BMP-2, BMP-4, and BMP-6. To determine the role of Bmper on cardiac development in vivo, we created Bmper null (Bmper −/−) mice by replacing exons 1 and 2 with GFP. Since Bmper −/− mice are perinatally lethal, we determined pre-natal cardiac function of Bmper −/− mice in utero just before birth. By echocardiography, E18.5 Bmper −/− embryos had decreased cardiac function (24.2 +/− 8.1% fractional shortening) compared to Bmper +/− and Bmper +/+ siblings (52.2 +/− 1.6% fractional shortening) (N=4/group). To further characterize the role of Bmper on cardiac function in adult mice, we performed echocardiography on 8-week old male and female Bmper +/− and littermate control Bmper +/+. Bmper +/− mice had an approximately 15% decrease in anterior and posterior wall thickness compared to sibling Bmper +/+ mice at baseline (n=10/group). Cross-sectional areas of Bmper +/− cardiomyocytes were approximately 20% less than wild type controls, indicating cardiomyocyte hypoplasia in adult Bmper +/− mice at baseline. Histologically, no significant differences were identified in representative H&E and trichrome stained adult Bmper +/− and Bmper +/+ cardiac sections at baseline. To determine the effects of Bmper expression on the development of cardiac hypertrophy, both Bmper +/− and Bmper +/+ sibling controls underwent transaortic constriction (TAC), followed by weekly echocardiography. While a deficit was identified in Bmper +/− mice at baseline, both anterior and posterior wall thicknesses increased after TAC, such that identical wall thicknesses were identified in Bmper +/− and Bmper +/+ mice 1–4 weeks after TAC. Notably, cardiac function (fractional shortening %) and histological evaluation revealed no differences between Bmper +/− and Bmper +/+ any time after TAC. These studies identify for the first time that Bmper expression plays a critical role in regulating cardiac muscle mass during development, and that Bmper regulates the development of hypertrophy in response to pressure overload in vivo.

Abstract 445: A Pro-Fibrotic Role of Interleukin-4 in Cardiac Remodeling and Dysfunction

Hypertension ◽  
2014 ◽  
Vol 64 (suppl_1) ◽  
Author(s):  
Hongmei Peng ◽  
Oscar Carretero ◽  
Xiao-Ping Yang ◽  
Pablo Nakagawa ◽  
Jiang Xu ◽  
...  
Keyword(s):  
Cardiac Fibrosis ◽  
Cardiac Fibroblasts ◽  
Interleukin 4 ◽  
Ang Ii ◽  
Collagen Production ◽  
And Function ◽  
First Time ◽  
Mini Pump

Elevated interleukin-4 (IL-4) levels are positively related to cardiac fibrosis in heart failure and hypertension. Using Balb/c exhibiting high circulating IL-4, Balb/c- Il4 tm2Nnt (IL-4 knockout with Balb/c background, IL-4 -/- ) and C57BL/6 mice, as well as cultured cardiac fibroblasts (CFs), we hypothesized that 1) high levels of IL-4 result in cardiac fibrosis, making the heart susceptible to angiotensin II (Ang II)-induced damage, and 2) IL-4 potently stimulates collagen production by CFs. Each strain (9- to 12-week old male) received vehicle or Ang II (1.4 mg/kg/day, s.c. via osmotic mini-pump) for 8 weeks. Cardiac fibrosis and function were determined by histology and echocardiography, respectively. Compared to C57BL/6, Balb/c mice had doubled interstitial collagen in the heart, enlarged left ventricle and decreased cardiac function along with elevated cardiac IL-4 protein (1.00±0.08 in C57BL/6 vs 2.61±0.46 in Balb/c, p <0.05); all those changes were significantly attenuated in IL-4 -/- (Table 1). Ang II further deteriorated cardiac fibrosis and dysfunction in Balb/c; these detrimental effects were attenuated in IL-4 -/- , although the three strains had a similar level of hypertension. In vitro study revealed that IL-4Rα was constitutively expressed in CFs (Western blot), and IL-4 potently stimulated collagen production by CFs (hydroxproline assay, from 18.89±0.85 to 38.81±3.61 μg/mg at 10 ng/ml, p <0.01). Our study demonstrates for the first time that IL-4, as a potent pro-fibrotic cytokine in the heart, contributes to cardiac fibrotic remodeling and dysfunction. Thus IL-4 may be a potential therapeutic target for cardiac fibrosis and dysfunction.

ACE inhibitors and cardiac ACE mRNA in volume overload-induced cardiac hypertrophy

1997 ◽  
Vol 273 (2) ◽  
pp. H641-H646 ◽  
Author(s):  
W. Lear ◽  
M. Ruzicka ◽  
F. H. Leenen
Keyword(s):  
Cardiac Hypertrophy ◽  
Ace Inhibitors ◽  
Cardiac Tissue ◽  
Ace Inhibitor ◽  
Internal Standard ◽  
Phosphoglycerate Kinase ◽  
Volume Overload ◽  
Ang Ii ◽  
Aortocaval Shunt

Quinapril, an angiotensin-converting enzyme (ACE) inhibitor with high affinity for cardiac ACE, prevents increases in both plasma and cardiac angiotensin II (ANG II) and development of cardiac hypertrophy after aortocaval shunt in rats. In contrast, enalapril, an ACE inhibitor with low affinity for cardiac ACE, only prevents the increase in plasma ANG II. In the present study, we assessed whether these differences between enalapril and quinapril reflect different inhibition of cardiac tissue ACE and local ANG II by measuring their effects on cardiac ACE mRNA. Treatment with enalapril (250 mg/l) and quinapril (200 mg/l in drinking water) was started 3 days before the shunt and sham surgery. After 1 wk of aortocaval shunt, the hearts were excised and the left ventricle and right ventricle were weighed and used for reverse transcriptase-polymerase chain reaction (RT-PCR) assays for ACE and phosphoglycerate kinase-1 (internal standard). Quinapril, but not enalapril, inhibited the development of cardiac hypertrophy by aortocaval shunt. The shunt increased ACE mRNA in both left and right ventricles about twofold. In animals with aortocaval shunt, quinapril markedly further upregulated ACE mRNA in both ventricles, whereas enalapril did not cause significant changes. In sham rats, both ACE inhibitors increased ACE mRNA, but the increase was more pronounced by treatment with quinapril. These studies show that in vivo ACE inhibitors with low (enalapril) vs. high (quinapril) affinity for cardiac ACE differ in their effects on cardiac ACE mRNA. This difference is more pronounced in volume overload-induced cardiac hypertrophy, presumably reflecting their different effects on cardiac ANG II.

scholarly journals Chronic Stress Promotes the Progression of Pressure Overload-Induced Cardiac Dysfunction Through Inducing More Apoptosis and Fibrosis

2015 ◽  
pp. 325-334 ◽  
Author(s):  
W. LIU ◽  
X. WANG ◽  
Z. MEI ◽  
J. GONG ◽  
X. GAO ◽  
...  
Keyword(s):  
Chronic Stress ◽  
Cardiac Dysfunction ◽  
Cardiac Fibroblasts ◽  
Pressure Overload ◽  
Chronic Restraint Stress ◽  
Neonatal Rats ◽  
Aortic Constriction ◽  
Collagen Expression ◽  
Abdominal Aortic ◽  
High Level

Stress serves as a risk factor in the etiology of hypertension. The present study was designed to decipher the effect and mechanism of chronic stress on the progression of pressure overload-induced cardiac dysfunction. We used abdominal aortic constriction (AAC) to induce pressure overload with or without chronic restraint stress to establish the animal models. Echocardiographic analysis showed pressure overload-induced cardiac dysfunction was worsened by chronic stress. Compared with the AAC rats, there is a significant increase in cardiac hypertrophy, injury, apoptosis and fibrosis of the AAC + stress rats. Furthermore, we found the secretion of norepinephrine (NE) increased after the AAC operation, while the level of NE was higher in the AAC + stress group. Cardiomyocytes and cardiac fibroblasts isolated from neonatal rats were cultured and separately treated with 1, 10, 100 μM NE. The higher concentration NE induced more cardiomyocytes hypertrophy and apoptosis, cardiac fibroblasts proliferation and collagen expression. These results revealed that high level of NE-induced cardiomyocytes hypertrophy and apoptosis, cardiac fibroblasts proliferation and collagen expression further contributes to the effect of chronic stress on acceleration of pressure overload-induced cardiac dysfunction.

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