Glucosamine inhibits angiotensin II-induced cytoplasmic Ca2+ elevation in neonatal cardiomyocytes via protein-associated O-linked N-acetylglucosamine

2006 ◽  
Vol 290 (1) ◽  
pp. C57-C65 ◽  
Author(s):  
Tamas Nagy ◽  
Voraratt Champattanachai ◽  
Richard B. Marchase ◽  
John C. Chatham
Keyword(s):  
Ventricular Myocytes ◽  
Neonatal Rat ◽  
Ang Ii ◽  
Neonatal Cardiomyocytes ◽  
Hexosamine Biosynthesis ◽  
Intracellular Ca ◽  
Glcnac Transferase ◽  
Neonatal Rat Ventricular Myocytes ◽  
The Relationship ◽  
Hexosamine Biosynthesis Pathway

We previously reported that glucosamine and hyperglycemia attenuate the response of cardiomyocytes to inositol 1,4,5-trisphosphate-generating agonists such as ANG II. This appears to be related to an increase in flux through the hexosamine biosynthesis pathway (HBP) and decreased Ca2+ entry into the cells; however, a direct link between HBP and intracellular Ca2+ homeostasis has not been established. Therefore, using neonatal rat ventricular myocytes, we investigated the relationship between glucosamine treatment; the concentration of UDP- N-acetylglucosamine (UDP-GlcNAc), an end product of the HBP; and the level of protein O-linked N-acetylglucosamine ( O-GlcNAc) on ANG II-mediated changes in intracellular free Ca2+ concentration ([Ca2+]i). We found that glucosamine blocked ANG II-induced [Ca2+]i increase and that this phenomenon was associated with a significant increase in UDP-GlcNAc and O-GlcNAc levels. O-(2-acetamido-2-deoxy-d-glucopyranosylidene)-amino- N-phenylcarbamate, an inhibitor of O-GlcNAcase that increased O-GlcNAc levels without changing UDP-GlcNAc concentrations, mimicked the effect of glucosamine on the ANG II-induced increase in [Ca2+]i. An inhibitor of O-GlcNAc-transferase, alloxan, prevented the glucosamine-induced increase in O-GlcNAc but not the increase in UDP-GlcNAc; however, alloxan abrogated the inhibition of the ANG II-induced increase in [Ca2+]i. These data support the notion that changes in O-GlcNAc levels mediated via increased HBP flux may be involved in the regulation of [Ca2+]i homeostasis in the heart.

scholarly journals Glucosamine protects neonatal cardiomyocytes from ischemia-reperfusion injury via increased protein O-GlcNAc and increased mitochondrial Bcl-2

2008 ◽  
Vol 294 (6) ◽  
pp. C1509-C1520 ◽  
Author(s):  
Voraratt Champattanachai ◽  
Richard B. Marchase ◽  
John C. Chatham
Keyword(s):  
Protective Effect ◽  
Ventricular Myocytes ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Neonatal Rat ◽  
Cellular Injury ◽  
Protective Effects ◽  
Neonatal Cardiomyocytes ◽  
Glcnac Transferase ◽  
Neonatal Rat Ventricular Myocytes

We have previously reported that glucosamine protected neonatal rat ventricular myocytes against ischemia-reperfusion (I/R) injury, and this was associated with an increase in protein O-linked- N-acetylglucosamine ( O-GlcNAc) levels. However, the protective effect of glucosamine could be mediated via pathways other that O-GlcNAc formation; thus the initial goal of the present study was to determine whether increasing O-GlcNAc transferase (OGT) expression, which catalyzes the formation of O-GlcNAc, had a protective effect similar to that of glucosamine. To better understand the potential mechanism underlying O-GlcNAc-mediated cytoprotection, we examined whether increased O-GlcNAc levels altered the expression and translocation of members of the Bcl-2 protein family. Both glucosamine (5 mM) and OGT overexpression increased basal and I/R-induced O-GlcNAc levels, significantly decreased cellular injury, and attenuated loss of cytochrome c. Both interventions also attenuated the loss of mitochondrial membrane potential induced by H2O2 and were also associated with an increase in mitochondrial Bcl-2 levels but had no effect on Bad or Bax levels. Compared with glucosamine and OGT overexpression, NButGT (100 μM), an inhibitor of O-GlcNAcase, was less protective against I/R and H2O2 and did not affect Bcl-2 expression, despite a 5- to 10-fold greater increase in overall O-GlcNAc levels. Decreased OGT expression resulted in lower basal O-GlcNAc levels, prevented the I/R-induced increase in O-GlcNAc and mitochondrial Bcl-2, and increased cellular injury. These results demonstrate that the protective effects of glucosamine are mediated via increased formation of O-GlcNAc and suggest that this is due, in part, to enhanced mitochondrial Bcl-2 translocation.

Glucosamine protects neonatal cardiomyocytes from ischemia-reperfusion injury via increased protein-associated O-GlcNAc

2007 ◽  
Vol 292 (1) ◽  
pp. C178-C187 ◽  
Author(s):  
Voraratt Champattanachai ◽  
Richard B. Marchase ◽  
John C. Chatham
Keyword(s):  
Cell Viability ◽  
Cell Survival ◽  
Ventricular Myocytes ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Neonatal Rat ◽  
Activated T Cells ◽  
Neonatal Cardiomyocytes ◽  
Hexosamine Biosynthesis ◽  
Glcnac Transferase

Increased levels of protein O-linked N-acetylglucosamine ( O-GlcNAc) have been shown to increase cell survival following stress. Therefore, the goal of this study was to determine whether in isolated neonatal rat ventricular myocytes (NRVMs) an increase in protein O-GlcNAcylation resulted in improved survival and viability following ischemia-reperfusion (I/R). NRVMs were exposed to 4 h of ischemia and 16 h of reperfusion, and cell viability, necrosis, apoptosis, and O-GlcNAc levels were assessed. Treatment of cells with glucosamine, hyperglycemia, or O-(2-acetamido-2-deoxy-d-glucopyranosylidene)-amino- N-phenylcarbamate(PUGNAc), an inhibitor of O-GlcNAcase, significantly increased O-GlcNAc levels and improved cell viability, as well as reducing both necrosis and apoptosis compared with untreated cells following I/R. Alloxan, an inhibitor of O-GlcNAc transferase, markedly reduced O-GlcNAc levels and exacerbated I/R injury. The improved survival with hyperglycemia was attenuated by azaserine, which inhibits glucose metabolism via the hexosamine biosynthesis pathway. Reperfusion in the absence of glucose reduced O-GlcNAc levels on reperfusion compared with normal glucose conditions and decreased cell viability. O-GlcNAc levels significantly correlated with cell viability during reperfusion. The effects of glucosamine and PUGNAc on cellular viability were associated with reduced calcineurin activation as measured by translocation of nuclear factor of activated T cells, suggesting that increased O-GlcNAc levels may attenuate I/R induced increase in cytosolic Ca2+. These data support the concept that activation of metabolic pathways leading to an increase in O-GlcNAc levels is an endogenous stress-activated response and that augmentation of this response improves cell survival. Thus strategies designed to activate these pathways may represent novel interventions for inducing cardioprotection.

H2O2-induced Ca2+ overload in NRVM involves ERK1/2 MAP kinases: role for an NHE-1-dependent pathway

2002 ◽  
Vol 283 (2) ◽  
pp. H598-H605 ◽  
Author(s):  
Emily C. Rothstein ◽  
Kenneth L. Byron ◽  
Ryan E. Reed ◽  
Larry Fliegel ◽  
Pamela A. Lucchesi
Keyword(s):  
Map Kinases ◽  
Ventricular Myocytes ◽  
Ischemia Reperfusion ◽  
Neonatal Rat ◽  
Dependent Manner ◽  
Low Doses ◽  
Extracellular Signal ◽  
Intracellular Ca ◽  
Neonatal Rat Ventricular Myocytes ◽  
The Relationship

Generation of reactive oxygen species (ROS) and intracellular Ca2+ overload are key mechanisms involved in ischemia-reperfusion (I/R)-induced myocardial injury. The relationship between I/R injury and Ca2+overload has not been fully characterized. The increase in Na+/H+ exchanger (NHE-1) activity observed during I/R injury is an attractive candidate to link increased ROS production with Ca2+ overload. We have shown that low doses of H2O2 increase NHE-1 activity in an extracellular signal-regulated kinase (ERK)-dependent manner. In this study, we examined the effect of low doses of H2O2 on intracellular Ca2+ in fura 2-loaded, spontaneously contracting neonatal rat ventricular myocytes. H2O2 induced a time- and concentration-dependent increase in diastolic intracellular Ca2+ concentration that was blocked by inhibition of ERK1/2 activation with 5 μM U-0126 (88%) or inhibition of NHE-1 with 5 μM HOE-642 (50%). Increased NHE activity was associated with phosphorylation of the NHE-1 carboxyl tail that was blocked by U-0126. These results suggest that H2O2 induced Ca2+ overload is partially mediated by NHE-1 activation secondary to phosphorylation of NHE-1 by the ERK1/2 MAP kinase pathway.

scholarly journals Suppressor of Cytokine Signaling 3 Is Induced by Angiotensin II in Heart and Isolated Cardiomyocytes, and Participates in Desensitization

Endocrinology ◽  
2003 ◽  
Vol 144 (10) ◽  
pp. 4586-4596 ◽  
Author(s):  
Vivian C. Calegari ◽  
Rosangela M. N. Bezerra ◽  
Márcio A. Torsoni ◽  
Adriana S. Torsoni ◽  
Kleber G. Franchini ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Rat Heart ◽  
Ventricular Myocytes ◽  
Janus Kinase ◽  
Neonatal Rat ◽  
Cytokine Signaling ◽  
Ang Ii ◽  
Suppressor Of Cytokine Signaling ◽  
Rat Ventricular Myocytes ◽  
Neonatal Rat Ventricular Myocytes

Angiotensin II (Ang II) exerts a potent growth stimulus on the heart and vascular wall. Activation of the Janus kinase/signal transducer and activator of transcription (JAK/STAT) intracellular signaling pathway by Ang II mediates at least some of the mitogenic responses to this hormone. In other signaling systems that use the JAK/STAT pathway, proteins of the suppressor of cytokine signaling (SOCS) family participate in signal regulation. In the present study it is demonstrated that SOCS3 is constitutively expressed at a low level in rat heart and neonatal rat ventricular myocytes. Ang II at a physiological concentration enhances the expression of SOCS3 mRNA and protein, mainly via AT1 receptors. After induction, SOCS3 associates with JAK2 and impairs further activation of the JAK2/STAT1 pathway. Pretreatment of rats with a specific phosphorthioate antisense oligonucleotide to SOCS3, reverses the desensitization to angiotensin signaling, as detected by a fall in c-Jun expression after repetitive infusions of the hormone. Thus, SOCS3 is induced by Ang II in rat heart and neonatal rat ventricular myocytes and participates in the modulation of the signal generated by this hormone.

Effect of angiotensin II on cytosolic free calcium in neonatal rat cardiomyocytes

1991 ◽  
Vol 261 (1) ◽  
pp. C77-C85 ◽  
Author(s):  
D. C. Kem ◽  
E. I. Johnson ◽  
A. M. Capponi ◽  
D. Chardonnens ◽  
U. Lang ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Sarcoplasmic Reticulum ◽  
Ventricular Myocytes ◽  
Acute Effect ◽  
Neonatal Rat ◽  
Free Calcium ◽  
Receptor Subtype ◽  
Ang Ii ◽  
Rat Cardiomyocytes ◽  
Neonatal Rat Ventricular Myocytes

The effect of angiotensin II (ANG II) on cytosolic free Ca2+ concentration ([Ca2+]i) was studied in cultured neonatal rat ventricular myocytes. [Ca2+]i was estimated in groups of one to three cells by dual-wavelength microfluorometry or in cell populations using conventional fluorometry. ANG II (10(-8) M) produced an acute short-lived increase over the control basal diastolic [Ca2+]i and increased the frequency of the [Ca2+]i transients. The amplitude of the [Ca2+]i transients was decreased to 64.4% of basal values. The effect of ANG II on [Ca2+]i was blocked by the selective AT1 receptor subtype antagonist Du Pont 753 but not by the AT2 antagonist PD 123319. Removal of extracellular Ca2+ or blockade of voltage-gated Ca2+ channels in cells cultured for 5-7 days abolished the [Ca2+]i transients, but only partially diminished the effect of ANG II on [Ca2+]i. Thapsigargin, an inhibitor of sarcoplasmic reticulum Ca(2+)-Mg(2+)-ATPase, reduced or abolished the [Ca2+]i response to ANG II. Phorbol 12-myristate 13-acetate (PMA), 10(-6) and 10(-7) M, also decreased the amplitude of the Ca2+ transients similar to ANG II. Pretreatment with 10(-6) M PMA or 10(-6) M 1-oleoyl-2-acetyl-glycerol (OAG) inhibited the initial rise in [Ca2+]i and the Ca2+ transients. Thus ANG II produces an acute rise in [Ca2+]i which is derived predominantly from sarcoplasmic reticulum intracellular stores. This acute effect is followed by a significant reduction in the amplitude for the Ca2+ transient and may be mediated by activation of protein kinase C.

Nav1.5-dependent persistent Na+ influx activates CaMKII in rat ventricular myocytes and N1325S mice

2011 ◽  
Vol 301 (3) ◽  
pp. C577-C586 ◽  
Author(s):  
Lina Yao ◽  
Peidong Fan ◽  
Zhan Jiang ◽  
Serge Viatchenko-Karpinski ◽  
Yuzhi Wu ◽  
...  
Keyword(s):  
Ventricular Myocytes ◽  
Neonatal Rat ◽  
Polymorphic Ventricular Tachycardia ◽  
Inhibitory Peptide ◽  
Rat Ventricular Myocytes ◽  
Protein Protein Interaction ◽  
Intracellular Ca ◽  
Dependent Protein ◽  
Neonatal Rat Ventricular Myocytes ◽  
Camkii Activation

Late Na+ current ( INaL) and Ca2+/calmodulin-dependent protein kinase II (CaMKII) are both increased in the diseased heart. Recently, CaMKII was found to phosphorylate the Na+ channel 1.5 (Nav1.5), resulting in enhanced INaL. Conversely, an increase of INaL would be expected to cause elevation of intracellular Ca2+ and activation of CaMKII. However, a relationship between enhancement of INaL and activation of CaMKII has yet to be demonstrated. We investigated whether Na+ influx via Nav1.5 leads to CaMKII activation and explored the functional significance of this pathway. In neonatal rat ventricular myocytes (NRVM), treatment with the INaL activators anemone toxin II (ATX-II) or veratridine increased CaMKII autophosphorylation and increased phosphorylation of CaMKII substrates phospholamban and ryanodine receptor 2. Knockdown of Nav1.5 (but not Nav1.1 or Nav1.2) prevented ATX-II-induced CaMKII phosphorylation, providing evidence for a specific role of Nav1.5 in CaMKII activation. In support of this view, CaMKII activity was also increased in hearts of transgenic mice overexpressing a gain-of-function Nav1.5 mutant (N1325S). The effects of both ATX-II and the N1325S mutation were reversed by either INaL inhibition (with ranolazine or tetrodotoxin) or CaMKII inhibition (with KN93 or autocamtide 2-related inhibitory peptide). Furthermore, ATX-II treatment also induced CaMKII-Nav1.5 coimmunoprecipitation. The same association between CaMKII and Nav1.5 was also found in N1325S mice, suggesting a direct protein-protein interaction. Pharmacological inhibitions of either CaMKII or INaL also prevented ATX-II-induced cell death in NRVM and reduced the incidence of polymorphic ventricular tachycardia induced by ATX-II in rat perfused hearts. Taken together, these results suggest that a Nav1.5-dependent increase in Na+ influx leads to activation of CaMKII, which in turn phosphorylates Nav1.5, further promoting Na+ influx. Pharmacological inhibition of either CaMKII or Nav1.5 can ameliorate cardiac dysfunction caused by excessive Na+ influx.

scholarly journals High-glucose-induced regulation of intracellular ANG II synthesis and nuclear redistribution in cardiac myocytes

2007 ◽  
Vol 293 (2) ◽  
pp. H939-H948 ◽  
Author(s):  
Vivek P. Singh ◽  
Bao Le ◽  
Vadiraja B. Bhat ◽  
Kenneth M. Baker ◽  
Rajesh Kumar
Keyword(s):  
High Glucose ◽  
Ventricular Myocytes ◽  
Intracellular Localization ◽  
Renin Angiotensin System ◽  
Neonatal Rat ◽  
Ang Ii ◽  
Cell Lysates ◽  
Prevailing Paradigm ◽  
Neonatal Rat Ventricular Myocytes

The prevailing paradigm is that cardiac ANG II is synthesized in the extracellular space from components of the circulating and/or local renin-angiotensin system. The recent discovery of intracrine effects of ANG II led us to determine whether ANG II is synthesized intracellularly in neonatal rat ventricular myocytes (NRVM). NRVM, incubated in serum-free medium, were exposed to isoproterenol or high glucose in the absence or presence of candesartan, which was used to prevent angiotensin type 1 (AT1) receptor-mediated internalization of ANG II. ANG II was measured in cell lysates and the culture medium, which represented intra- and extracellularly synthesized ANG II, respectively. Isoproterenol increased ANG II concentration in cell lysates and medium of NRVM in the absence or presence of candesartan. High glucose markedly increased ANG II synthesis only in cell lysates in the absence and presence of candesartan. Western analysis showed increased intracellular levels of angiotensinogen, renin, and chymase in high-glucose-exposed cells. Confocal immunofluorocytometry confirmed the presence of ANG II in the cytoplasm and nucleus of high-glucose-exposed NRVM and along the actin filaments in isoproterenol-exposed cells. ANG II synthesis was dependent on renin and chymase in high-glucose-exposed cells and on renin and angiotensin-converting enzyme in isoproterenol-exposed cells. In summary, the site of ANG II synthesis, intracellular localization, and the synthetic pathway in NRVM are stimulus dependent. Significantly, NRVM synthesized and retained ANG II intracellularly, which redistributed to the nucleus under high-glucose conditions, suggesting a role for an intracrine mechanism in diabetic conditions.

Abstract 1508: Stim1-Mediated Store-Operated Calcium (SOC) Influx in Calcineurin-Dependent Cardiac Hypertrophy

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Xiang Luo ◽  
Samvit Tandan ◽  
Nan Jiang ◽  
Beverly A Rothermel ◽  
Joseph A Hill
Keyword(s):  
Ventricular Myocytes ◽  
Cyclopiazonic Acid ◽  
Heart Association ◽  
Cell Types ◽  
Dominant Negative ◽  
Neonatal Rat ◽  
Isolated Cells ◽  
Neonatal Cardiomyocytes ◽  
South Central ◽  
Intracellular Ca

Introduction : Calcineurin is activated by Ca 2+ /calmodulin and promotes pathological remodeling of the heart. In many cell types, store-operated calcium (SOC) entry, a process triggered by depletion of ER Ca stores, plays an obligate role in repleting Ca stores, and hence, in subsequent sustained increases in intracellular Ca. Little is known regarding SOC Ca influx in heart or its role in stress responsiveness. Methods and Results : Using RT-PCR, immunofluorescence staining, and Western blot methods, we found that Stim1, a recently identified molecular component of the SOC channel, is expressed in both neonatal rat ventricular myocytes (NRVMs) and adult myocytes. Working with isolated cells, we used Fura-2 to measure SOC Ca influx, finding that this mechanism does, in fact, exist in cardiomyocytes. However, SOC Ca influx was substantially more robust in neonatal myocytes than adult. Given that SOC current was prominent in neonatal cells, we tested ventricular myocytes isolated from calcineurin-transgenic mice, a model where the fetal gene program is prominently activated. Here, we found that Stim1 is up-regulated (1.9±0.4-fold, p<0.05). Treatment of NRVMs with angiotensin II (100nM) elicited similar increases in Stim1 (2.3±0.2-fold, p<0.01). To probe the molecular basis of cardiac SOC current, we expressed mutant (D76A, constitutively active; ΔERM, dominant negative) forms of human Stim1 in NRVMs. D76A markedly increased SOC Ca influx triggered by thapsigargin (2μM) or cyclopiazonic acid (50μM). In contrast, ΔERM blocked SOC Ca influx. Conclusion: SOC Ca entry exists prominently in neonatal cardiomyocytes but is down-regulated in adult cells. Stim1 participates in SOC current and is up-regulated during hypertrophic transformation of the myocardium. We conclude that SOC Ca currents are part of the fetal gene program in heart and may play a significant role in the sustained Ca overload of heart failure. This research has received full or partial funding support from the American Heart Association, AHA South Central Affiliate (Arkansas, New Mexico, Oklahoma & Texas).

Phosphoinositide 3-kinase regulates excitation-contraction coupling in neonatal cardiomyocytes

2004 ◽  
Vol 286 (2) ◽  
pp. H796-H805 ◽  
Author(s):  
Susan A. McDowell ◽  
Eileen McCall ◽  
William F. Matter ◽  
Thomas B. Estridge ◽  
Chris J. Vlahos
Keyword(s):  
Steady State ◽  
Ventricular Myocytes ◽  
Neonatal Rat ◽  
Dependent Manner ◽  
Neonatal Cardiomyocytes ◽  
Reverse Mode ◽  
Ec Coupling ◽  
Intracellular Ca ◽  
Phosphoinositide 3 Kinase ◽  
State Contraction

The phosphoinositide 3-kinase (PI3K) inhibitor LY-294002 decreased steady-state contraction in neonatal rat ventricular myocytes (NRVM). To determine whether the effect on steady-state contraction could be due to decreased intracellular Ca2+ content, Ca2+ content was assessed with fluorescent plate reader analysis by using the caffeine-releasable Ca2+ stores as an index of sarcoplasmic reticulum (SR) Ca2+ content. Caffeine-releasable Ca2+ content was diminished in a dose-dependent manner with LY-294002, suggesting that the decrease in steady-state contraction was due to diminished intracellular Ca2+ content. Activation of the L-type Ca2+ channel by BAY K 8644 was attenuated by LY-294002, suggesting the effect of LY-294002 is to reduce Ca2+ influx at this channel. To investigate whether additional proteins involved in excitation-contraction (EC) coupling are likewise regulated by PI3K activity, the effects of compounds acting at sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA2a), the ryanodine receptor, and the Na/Ca exchanger (NCX) were compared with LY-294002. Inhibition of SERCA2a by thapsigargin increased basal Ca2+ levels in contrast to LY-294002, indicating that SERCA2a activity is sustained in the presence of LY-294002. Ryanodine decreased SR Ca2+ content. The additive effect with coadministration of LY-294002 could be attributed to a decrease in Ca2+ influx at the L-type Ca2+ channel. The NCX inhibitor Ni2+ was used to investigate whether the decrease in intracellular Ca2+ content with LY-294002 could be due to inhibition of the NCX reverse-mode activity. The minimal effect of LY-294002 with Ni2+ suggests that the primary effect of LY-294002 on EC coupling occurs through inhibition of PI3K-mediated L-type Ca2+ channel activity.

CARP Plays a Key Role in Cellular Growth Under Hypertrophic Stimuli in Neonatal Rat Ventricular Myocytes

2013 ◽  
Vol 9 ◽  
Author(s):  
Tara A Shrout
Keyword(s):  
Gene Expression ◽  
Ventricular Myocytes ◽  
Cellular Growth ◽  
Neonatal Rat ◽  
Transcriptional Level ◽  
Dual Nature ◽  
Hypertrophic Growth ◽  
Rat Ventricular Myocytes ◽  
Neonatal Rat Ventricular Myocytes ◽  
Over Time

Cardiac hypertrophy is a growth process that occurs in response to stress stimuli or injury, and leads to the induction of several pathways to alter gene expression. Under hypertrophic stimuli, sarcomeric structure is disrupted, both as a consequence of gene expression and local changes in sarcomeric proteins. Cardiac-restricted ankyrin repeat protein (CARP) is one such protein that function both in cardiac sarcomeres and at the transcriptional level. We postulate that due to this dual nature, CARP plays a key role in maintaining the cardiac sarcomere. GATA4 is another protein detected in cardiomyocytes as important in hypertrophy, as it is activated by hypertrophic stimuli, and directly binds to DNA to alter gene expression. Results of GATA4 activation over time were inconclusive; however, the role of CARP in mediating hypertrophic growth in cardiomyocytes was clearly demonstrated. In this study, Neonatal Rat Ventricular Myocytes were used as a model to detect changes over time in CARP and GATA4 under hypertrophic stimulation by phenylephrine and high serum media. Results were detected by analysis of immunoblotting. The specific role that CARP plays in mediating cellular growth under hypertrophic stimuli was studied through immunofluorescence, which demonstrated that cardiomyocyte growth with hypertrophic stimulation was significantly blunted when NRVMs were co-treated with CARP siRNA. These data suggest that CARP plays an important role in the hypertrophic response in cardiomyocytes.

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