Abstract 744: Arrhythmogenesis in Heart Failure: Role of Interstitial Fibrosis

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Jorge E Massare ◽  
R. Haris Naseem ◽  
Jeff M Berry ◽  
Farhana Rob ◽  
Joseph A Hill
Keyword(s):  
Heart Failure ◽  
Interstitial Fibrosis ◽  
Systolic Dysfunction ◽  
Ventricular Tachyarrhythmia ◽  
Severe Heart Failure ◽  
Pressure Overload ◽  
Cellular Events ◽  
Action Potential Prolongation

Background: Sudden cardiac death due to ventricular tachyarrhythmia (VT) accounts for a large number of deaths in patients with heart failure. Several cellular events which occur during pathological remodeling of the failing ventricle are implicated in the genesis of VT, including action potential prolongation, dysregulation of intercellular coupling, and fibrosis. Interestingly, transgenic mice over-expressing constitutively active PKD (caPKD) develop severe heart failure without interstitial fibrosis, an otherwise prominent feature of the disease. The goal here was to define the role of interstitial fibrosis in the proarrhythmic phenotype of failing myocardium. Methods and Results: We performed echocardiographic, electrocardiographic, and in vivo electrophysiologic studies in 8 –10 week old caPKD mice (n=12). Similar studies were performed in mice with load-induced heart failure induced by surgical pressure overload (sTAB, n=10), a model of heart failure with prominent interstitial fibrosis. caPKD and sTAB mice showed similar degrees of ventricular dilation (LV systolic dimension caPKD 2.4±0.8 mm vs 3.0±0.9 sTAB, p=0.18) and severe systolic dysfunction (% fractional shortening caPKD 25±11 vs 28±11 sTAB, p=0.62). Yet, caPKD mice showed minimal interstitial fibrosis, comparable to unoperated controls. With the exception of ventricular refractory period, which was higher in caPKD (48±11 msec vs 36±7 TAB and 40±8 WT, p<0.05), other electrocardiographic and electrophysiologic variables were similar among the 3 groups (p=NS), including heart rate, QT duration, and mean VT threshold. As expected, VT (≥3beats) was readily inducible by programmed stimulation in sTAB mice (7/10). By contrast, VT was less inducible in caPKD mice (4/12; p=0.1 vs TAB and <0.05 vs WT), and uninducible in unoperated controls (0/12). VT was polymorphic in both models, but episodes of VT were both slower (VT cycle length caPKD 58±4.0 msec vs 48±1 sTAB, p=0.016) and longer in caPKD mice (caPKD 1.8±0.7 sec vs 0.47±0.3 sTAB, p=0.038). Conclusion: Interstitial fibrosis contributes to the inducibility, maintenance, and rate of VT in heart failure. These findings highlight the importance of anti-remodeling therapies known to target fibrosis in heart disease.

scholarly journals Lats2 promotes heart failure by stimulating p53-mediated apoptosis during pressure overload

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Dan Shao ◽  
Peiyong Zhai ◽  
Chengchen Hu ◽  
Risa Mukai ◽  
Sebastiano Sciarretta ◽  
...  
Keyword(s):  
Heart Failure ◽  
Interstitial Fibrosis ◽  
Hippo Pathway ◽  
Pressure Overload ◽  
Mouse Heart ◽  
Response To Stress ◽  
The Hippo Pathway ◽  
Dependent Mechanism

AbstractThe Hippo pathway plays a wide variety of roles in response to stress in the heart. Lats2, a component of the Hippo pathway, is phosphorylated by Mst1/2 and, in turn, phosphorylates YAP, causing inactivation of YAP. Lats2 stimulates apoptosis and negatively affects hypertrophy in cardiomyocytes. However, the role of Lats2 during cardiac stress is poorly understood in vivo. Lats2 is activated in the mouse heart in response to transverse aortic constriction (TAC). We used systemic Lats2 +/- mice to elucidate the role of endogenous Lats2. Cardiac hypertrophy and dysfunction induced by 4 weeks of TAC were attenuated in Lats2 +/- mice, and interstitial fibrosis and apoptosis were suppressed. Although TAC upregulated the Bcl-2 family proapoptotic (Bax and Bak) and anti-apoptotic (Bcl-2 and Bcl-xL) molecules in non-transgenic mice, TAC-induced upregulation of Bax and Bak was alleviated and that of Bcl-2 was enhanced in Lats2 +/- mice. TAC upregulated p53, but this upregulation was abolished in Lats2 +/- mice. Lats2-induced increases in apoptosis and decreases in survival in cardiomyocytes were inhibited by Pifithrin-α, a p53 inhibitor, suggesting that Lats2 stimulates apoptosis via a p53-dependent mechanism. In summary, Lats2 is activated by pressure overload, thereby promoting heart failure by stimulating p53-dependent mechanisms of cell death.

scholarly journals Orai1 Channel Inhibition Preserves Left Ventricular Systolic Function and Normal Ca 2+ Handling After Pressure Overload

Circulation ◽  
2020 ◽  
Vol 141 (3) ◽  
pp. 199-216 ◽  
Author(s):  
Fiona Bartoli ◽  
Marc A. Bailey ◽  
Baptiste Rode ◽  
Philippe Mateo ◽  
Fabrice Antigny ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Systolic Function ◽  
Systolic Dysfunction ◽  
Pressure Overload ◽  
Left Ventricular Systolic Function ◽  
Left Ventricular ◽  
Specific Expression ◽  
Channel Inhibition

Background: Orai1 is a critical ion channel subunit, best recognized as a mediator of store-operated Ca 2+ entry (SOCE) in nonexcitable cells. SOCE has recently emerged as a key contributor of cardiac hypertrophy and heart failure but the relevance of Orai1 is still unclear. Methods: To test the role of these Orai1 channels in the cardiac pathophysiology, a transgenic mouse was generated with cardiomyocyte-specific expression of an ion pore-disruptive Orai1 R91W mutant (C-dnO1). Synthetic chemistry and channel screening strategies were used to develop 4-(2,5-dimethoxyphenyl)-N-[(pyridin-4-yl)methyl]aniline (hereafter referred to as JPIII), a small-molecule Orai1 channel inhibitor suitable for in vivo delivery. Results: Adult mice subjected to transverse aortic constriction (TAC) developed cardiac hypertrophy and reduced ventricular function associated with increased Orai1 expression and Orai1-dependent SOCE (assessed by Mn 2+ influx). C-dnO1 mice displayed normal cardiac electromechanical function and cellular excitation-contraction coupling despite reduced Orai1-dependent SOCE. Five weeks after TAC, C-dnO1 mice were protected from systolic dysfunction (assessed by preserved left ventricular fractional shortening and ejection fraction) even if increased cardiac mass and prohypertrophic markers induction were observed. This is correlated with a protection from TAC-induced cellular Ca 2+ signaling alterations (increased SOCE, decreased [Ca 2+ ] i transients amplitude and decay rate, lower SR Ca 2+ load and depressed cellular contractility) and SERCA2a downregulation in ventricular cardiomyocytes from C-dnO1 mice, associated with blunted Pyk2 signaling. There was also less fibrosis in heart sections from C-dnO1 mice after TAC. Moreover, 3 weeks treatment with JPIII following 5 weeks of TAC confirmed the translational relevance of an Orai1 inhibition strategy during hypertrophic insult. Conclusions: The findings suggest a key role of cardiac Orai1 channels and the potential for Orai1 channel inhibitors as inotropic therapies for maintaining contractility reserve after hypertrophic stress.

scholarly journals Protective Effect of Qiliqiangxin Capsule on Energy Metabolism and Myocardial Mitochondria in Pressure Overload Heart Failure Rats

2013 ◽  
Vol 2013 ◽  
pp. 1-9 ◽  
Author(s):  
Junfang Zhang ◽  
Cong Wei ◽  
Hongtao Wang ◽  
Siwen Tang ◽  
Zhenhua Jia ◽  
...  
Keyword(s):  
Heart Failure ◽  
Energy Metabolism ◽  
Mitochondrial Function ◽  
Pressure Overload ◽  
Metabolic Intermediate ◽  
Substrate Metabolism ◽  
Myocardial Mitochondria ◽  
Tcm Theory

Qiliqiangxin capsule (QL) was developed under the guidance of TCM theory of collateral disease and had been shown to be effective and safe for the treatment of heart failure. The present study explored the role of and mechanism by which the herbal compounds QL act on energy metabolism,in vivo, in pressure overload heart failure. SD rats received ascending aorta constriction (TAC) to establish a model of myocardial hypertrophy. The animals were treated orally for a period of six weeks. QL significantly inhibited cardiac hypertrophy due to ascending aortic constriction and improved hemodynamics. This effect was linked to the expression levels of the signaling factors in connection with upregulated energy and the regulation of glucose and lipid substrate metabolism and with a decrease in metabolic intermediate products and the protection of mitochondrial function. It is concluded that QL may regulate the glycolipid substrate metabolism by activating AMPK/PGC-1αaxis and reduce the accumulation of free fatty acids and lactic acid, to protect cardiac myocytes and mitochondrial function.

Abstract 278: Domain-specific Roles for GRK2 in Cardiac Hypertrophy and Heart Failure

2016 ◽  
Vol 119 (suppl_1) ◽  
Author(s):  
Sarah M Schumacher ◽  
Erhe Gao ◽  
J. Kurt Chuprun ◽  
Walter J. Koch
Keyword(s):  
Heart Failure ◽  
Interstitial Fibrosis ◽  
Heart Function ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Cross Sectional ◽  
Amino Terminal ◽  
Domain Specific ◽  
Rgs Domain

During heart failure (HF), cardiac levels and activity of the G protein-coupled receptor (GPCR) kinase (GRK) GRK2 are elevated and contribute to adverse remodeling and contractile dysfunction, while inhibition via a carboxyl-terminal peptide, βARKct, enhances heart function and can prevent HF. Mounting evidence supports the idea of a dynamic “interactome” in which GRK2 can uncouple GPCRs via novel protein-protein interactions. Several GRK2 interacting partners are important for adaptive and maladaptive myocyte growth; therefore, an understanding of domain-specific interactions with signaling and regulatory molecules could lead to novel targets for HF therapy. For instance, GRK2 contains a putative amino-terminal R egulator of G protein S ignaling (RGS) domain (βARKrgs) that directly interacts with Gαq and inhibits signaling. Previously, our lab investigated cardiac-specific transgenic expression of a fragment of this RGS domain (βARKnt), that did not reduce acute hypertrophy after pressure overload or demonstrate RGS activity in vivo against Gαq-mediated signaling. In contrast, βARKnt induced hypertrophy and elevated β-adrenergic receptor (βAR) density without altering agonist-induced contractility or adenylyl cyclase activity, due to a compensatory increase in GRK2 activity. Importantly, βAR downregulation in response to chronic agonist administration was attenuated by βARKnt expression, indicating a novel regulation of βAR receptor density. Herein, we investigated the effect of βARKnt expression during chronic pressure overload post trans-aortic constriction (TAC). Echocardiographic analysis revealed increased posterior wall thickness and left-ventricular mass 4 weeks post-TAC compared to non-transgenic littermate controls. Importantly, despite enhanced hypertrophy, the progression to HF was inhibited in βARKnt mice 14 weeks post-TAC. Histological analysis of interstitial fibrosis and cross-sectional area is underway to determine alterations in maladaptive remodeling. Further, cardiomyocyte signaling and βARKnt protein-binding partners are a focus, since our data indicate that βARKnt-mediated regulation of βAR density may provide a novel means of cardioprotection during pressure-overload induced HF.

Abstract 381: Mcur1 is a Potential Target to Modulate Cardiac Contractility and Alleviate Cardiac Function During Heart Failure

2020 ◽  
Vol 127 (Suppl_1) ◽  
Author(s):  
Rajika Roy ◽  
Santhanam Shanmughapriya ◽  
Xueqian Zhang ◽  
Jianliang Song ◽  
Dhanendra Tomar ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Function ◽  
Contractile Function ◽  
Cardiac Contractility ◽  
Pressure Overload ◽  
Dominant Negative ◽  
Selective Channel

Cardiac contractility is regulated by the intracellular Ca 2+ concentration fluxes which are actively regulated by multiple channels and transporters. Ca 2+ uptake into the mitochondrial matrix is precisely controlled by the highly Ca 2+ selective channel, Mitochondrial Calcium Uniporter (MCU). Earlier studies on the cardiac-specific acute MCU knockout and a transgenic dominant-negative MCU mice have demonstrated that mitochondrial Ca 2+ ( m Ca 2+ ) signaling is necessary for cardiac ‘‘fight-or-flight’’ contractile response, however, the role of m Ca 2+ buffering to shape global cytosolic Ca 2+ levels and affect E-C coupling, particularly the Ca 2+ transient, on a beat-to-beat basis still remains to be solved. Our earlier studies have demonstrated that loss of MCU Regulator 1 (MCUR1) in cardiomyocytes results in the impaired m Ca 2+ uptake. We have now employed the cardiac-specific MCUR1 knockout mouse to dissect the precise role of MCU in regulating cytosolic Ca 2+ transients associated with excitation-contraction (E-C) coupling and cardiac function. Results from our studies including the in vivo analyses of cardiac physiology during normal and pressure-overloaded mouse models and in vitro experiments including single-cell cardiac contractility, calcium transients, and electrophysiology measurements demonstrate that MCUR1/MCU regulated m Ca 2+ buffering in cardiomyocytes, although insignificant under basal condition, becomes critical in stress induced conditions and actively participates in regulating the c Ca 2+ transients. Also, the ablation of MCUR1 in cardiomyocytes during stress conditions prevents m Ca 2+ overload and subsequent mROS overproduction. Our data indicate that MCUR1 ablation offers protection against pressure-overload cardiac hypertrophy. In summary, our results provide critical insights into the mechanisms by which the MCU channel contributes in regulating the contractile function of the cardiomyocytes and the role of m Ca 2+ in the development and progression of heart failure.

scholarly journals CaMKII inhibition in heart failure, beneficial, harmful, or both

2012 ◽  
Vol 302 (7) ◽  
pp. H1454-H1465 ◽  
Author(s):  
Jun Cheng ◽  
Lin Xu ◽  
Dongwu Lai ◽  
Arnaud Guilbert ◽  
Hyun Joung Lim ◽  
...  
Keyword(s):  
Heart Failure ◽  
Diastolic Function ◽  
Troponin I ◽  
Interstitial Fibrosis ◽  
Pressure Overload ◽  
Inactivation Kinetics ◽  
Adrenergic Stimulation ◽  
Adrenergic Regulation ◽  
Cardiac Reserve

Calmodulin-dependent protein kinase II (CaMKII) has been proposed to be a therapeutic target for heart failure (HF). However, the cardiac effect of chronic CaMKII inhibition in HF has not been well understood. We have tested alterations of Ca2+ handling, excitation-contraction coupling, and in vivo β-adrenergic regulation in pressure-overload HF mice with CaMKIIδ knockout (KO). HF was produced in wild-type (WT) and KO mice 1 wk after severe thoracic aortic banding (sTAB) with a continuous left ventricle (LV) dilation and reduction of ejection fraction for up to 3 wk postbanding. Cardiac hypertrophy was similar between WT HF and KO HF mice. However, KO HF mice manifested exacerbation of diastolic function and reduction in cardiac reserve to β-adrenergic stimulation. Compared with WT HF, L-type calcium channel current ( ICa) density in KO HF LV was decreased without changes in ICa activation and inactivation kinetics, whereas ICa recovery from inactivation was accelerated and Ca2+-dependent ICa facilitation, a positive staircase blunted in WT HF, was recovered. However, ICa response to isoproterenol was reduced. KO HF myocytes manifested dramatic decrease in sarcoplasmic reticulum (SR) Ca2+ leak and slowed cytostolic Ca2+ concentration decline. Sarcomere shortening was increased, but relaxation was slowed. In addition, an increase in myofilament sensitivity to Ca2+ and the slow skeletal muscle troponin I-to-cardiac troponin I ratio and interstitial fibrosis and a decrease in Na/Ca exchange function and myocyte apoptosis were observed in KO HF LV. CaMKIIδ KO cannot suppress severe pressure-overload-induced HF. Although cellular contractility is improved, it reduces in vivo cardiac reserve to β-adrenergic regulation and deteriorates diastolic function. Our findings challenge the strategy of CaMKII inhibition in HF.

Abstract 988: Tissue Inhibitor Of Metalloproteinase-3 Regulates Myocardial Fibrosis By Regulating The TGFβ-TNF Interaction

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Zamaneh Kassiri ◽  
Mehrdad Hariri ◽  
Shalini Anthwal ◽  
Gavin Y Oudit ◽  
Fayez Dawood ◽  
...  
Keyword(s):  
Heart Failure ◽  
Interstitial Fibrosis ◽  
Heart Function ◽  
Systolic Heart Failure ◽  
Pressure Overload ◽  
Neutralizing Antibody ◽  
Left Ventricular ◽  
Tissue Inhibitor Of Metalloproteinase ◽  
Extracellular Matrix Components

Fibrosis is the outcome of excess deposition of extracellular matrix components and underlies diastolic and systolic heart failure. Metalloproteinases (MMPs and ADAMs) and their inhibitors (TIMPs) are critical regulators of ECM turnover and fibrosis. TIMP3 is a potent inhibitor of MMPs and ADAMs, whereby it regulates tissue proteolysis and cytokine bioavailability. TIMP3 levels are reduced in human heart disease, and we found that mice lacking Timp3 (KO) exhibit severe dilated cardiomyopathy (DCM), extensive interstitial fibrosis and early heart failure (HF) following pressure overload compared to wild type (WT) mice. We showed upregulated TNF signaling within 6 hrs of aortic banding (AB) which when blocked, significantly improved DCM and prevented HF. We then investigated the mechanism underlying the extensive fibrosis despite the increased MMP activity in the TIMP3KO mice. Comparative microarray analyses show a significant upregulation of the TGFβ1 signaling pathway within 6 hrs of AB in KO vs WT hearts. In vivo treatment of KO-AB mice with a TGFβ1-neutralizing antibody (1D11) completely abolishes fibrosis, markedly improves left ventricular dilation, systolic and diastolic heart function (LVEDD(mm): 4.3 ± 0.1 in WT, 5.4 ± 0.1 in KO, 4.7 ± 0.1 in KO+ 1D11; fractional shortening(%): 40.2 ± 1.7 in WT, 19.6 ± 2.2 in KO, 36.2 ± 0.7 in KO+ 1D11; E/Ac ratio: 2.5 ± 0.3 in WT, 1.8 ± 0.3 in KO, 2.4 ± 0.2 in KO + 1D11; n = 22, P < 0.05). Interestingly, blocking TGFβ1 also prevented the early rise in TNF in KO hearts. Using primary neonatal culture systems, we found that cardiomyocyte-fibroblast interaction is essential for a fibrotic response to agonists (Ang II, PE). Further, KO co-cultures generate a 5-fold greater fibrosis (P < 0.05) through activation of Smad2/3 pathway compared to WT. TGFβ also regulates TNF transcription more potently in KO cells since a 3-fold higher TNF induction occurred in response to recombinant TGFβ1 in KO vs WT co-cultures (P < 0.05). In conclusion, TIMP3 is a critical regulator of TGFβ1 and TNF, and its deficiency induces parallel dysregulations in the signaling of these cytokines very early after pressure overload, leading to severe interstitial fibrosis and DCM, hence, TIMP3-based therapies can simultaneously impact fibrosis and DCM.

Abstract 1342: The NF-kappaB P50 Subunit Protects Against Remodeling and Cardiac Dysfunction Following Myocardial Infarction

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Leo Timmers ◽  
J Karlijn van Keulen ◽  
Imo I Hoefer ◽  
Joost P Sluijter ◽  
Marie Jose Goumans ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Heart Failure ◽  
Molecular Mechanisms ◽  
Interstitial Fibrosis ◽  
Systolic Dysfunction ◽  
Protective Role ◽  
Left Ventricular ◽  
Lv Remodeling ◽  
Nf Kappab

Introduction Left ventricular (LV) remodeling leads to congestive heart failure and is a main determinant of morbidity and mortality following myocardial infarction (MI). To further improve the treatment of post infarct LV remodeling, a better understanding of the molecular mechanisms involved in this complicated process is required. The nuclear factor (NF)- κB family (p50, p52, p65) usually forms dimers that regulate DNA transcription in response to a variety of stimuli including pro-inflammatory cytokines, oxidative stress and also ischemia. Inhibition of NF- κB has been shown to reduce heart failure following MI in rats. The specific role of the different NF- κB subunits during LV remodeling, however, has not been clarified thus far. In this study, we elucidate the role of the NF- κB p50 subunit in post infarct LV remodeling. Methods and Results MI was induced in wild type C57Bl6 mice and NF- κB p50 KO mice. Without affecting infarct size (45.4 ± 4.3 vs. 42.5 ± 4.6%; p=0.461), the absence of NF- κB p50 increased the extent of LV remodeling (EDV: 175 ± 13 vs. 107 ± 11 μl; p=0.005) and aggravated systolic dysfunction (LVEF: 16.1 ± 1.5 % vs. 24.7 ± 3.7%; p=0.045) 28 days following MI as assessed by magnetic resonance imaging (9.4 T). In the non-infarcted myocardium, interstitial fibrosis (1.53 ± 0.28 vs. 1.05 ± 0.15 grayvalue/μm 2 ; p=0.042) and hypertrophy (426 ± 51 vs. 251 ± 12 μm 2 /cardiomyocyte; p=0.018) were increased in NF-κB p50 KO mice. In the infarct area, however, collagen density was decreased (15.11 ± 1.16 vs. 27.28 ± 4.93 grayvalue/μm 2 ; p=0.028), which was accompanied by increased TNF-alpha mRNA expression (0.086 ± 0.04 vs. 0.026 ± 0.015; p=0.046) and increased MMP9 activity (0.31 ± 0.03 vs. 0.19 ± 0.03; p=0.049) Conclusion These data provide evidence for a protective role of NF- κB p50 in post infarct maladaptive LV remodeling, most likely by reducing inflammatory cytokine production and matrix degradation.

scholarly journals CITED4 Protects Against Adverse Remodeling in Response to Physiological and Pathological Stress

2020 ◽  
Author(s):  
Carolin Lerchenmüller ◽  
Charles P Rabolli ◽  
Ashish Suresh Yeri ◽  
Robert Kitchen ◽  
Ane M Salvador ◽  
...  
Keyword(s):  
Cardiac Remodeling ◽  
Cardiac Dysfunction ◽  
Ventricular Remodeling ◽  
Interstitial Fibrosis ◽  
Severe Heart Failure ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Mtor Activity

Rationale: Cardiac CITED4 is induced by exercise and is sufficient to cause physiological hypertrophy and mitigate adverse ventricular remodeling after ischemic injury. However, the role of endogenous CITED4 in response to physiological or pathological stress is unknown. Objective: To investigate the role of CITED4 in murine models of exercise and pressure overload. Methods and Results: We generated cardiomyocyte-specific CITED4 knockout mice (C4KO) and subjected them to an intensive swim exercise protocol as well as transverse aortic constriction (TAC). Echocardiography, western blotting, qPCR, immunohistochemistry, immunofluorescence, and transcriptional profiling for mRNA and miRNA expression were performed. Cellular crosstalk was investigated in vitro. CITED4 deletion in cardiomyocytes did not affect baseline cardiac size or function in young adult mice. C4KO mice developed modest cardiac dysfunction and dilation in response to exercise. After TAC, C4KOs developed severe heart failure with left ventricular dilation, impaired cardiomyocyte growth accompanied by reduced mammalian target of rapamycin (mTOR) activity and maladaptive cardiac remodeling with increased apoptosis, autophagy, and impaired mitochondrial signaling. Interstitial fibrosis was markedly increased in C4KO hearts after TAC. RNAseq revealed induction of a pro-fibrotic miRNA network. miR30d was decreased in C4KO hearts after TAC and mediated crosstalk between cardiomyocytes and fibroblasts to modulate fibrosis. miR30d inhibition was sufficient to increase cardiac dysfunction and fibrosis after TAC. Conclusions: CITED4 protects against pathological cardiac remodeling by regulating mTOR activity and a network of miRNAs mediating cardiomyocyte to fibroblast crosstalk. Our findings highlight the importance of CITED4 in response to both physiological and pathological stimuli.

Abstract 312: STIM1 And The Development Of Pressure-overload Induced Cardiac Hypertrophy In Rodents

2013 ◽  
Vol 113 (suppl_1) ◽  
Author(s):  
Ludovic O Bénard ◽  
Daniel S Matasic ◽  
Mathilde Keck ◽  
Anne-Marie Lompré ◽  
Roger J Hajjar ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Contractile Function ◽  
Interstitial Fibrosis ◽  
Pressure Overload ◽  
Aortic Pressure ◽  
Cellular Level ◽  
Left Ventricular ◽  
Cross 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 studied the role of STIM1 in a pressure-overload induced cardiac hypertrophy model in mice. We observed that STIM1 cardiac expression is increased during left ventricular hypertrophy (LVH) induced by Transverse Aortic Constriction (TAC). We then used recombinant Associated Adenovirus 9 (AAV9) to perform cardiac-targeted gene silencing in vivo. C57Bl/6 mice were injected with saline (noAAV) or with AAV9 expressing shRNA against STIM1 (shSTIM1) at the dose of 1e+11 viral genome which resulted in 70% decrease of STIM1 cardiac expression compared to control mice. Three weeks later, TAC was performed and mice were studied three other weeks later. We found that TAC-shSTIM1 treated mice did not develop LVH compared to noAAV despite the same increase in aortic pressure. Echocardiographic and hemodynamic measurements (see table) showed that TAC-shSTIM1-treated mice had LV dilation and a decreased left ventricular contractile function in line with the absence of compensatory LVH in these mice. Immunohistochemistry demonstrated that LVH prevention was observed at the cellular level with cardiac myocytes cross-section area comparable to sham littermates however with a trend towards more interstitial fibrosis. This study reveals the essential role of STIM1 in the development of compensatory LVH in mice.

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