Abstract 186: Increased STIM1 Expression Results in Altered Calcium Handling and Heart Failure

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Robert N Correll ◽  
Sanjeewa A Goonasekera ◽  
Jop H van Berlo ◽  
Adam R Burr ◽  
Federica Accornero ◽  
...  
Keyword(s):  
Heart Failure ◽  
Transgenic Mice ◽  
Cardiac Disease ◽  
Functional Performance ◽  
Pressure Overload ◽  
Calcium Handling ◽  
Activated T Cells ◽  
Baseline Activity ◽  
Mitochondrial Pathology ◽  
Dependent Protein

Stromal interaction molecule 1 (STIM1) is a Ca2+ sensor that partners with Orai1, resulting in store-operated Ca2+ entry (SOCE) that is important for maintaining endoplasmic reticulum (ER) Ca2+ homeostasis. STIM1 is expressed in the heart and upregulated during disease, but its role in disease progression is unclear. In this study we used transgenic mice with STIM1 overexpression in the heart to model the known increase of this protein in response to cardiac disease. We found that STIM1 transgenic myocytes showed elevated Ca2+ entry following store depletion and STIM1 co-localized with the type 2 ryanodine receptor (RyR2) in the sarcoplasmic reticulum (SR). In addition, STIM1 transgenic mice exhibited sudden cardiac death as early as 6 weeks of age, while mice that survived past 12 weeks developed cardiac hypertrophy that progressed to heart failure, pulmonary edema, activation of the fetal gene program, alterations in mitochondrial structure, and reduced ventricular functional performance. When pre-symptomatic STIM1 transgenic mice were subjected to disease stimuli including pressure overload stimulation or neurohumoral agonist infusion, they showed greater pathology compared to control mice. STIM1 elevation also disrupted normal Ca2+ handling in cardiac myocytes, which showed spontaneous Ca2+ transients that could be inhibited by the SOCE blocker SKF-96265, as well as increased diastolic Ca2+ levels and elevated Ca2+ spark frequency. In keeping with this increase in Ca2+ cycling we also found that STIM1 elevation resulted in an increased baseline activity of cardiac nuclear factor of activated T-cells (NFAT) and Ca2+/calmodulin-dependent protein kinase II (CaMKII). This increased CaMKII activity did not, however, translate into additional RyR2 phosphorylation, suggesting that the augmented Ca2+ spark frequency observed was likely due to an elevation in SR Ca2+ load. Our results suggest that increased STIM1 expression elicits augmented Ca2+ entry, SR Ca2+ load and Ca2+ spark frequency, that leads to mitochondrial pathology and the induction of Ca2+ sensitive hypertrophic signaling pathways that contribute to cardiac disease.

scholarly journals A Neuroligin Isoform Translated by circNlgn Contributes to Cardiac Remodeling

2021 ◽  
Author(s):  
William W Du ◽  
Jindong Xu ◽  
Weining Yang ◽  
Nan Wu ◽  
FeiYa Li ◽  
...  
Keyword(s):  
Heart Failure ◽  
Transgenic Mice ◽  
Rna Sequencing ◽  
Nuclear Localization ◽  
Cardiac Disease ◽  
Cardiac Remodeling ◽  
Pressure Overload ◽  
Left Ventricular Pressure ◽  
Circular Rna ◽  
Left Ventricular

Rationale: Fibrotic cardiac remodeling is a maladaptive response to acute or chronic injury that leads to arrythmia and progressive heart failure. The underlying mechanisms remain unclear. Objective: We performed high-throughput RNA sequencing to analyze circular RNA (circRNA) profile in human cardiac disease and developed transgenic mice to explore the roles of circNlgn. Methods and Results: Using RNA sequencing, we found that circular neuroligin RNA (circNlgn) was highly upregulated in myocardial tissues of patients with selected congenital heart defects with cardiac overload. Back-splicing of the neuroligin gene led to the translation of a circular RNA-derived peptide (Nlgn173) with a 9-amino-acid nuclear localization motif. Binding of this motif to the structural protein LaminB1 facilitated the nuclear localization of Nlgn173. CHIP analysis demonstrated subsequent binding of Nlgn173 to both ING4 and C8orf44-SGK3 promoters, resulting in aberrant collagen deposition, cardiac fibroblast proliferation, and reduced cardiomyocyte viability. Three-dimensional ultrasound imaging of circNlgn transgenic mice showed impaired left ventricular function, with further impairment when subjected to left ventricular pressure overload compared to wild type mice. Nuclear translocation of Nlgn173, dysregulated expression of ING4 and C8orf44-SGK3, and immunohistochemical markers of cardiac fibrosis were detected in a panel of 145 patient specimens. Phenotypic changes observed in left ventricular pressure overload and transgenic mice were abrogated with silencing of circNlgn or its targets ING4 and SGK3. Conclusions: We show that a circular RNA can be translated into a novel protein isoform. Dysregulation of this process contributes to fibrosis and heart failure in cardiac overload-induced remodeling. This mechanism may hold therapeutic implications for cardiac disease.

scholarly journals Cardiac Protection of Valsartan on Juvenile Rats with Heart Failure by Inhibiting Activity of CaMKII via Attenuating Phosphorylation

2017 ◽  
Vol 2017 ◽  
pp. 1-7
Author(s):  
Yao Wu ◽  
Feifei Si ◽  
Xiaojuan Ji ◽  
Kunfeng Jiang ◽  
Sijie Song ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Myocyte ◽  
Pressure Overload ◽  
The Other ◽  
Calcium Handling ◽  
Juvenile Rats ◽  
Abdominal Aortic ◽  
Calcium Handling Proteins ◽  
Increased Activity ◽  
Induce Heart Failure

Background. This study was undertaken to determine relative contributions of phosphorylation and oxidation to the increased activity of calcium/calmodulin-stimulated protein kinase II (CaMKII) in juveniles with cardiac myocyte dysfunction due to increased pressure overload. Methods. Juvenile rats underwent abdominal aortic constriction to induce heart failure. Four weeks after surgery, rats were then randomly divided into two groups: one group given valsartan (HF + Val) and the other group given placebo (HF + PBO). Simultaneously, the sham-operated rats were randomly given valsartan (Sham + Val) or placebo (Sham + PBO). After 4 weeks of treatment, Western blot analysis was employed to quantify CaMKII and relative calcium handling proteins (RyR2 and PLN) in all groups. Results. The deteriorated cardiac function was reversed by valsartan treatment. In ventricular muscle cells of group HF + PBO, Thr287 phosphorylation of CaMKII and S2808 phosphorylation of RyR2 and PLN were increased and S16 phosphorylation of PLN was decreased compared to the other groups, while Met281 oxidation was not significantly elevated. In addition, these changes in the expression of calcium handling proteins were ameliorated by valsartan administration. Conclusions. The phosphorylation of Thr286 is associated with the early activation of CaMKII rather than the oxidation of Met281.

scholarly journals The SGLT2i Dapagliflozin Reduces RV Hypertrophy Independent of Changes in RV Pressure Induced by Pulmonary Artery Banding

2021 ◽  
Author(s):  
Kim Connelly ◽  
Ellen Wu ◽  
Aylin Visram ◽  
Mark K. Friedberg ◽  
Sri Nagarjun Batchu ◽  
...  
Keyword(s):  
Heart Failure ◽  
Pulmonary Artery ◽  
Protein Expression ◽  
Right Ventricular ◽  
Sglt2 Inhibitor ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Pulmonary Artery Banding ◽  
Calcium Handling ◽  
Sglt2 Inhibition

Abstract Background— Sodium glucose linked transporter 2 (SGLT2) inhibition not only reduces morbidity and mortality in patients with diagnosed heart failure but also prevents the development of heart failure hospitalization in those at risk. While studies to date have focused on the role of SGLT2 inhibition in left ventricular failure, whether this drug class might be similarly efficacious in the treatment and prevention of right heart failure has not been unexplored. Hypothesis: We hypothesized that SGLT2 inhibition would reduce the structural, functional and molecular responses to pressure overload of the right ventricle. Methods: Thirteen-week-old Fischer F344 rats underwent pulmonary artery banding (PAB) or sham surgery prior to being randomized to receive either the SGLT2 inhibitor: dapagliflozin (0.5mg/kg/day) or vehicle by oral gavage. After six weeks of treatment, animals underwent transthoracic echocardiography and invasive hemodynamic studies. Animals were then terminated, and their hearts harvested for structural and molecular analyses. Results: PAB induced features consistent with a compensatory response to increased right ventricular (RV) afterload with elevated mass, end systolic pressure, collagen content and alteration in calcium handling protein expression (all p<0.05 when compared to sham + vehicle). Dapagliflozin reduced RV mass, including both wet and dry weight as well as normalizing the protein expression of SERCA 2A, AMPkinase and LC3I/II ratio expression (all p<0.05). Significance: Dapagliflozin reduces the structural, functional, and molecular manifestations of right ventricular pressure overload. Whether amelioration of these early changes in the RV may ultimately lead to a reduction in RV failure remains to be determined.

Abstract 159: Ablation of the Hypertension Candidate Gene ATP2B1 Leads To Deficient Calcium Cycling, Systolic Dysfunction and Heart Failure Following Pressure Overload

2014 ◽  
Vol 115 (suppl_1) ◽  
Author(s):  
Nicholas P Stafford ◽  
Min Zi ◽  
Ludwig Neyses ◽  
Elizabeth J Cartwright
Keyword(s):  
Heart Failure ◽  
Systolic Dysfunction ◽  
Pressure Overload ◽  
Early Response ◽  
Left Ventricular ◽  
Calcium Handling ◽  
Calcium Cycling ◽  
Lung Weight ◽  
Hypertrophic Growth ◽  
Ventricular Elastance

Mutations in ATP2B1 encoding the ubiquitous calcium extrusion pump Plasma Membrane Calcium ATPase 1 (PMCA1) have recently identified it as having the strongest association of any gene to hypertension, yet the role of PMCA1 in the pressure-overloaded heart is not known. To investigate this we generated a novel mouse line carrying cardiomyocyte-specific deletion of PMCA1 (PMCA1 cko ) and challenged them with transverse aortic constriction (TAC) alongside littermate ‘floxed’ controls (PMCA1 f/f ). After two weeks, echocardiographic analysis revealed signs of systolic dysfunction and left ventricular (LV) dilation in PMCA1 cko hearts as evidenced by reduced fractional shortening and increased diastolic diameter (both p<0.05), whilst function in PMCA1 f/f TAC controls remained preserved. This was accompanied by an increase in normalised lung weight in PMCA1 cko mice compared to sham operated and TAC controls (p<0.05) indicative of pulmonary congestion and a progression into LV failure, despite comparable hypertrophic growth amongst the two TAC cohorts. Hemodynamic analysis following LV catheterisation revealed contractility, as measured by left ventricular elastance (E es ), to be increased in controls after TAC (PMCA1 f/f TAC 12.69 ± 1.63 vs sham 7.02 ± 1.11 mmHg/μl, p<0.05), a change which was not reciprocated in knockout hearts (PMCA1 cko TAC 7.70 ± 1.19 vs sham 7.22 ± 1.55 mmHg/μl). To examine whether altered calcium handling could be the underlying cause of the observed phenotype, cardiomyocytes were isolated following one week TAC and loaded with Indo-1, prior to the onset of failure in PMCA1 cko hearts. Compatible with an increase in E es , systolic calcium levels were higher in PMCA1 f/f myocytes following pressure overload compared to sham controls (p<0.05), whilst PMCA1 cko TAC myocytes displayed equivalent peak calcium levels to their respective sham controls. These results suggest that PMCA1 may play a necessary role in enhancing calcium cycling during the early response to pressure overload, and that disrupting this gene may increase the susceptibility to heart failure under these conditions. This may provide first evidence of a novel genetic basis for the development of heart failure in a proportion of hypertensive patients.

scholarly journals Cardiac 12/15 lipoxygenase–induced inflammation is involved in heart failure

2009 ◽  
Vol 206 (7) ◽  
pp. 1565-1574 ◽  
Author(s):  
Yosuke Kayama ◽  
Tohru Minamino ◽  
Haruhiro Toko ◽  
Masaya Sakamoto ◽  
Ippei Shimizu ◽  
...  
Keyword(s):  
Heart Failure ◽  
Transgenic Mice ◽  
Cardiac Fibrosis ◽  
Cardiac Fibroblasts ◽  
Systolic Dysfunction ◽  
Pressure Overload ◽  
Eicosatetraenoic Acid ◽  
Wild Type ◽  
Monocyte Chemoattractant Protein 1 ◽  
Novel Target

To identify a novel target for the treatment of heart failure, we examined gene expression in the failing heart. Among the genes analyzed, Alox15 encoding the protein 12/15 lipoxygenase (LOX) was markedly up-regulated in heart failure. To determine whether increased expression of 12/15-LOX causes heart failure, we established transgenic mice that overexpressed 12/15-LOX in cardiomyocytes. Echocardiography showed that Alox15 transgenic mice developed systolic dysfunction. Cardiac fibrosis increased in Alox15 transgenic mice with advancing age and was associated with the infiltration of macrophages. Consistent with these observations, cardiac expression of monocyte chemoattractant protein 1 (MCP-1) was up-regulated in Alox15 transgenic mice compared with wild-type mice. Treatment with 12-hydroxy-eicosatetraenoic acid, a major metabolite of 12/15-LOX, increased MCP-1 expression in cardiac fibroblasts and endothelial cells but not in cardiomyocytes. Inhibition of MCP-1 reduced the infiltration of macrophages into the myocardium and prevented both systolic dysfunction and cardiac fibrosis in Alox15 transgenic mice. Likewise, disruption of 12/15-LOX significantly reduced cardiac MCP-1 expression and macrophage infiltration, thereby improving systolic dysfunction induced by chronic pressure overload. Our results suggest that cardiac 12/15-LOX is involved in the development of heart failure and that inhibition of 12/15-LOX could be a novel treatment for this condition.

scholarly journals Excessive O -GlcNAcylation Causes Heart Failure and Sudden Death

Circulation ◽  
2021 ◽  
Vol 143 (17) ◽  
pp. 1687-1703
Author(s):  
Priya Umapathi ◽  
Olurotimi O. Mesubi ◽  
Partha S. Banerjee ◽  
Neha Abrol ◽  
Qinchuan Wang ◽  
...  
Keyword(s):  
Heart Failure ◽  
Transgenic Mice ◽  
Complex I ◽  
Metabolic Flux ◽  
Pressure Overload ◽  
Premature Death ◽  
Wild Type ◽  
Wild Type Littermate ◽  
Functional Studies ◽  
Complex I Activity

Background: Heart failure is a leading cause of death worldwide and is associated with the rising prevalence of obesity, hypertension, and diabetes. O -GlcNAcylation (the attachment of O -linked β-N-acetylglucosamine [ O -GlcNAc] moieties to cytoplasmic, nuclear, and mitochondrial proteins) is a posttranslational modification of intracellular proteins and serves as a metabolic rheostat for cellular stress. Total levels of O -GlcNAcylation are determined by nutrient and metabolic flux, in addition to the net activity of 2 enzymes: O -GlcNAc transferase (OGT) and O -GlcNAcase (OGA). Failing myocardium is marked by increased O -GlcNAcylation, but whether excessive O -GlcNAcylation contributes to cardiomyopathy and heart failure is unknown. Methods: We developed 2 new transgenic mouse models with myocardial overexpression of OGT and OGA to control O -GlcNAcylation independent of pathologic stress. Results: We found that OGT transgenic hearts showed increased O -GlcNAcylation and developed severe dilated cardiomyopathy, ventricular arrhythmias, and premature death. In contrast, OGA transgenic hearts had lower O -GlcNAcylation but identical cardiac function to wild-type littermate controls. OGA transgenic hearts were resistant to pathologic stress induced by pressure overload with attenuated myocardial O -GlcNAcylation levels after stress and decreased pathologic hypertrophy compared with wild-type controls. Interbreeding OGT with OGA transgenic mice rescued cardiomyopathy and premature death, despite persistent elevation of myocardial OGT. Transcriptomic and functional studies revealed disrupted mitochondrial energetics with impairment of complex I activity in hearts from OGT transgenic mice. Complex I activity was rescued by OGA transgenic interbreeding, suggesting an important role for mitochondrial complex I in O -GlcNAc–mediated cardiac pathology. Conclusions: Our data provide evidence that excessive O -GlcNAcylation causes cardiomyopathy, at least in part, attributable to defective energetics. Enhanced OGA activity is well tolerated and attenuation of O -GlcNAcylation is beneficial against pressure overload–induced pathologic remodeling and heart failure. These findings suggest that attenuation of excessive O -GlcNAcylation may represent a novel therapeutic approach for cardiomyopathy.

Abstract 3465: Fkbp12.6 Overexpression in Mouse Cardiac Myocytes Offers Minor Protection Against Pressure Overload-Induced Cardiac Remodeling and Failure

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Laurent Vinet ◽  
Mylène Pezet ◽  
Miresta Prévilon ◽  
Barnabas Gellen ◽  
Celine Dachez ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Remodeling ◽  
Protein Level ◽  
Mrna Level ◽  
Pressure Overload ◽  
Calcium Handling ◽  
Heart Catheterization ◽  
Mrna Ratio ◽  
Gravimetric Data ◽  
Actin Mrna

Alterations in RyR2 function is a hallmark of heart failure (HF). Decreased FKBP12.6 binding to RyR2 has been put forward to explain the diastolic SR Ca 2+ leakage observed in this condition. Previous work in the mouse has shown that cardiac FKBP12.6 overexpression protects against the development of myocardial infarction-induced heart failure. We tested the hypothesis that cardiac FKBP12.6 overexpression protects against transverse aortic constriction (TAC)-induced cardiac remodeling and failure. We used a mouse model of conditional cardiac-specific FKBP12.6 overexpression. Ten weeks after TAC, male transgenic mice (TG) and their wild-type controls (WT) underwent heart catheterization. Hemodynamic and gravimetric data are shown in the table . Ventricular expression of the hypertrophic gene program and calcium handling proteins were assessed by real-time PCR and Western blot, respectively. Ten weeks after TAC, the mortality rate was 23% in WT and 13% in TG (14/60 vs 5/39, ns). The percentage of mice with HF, estimated on the presence of pulmonary oedema, was 42% in WT-TAC and 32% in TG-TAC (15/36 vs 7/22, ns). BNP mRNA level increased 2.8 fold in WT-TAC (p<0.01 vs WT-Shams) and 2.4 fold in TG-TAC (p<0.01 vs TG-Shams). α-skeletal actin mRNA level increased 4.3 fold in WT-TAC (p<0.001 vs WT-Shams) and 3.8 fold in TG-TAC (p<0.001 vs TG-Shams). β-MHC/α-MHC mRNA ratio increased 2.8 fold in WT-TAC (p<0.01 vs WT-Shams) and 4.3 fold in TG-TAC (p<0.05 vs TG-Shams). RyR2 protein level decreased by 58% in WT-TAC and 41% in TG-TAC (p<0.01 and p<0.05 vs sham-operated mice, respectively). SERCA2a protein level decreased by 29% in WT-TAC and 16% in TG-TAC (p<0.01 and p<0.05 vs sham-operated mice, respectively). No statistical difference was found between TG-TAC and WT-TAC for any of these parameters. Conclusion: Cardiac FKBP 12.6 overexpression offers weak protection if any against TAC-induced cardiac remodeling and failure in the mouse.

scholarly journals Targeted Disruption of NFATc3, but Not NFATc4, Reveals an Intrinsic Defect in Calcineurin-Mediated Cardiac Hypertrophic Growth

2002 ◽  
Vol 22 (21) ◽  
pp. 7603-7613 ◽  
Author(s):  
Benjamin J. Wilkins ◽  
Leon J. De Windt ◽  
Orlando F. Bueno ◽  
Julian C. Braz ◽  
Betty J. Glascock ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Pressure Overload ◽  
Calcium Handling ◽  
Intrinsic Defect ◽  
Regulatory Pathway ◽  
Targeted Disruption ◽  
Activated T Cells ◽  
Hypertrophic Growth ◽  
Downstream Effectors

ABSTRACT A calcineurin-nuclear factor of activated T cells (NFAT) regulatory pathway has been implicated in the control of cardiac hypertrophy, suggesting one mechanism whereby alterations in intracellular calcium handling are linked to the expression of hypertrophy-associated genes. Although recent studies have demonstrated a necessary role for calcineurin as a mediator of cardiac hypertrophy, the potential involvement of NFAT transcription factors as downstream effectors of calcineurin signaling has not been evaluated. Accordingly, mice with targeted disruptions in NFATc3 and NFATc4 genes were characterized. Whereas the loss of NFATc4 did not compromise the ability of the myocardium to undergo hypertrophic growth, NFATc3-null mice demonstrated a significant reduction in calcineurin transgene-induced cardiac hypertrophy at 19 days, 26 days, 6 weeks, 8 weeks, and 10 weeks of age. NFATc3-null mice also demonstrated attenuated pressure overload- and angiotensin II-induced cardiac hypertrophy. These results provide genetic evidence that calcineurin-regulated responses require NFAT effectors in vivo.

scholarly journals Inhibition of Tumor Necrosis Factor-α Improves Postischemic Recovery of Hypertrophied Hearts

Circulation ◽  
2001 ◽  
Vol 104 (suppl_1) ◽  
Author(s):  
Christof Stamm ◽  
Ingeborg Friehs ◽  
Douglas B. Cowan ◽  
Adrian M. Moran ◽  
Hung Cao-Danh ◽  
...  
Keyword(s):  
Heart Failure ◽  
Tumor Necrosis Factor ◽  
Intracellular Calcium ◽  
Tumor Necrosis ◽  
Ischemia Reperfusion ◽  
Pressure Overload ◽  
Calcium Handling ◽  
Tnf Α ◽  
Postischemic Recovery ◽  
Necrosis Factor

Background Tumor necrosis factor (TNF)-α has been implicated in the pathogenesis of heart failure and ischemia-reperfusion injury. Effects of TNF-α are initiated by membrane receptors coupled to sphingomyelinase signaling and include altered metabolism and calcium cycling, contractile dysfunction, and cell death. We postulate that pressure-overload hypertrophy results in increased myocardial TNF-α expression and that it contributes to decreased contractility in hypertrophied infant hearts subjected to ischemia-reperfusion. Methods and Results Neonatal rabbits underwent aortic banding to induce LV hypertrophy. Myocardial TNF-α protein expression increased progressively with LV hypertrophy. Serum TNF-α was detected only after the onset of heart failure. Before onset of ventricular dilatation and heart failure (determined by serial echocardiograms), hearts from aortic banded and age-matched control rabbits were perfused in the Langendorff mode and subjected to 45 minutes of ischemia and 30 minutes of reperfusion. Postischemic recovery was impaired in hypertrophied hearts, but addition of neutralizing anti-rabbit TNF-α antibody to cardioplegia and perfusate solutions restored postischemic function. This effect was mimicked by treatment with the ceramidase inhibitor N -oleoyl ethanolamine. TNF-α inhibition also was associated with faster postischemic recovery of phosphocreatine, ATP, and pH as assessed by 31 P nuclear magnetic resonance spectroscopy. Intracellular calcium handling, measured by Rhod 2 spectrofluorometry, demonstrated lower diastolic calcium levels and higher systolic calcium transients in anti-TNF-α treated hearts. Conclusions TNF-α is expressed in myocardium during compensated pressure-overload hypertrophy and contributes to postischemic myocardial dysfunction. Inhibition of TNF-α signaling significantly improves postischemic contractile function, myocardial energetics, and intracellular calcium handling.

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