Abstract 17385: Endothelium Specific Reduction in Mitochondrial ROS Reverses the Deleterious Effects on Coronary Endothelium Caused by Prolonged Increase in NADPH Oxidase Derived ROS

Circulation ◽  
2018 ◽  
Vol 138 (Suppl_1) ◽  
Author(s):  
Isabella McCormack ◽  
Bonnie Colantuono ◽  
Melissa Stanley ◽  
Frank Sellke ◽  
Ruhul Abid
Keyword(s):  
Transgenic Mice ◽  
Nadph Oxidase ◽  
Cardiac Function ◽  
Cardiovascular Health ◽  
Prolonged Exposure ◽  
Capillary Density ◽  
Mouse Heart ◽  
Therapeutic Modalities ◽  
Mitochondrial Ros ◽  
Coronary Endothelium

Introduction: Recent findings from our lab demnstrated that prolonged increase in NADPH oxidase (NOX)-derived ROS results in increased mitochondrial (mito) ROS levels, reduced aspartate/dNTP synthesis, reduced coronary endothelial cell (EC) proliferation, and decreased recovery of post-MI cardiac function. Hypothesis: We hypothesized that endothelium-specific reduction in mitochondrial ROS will reverse the deleterious effects of prolonged NOX-ROS increase by improving mitochondrial function and aspartate/dNTP synthesis. Methods: Tetracycline (Tet)-ON/Tet-OFF binary transgenic mice, Tet-Nox2:VE-Cad-tTA (NOX-OE), were used as a model for endothelium-specific increase in the expression of the catalytic subunit of NADPH oxidase resulting in increased ROS. Mouse heart EC (MHEC) were isolated from Tet-ON and Tet-OFF Tg-Nox2 mice that were exposed to >16 weeks of increased EC-ROS. MHECs were then subject to mitochondrial antioxidants nitroxide (XJB-131) and nanoparticle (CeTiO2) followed by determination of mito-ROS, aspartate/dNTP synthesis, and EC proliferation. NOX-OE was crossbred with SOD-OE to generate a double-transgenic mice with EC-specific overexpression of mitochondrial antioxidant MnSOD (Sod2), Tet-Sod2:Tet-Nox2:VE-Cad-tTA ( SOD-OE ). Both NOX-OE and SOD-OE were subject to myocardial infarction (MI) LAD ligation experiments. Results: Mito-ROS levels were significantly reduced (by >2-fold) in MHEC from SOD-OE compared to NOX-OE. Both dNTP and proliferation were increased in SOD-OE, and also in NOX-EC treated with XJB-131 and CeTiO2. Together, these data suggest that reduction in mito-ROS abrogated negative effects of NOX-ROS in EC. Preliminary data demonstrate that there was an increase in capillary density (by 34± 5.8 %; p<0.05) and angiogenesis (by 2-fold) in SOD-OE post-MI myocardium compared to that of NOX-OE. Infarct sizes and cardiac function between NOX-OE and SOD-OE will be presented. Conclusion: These results suggest that reduction in mito-ROS can abrogate deleterious effects coronary endothelium caused by prolonged exposure to NOX-ROS. EC-specific modulation of mito-ROS may thus help develop therapeutic modalities to improve cardiovascular health and myocardial preservation in the post-MI heart.

Abstract 19979: Endothelium-specific Increase in ROS has Protective Effects on Vascular Endothelium in Ischemic Myocardium

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Ehtesham Shafique ◽  
Karla Reichert ◽  
Bonnie Colantuono ◽  
Anali Torina ◽  
Elizabeth Harrington ◽  
...  
Keyword(s):  
Nadph Oxidase ◽  
Vascular Endothelium ◽  
Fold Increase ◽  
Capillary Density ◽  
Ischemic Myocardium ◽  
Vascular Pathology ◽  
Mouse Heart ◽  
Protective Effects ◽  
Specific Increase ◽  
Coronary Endothelium

Introduction: Increased ROS is often associated with vascular pathology. Recent findings demonstrated that increases in NADPH oxidase-derived endothelium (EC)-specific ROS improved coronary endothelial function by activating AMPK-eNOS signaling pathway. Here, we examined the effects of EC-ROS on vessel density in post-infarct ischemic myocardium. Hypothesis: We tested the hypothesis that increased EC-ROS induces AMPK-FOXO1-mediated overexpression of mitochondrial antioxidant MnSOD, which in turn has protective effects on vascular endothelium in ischemic myocardium. Methods: Our binary (Tet-ON/OFF) conditional transgenic mouse (Tet-Nox2:VE-Cad-tTA) induces 1.8±0.42-fold increase in NADPH oxidase-derived ROS in endothelium. Using these animals, we have induced myocardial infarction by LAD (left anterior descending) ligation. Results: Co-immunostaining of the ischemic myocardium using anti-CD31 and anti-SMA antibodies demonstrated that there was an increase in capillary density (by 38± 6.45; p<0.05) in Tet-Nox2:VE-Cad-tTA mice with high EC-ROS. Isolated mouse heart ECs showed an increase in AMPK-Foxo1-mediated expression of MnSOD in Tet-Nox2:VE-Cad-tTA mice compared to control. Together, these findings suggest that increase in EC-ROS increases mitochondrial antioxidant MnSOD, which in turn protects coronary endothelium in myocardial ischemia. Conclusion: This study demonstrates that the endothelial ROS may play an important role in myocardial preservation.

Abstract 28: In Vivo Knockdown of Mirna-15b Results in Increased Cardiac Hypertrophy and Fibrosis in Response to Pressure Overload of the Mouse Heart

2012 ◽  
Vol 111 (suppl_1) ◽  
Author(s):  
Anke J Tijsen ◽  
Ingeborg van der Made ◽  
Elza D van Deel ◽  
Monika Hiller ◽  
Yolan J Reckman ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Cardiac Function ◽  
Cardiac Fibrosis ◽  
Negative Control ◽  
Heart Weight ◽  
Mouse Heart ◽  
Hypertrophic Response ◽  
Wide Range ◽  
Tgfβ Pathway

MiRNAs play an important role in the control of diverse aspects of cardiac function. MiR-15b is highly expressed in the heart and is found consistently upregulated in hypertrophic and failing hearts. To investigate the function of miR-15b in the heart we set out two experiments. In the first experiment we generated two independent transgenic mouse lines that drive miR-15b expression under the αMHC-promotor and show a three and four fold overexpression of miR-15b. Strikingly, both lines show a decrease in heart weight/tibia length of 20% in adult and aged mice when compared to littermate controls. We investigated the response of these transgenic mice to thoracic aorta constriction (TAC) and found no differences in the hypertrophic response or in cardiac function measured by echocardiography between wild-type and transgenic mice. In a second experiment, we inhibited miR-15b using LNA-based antimiRs. In these mice, TAC resulted in an increased hypertrophic response and increased cardiac fibrosis when compared to a negative control antimiR. A wide range of predicted targets of miR-15 belong to the pathways of the TGFβ-superfamily and using a smad-dependent reporter we show that miR-15b inhibits TGFβ-induced Smad activity in HepG2 cells. One of the predicted targets in the TGFβ pathway is TGFβ receptor 1 (TGFβR1), of which the 3’UTR contains six predicted miR-15 binding sites. This suggests that the phenotype in the transgenic mice and after knockdown of miR-15b may be (partly) mediated by repression of TGFβR1. Indeed, in the adult miR-15b transgenic hearts we found a downregulation of TGFβR1 mRNA and protein and we confirmed binding of miR-15 to the TGFβR1 3’UTR by luciferase assays. In conclusion, miR-15b causes a cardiac hypotrophic phenotype at baseline in transgenic mice and inhibition of miR-15b leads to a stronger hypertrophic and fibrotic response after TAC. Furthermore miR-15b inhibits the TGFβ pathway by targeting the TGFβR1 and possibly other targets in this pathway. This research is funded by the Dutch Heart Foundation (NHF grant #2007B077).

Abstract 17169: Endothelium-Specific Reduction in Mitochondrial ROS Induces Coronary Angiogenesis in Ischemic Myocardium via Activation of PI3k/Akt/ERG, ERK1/2, and Jag-1 Signaling

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Rayane Brinck Teixeira ◽  
Melissa Pfeiffer ◽  
Catherine Karbasiafshar ◽  
Giana Blume Corssac ◽  
Nagib Ahsan ◽  
...  
Keyword(s):  
Cardiac Function ◽  
De Novo ◽  
Ischemic Myocardium ◽  
Mouse Heart ◽  
Western Blots ◽  
Mitochondrial Ros ◽  
Acute Mi ◽  
Student’S T ◽  
Related Proteins ◽  
Coronary Angiogenesis

Introduction: Global reduction in reactive oxygen species (ROS) failed to improve outcomes in cardiovascular disease patients. Recent reports suggest that subcellular, rather than global ROS, play a crucial role in endothelial cell (EC) health. To that end, we generated a novel transgenic mouse model that overexpresses mitochondrial antioxidant MnSOD in EC-specific manner (MnSODVE-OE). Hypothesis: We hypothesized that decreased EC mitochondrial-ROS will improve post-myocardial infarction (MI) cardiac function by inducing coronary angiogenesis in ischemic myocardium. Methods: MnSODVE mice were assigned to Tet-ON (control) or Tet-OFF (MnSODVE-OE) group. To turn off the transgene, Tetracycline (Tet) (2mg/kg) was added to the drinking water (Tet-ON), while Tet-OFF mice did not receive Tet. Both groups underwent left anterior descending coronary artery (LAD) ligation surgery to mimic acute MI. Echocardiography was done 28 days after LAD ligation. Capillaries, arteriole density, and proliferating ECs were measured in heart sections using anti-CD31, anti-αSMA, and anti-PCNA immunofluorescence. Western blot, proteomic and phosphoproteomic analyses of mouse heart ECs isolated from MnSODVE (Tet-ON and Tet-OFF) animals were performed to study modulation of signaling cascades. Results: MnSODVE-OE mice demonstrated improved cardiac function (EF and FS increased by 16±7.87% and 21.73±10.31%, respectively, p <0.01), increase in capillary and arteriole densities by 4.13±4.10-fold, p<0.05 and 5.48±3.51-fold, p<0.001, respectively, and in EC proliferation by 1.46±0.80-fold, p <0.01, suggesting de novo coronary angiogenesis. Western blots showed activation of Akt (80.46±3.95% increase in p-Akt/ t-Akt ratio, p<0.05) and ERK1/2 (21.05±4.45% increase in p-ERK/ t-ERK 1/2 ratio, p<0.05). Proteome and phosphoproteome analyses showed upregulation of mitochondrial complex I biogenesis, RNA metabolism, and upregulation of Notch-related proteins ERG and Jag-1 (p<0.05). Student’s t-test was used for data analyses. Conclusions: Taken together, these results suggest that decreased mito-ROS in ECs improves post-MI cardiac function by inducing coronary angiogenesis through activation of PI3k/Akt/ERG, ERK1/2, and Jag-1 signaling.

scholarly journals New Insights on NETosis Induced by Entamoeba histolytica: Dependence on ROS from Amoebas and Extracellular MPO Activity

Antioxidants ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 974
Author(s):  
César Díaz-Godínez ◽  
Joshue Fabián Jorge-Rosas ◽  
Mario Néquiz ◽  
Santiago Martínez-Calvillo ◽  
Juan P. Laclette ◽  
...  
Keyword(s):  
Cell Surface ◽  
Nadph Oxidase ◽  
Entamoeba Histolytica ◽  
Pathogen Detection ◽  
Dependent Manner ◽  
Antimicrobial Proteins ◽  
Nadph Oxidase Activity ◽  
Mitochondrial Ros ◽  
Pre Treatment ◽  
Dose Dependent

NETosis is a neutrophil process involving sequential steps from pathogen detection to the release of DNA harboring antimicrobial proteins, including the central generation of NADPH oxidase dependent or independent ROS. Previously, we reported that NETosis triggered by Entamoeba histolytica trophozoites is independent of NADPH oxidase activity in neutrophils, but dependent on the viability of the parasites and no ROS source was identified. Here, we explored the possibility that E. histolytica trophozoites serve as the ROS source for NETosis. NET quantitation was performed using SYTOX® Green assay in the presence of selective inhibitors and scavengers. We observed that respiratory burst in neutrophils was inhibited by trophozoites in a dose dependent manner. Mitochondrial ROS was not also necessary, as the mitochondrial scavenger mitoTEMPO did not affect the process. Surprisingly, ROS-deficient amoebas obtained by pre-treatment with pyrocatechol were less likely to induce NETs. Additionally, we detected the presence of MPO on the cell surface of trophozoites after the interaction with neutrophils and found that luminol and isoluminol, intracellular and extracellular scavengers for MPO derived ROS reduced the amount of NET triggered by amoebas. These data suggest that ROS generated by trophozoites and processed by the extracellular MPO during the contact with neutrophils are required for E. histolytica induced NETosis.

scholarly journals p90 ribosomal S6 kinase 3 contributes to cardiac insufficiency in α-tropomyosin Glu180Gly transgenic mice

2013 ◽  
Vol 305 (7) ◽  
pp. H1010-H1019 ◽  
Author(s):  
Catherine L. Passariello ◽  
Marjorie Gayanilo ◽  
Michael D. Kritzer ◽  
Hrishikesh Thakur ◽  
Zoharit Cozacov ◽  
...  
Keyword(s):  
Heart Failure ◽  
Transgenic Mice ◽  
Cardiac Function ◽  
Interstitial Fibrosis ◽  
Cardiac Insufficiency ◽  
S6 Kinase ◽  
Transgenic Expression ◽  
P90 Ribosomal S6 Kinase ◽  
Ribosomal S6 Kinase

Myocardial interstitial fibrosis is an important contributor to the development of heart failure. Type 3 p90 ribosomal S6 kinase (RSK3) was recently shown to be required for concentric myocyte hypertrophy under in vivo pathological conditions. However, the role of RSK family members in myocardial fibrosis remains uninvestigated. Transgenic expression of α-tropomyosin containing a Glu180Gly mutation (TM180) in mice of a mixed C57BL/6:FVB/N background induces a cardiomyopathy characterized by a small left ventricle, interstitial fibrosis, and diminished systolic and diastolic function. Using this mouse model, we now show that RSK3 is required for the induction of interstitial fibrosis in vivo. TM180 transgenic mice were crossed to RSK3 constitutive knockout ( RSK3−/−) mice. Although RSK3 knockout did not affect myocyte growth, the decreased cardiac function and mild pulmonary edema associated with the TM180 transgene were attenuated by RSK3 knockout. The improved cardiac function was consistent with reduced interstitial fibrosis in the TM180; RSK3−/− mice as shown by histology and gene expression analysis, including the decreased expression of collagens. The specific inhibition of RSK3 should be considered as a potential novel therapeutic strategy for improving cardiac function and the prevention of sudden cardiac death in diseases in which interstitial fibrosis contributes to the development of heart failure.

scholarly journals Overexpression of antizyme in the hearts of transgenic mice prevents the isoprenaline-induced increase in cardiac ornithine decarboxylase activity and polyamines, but does not prevent cardiac hypertrophy

2000 ◽  
Vol 350 (3) ◽  
pp. 645-653 ◽  
Author(s):  
Caroline A. MACKINTOSH ◽  
David J. FEITH ◽  
Lisa M. SHANTZ ◽  
Anthony E. PEGG
Keyword(s):  
Transgenic Mice ◽  
Ornithine Decarboxylase ◽  
Prolonged Exposure ◽  
Constitutive Expression ◽  
Decarboxylase Activity ◽  
Cardiac Growth ◽  
Polyamine Content ◽  
Transgenic Lines ◽  
Response To Stress ◽  
Polyamine Uptake

Two lines of transgenic mice were produced with constitutive expression of antizyme-1 in the heart, driven from the cardiac α-myosin heavy chain promoter. The use of engineered antizyme cDNA in which nucleotide 205 had been deleted eliminated the need for polyamine-mediated frameshifting, normally necessary for translation of antizyme mRNA, and thus ensured the constitutive expression of antizyme. Antizyme-1 is thought to be a major factor in regulating cellular polyamine content, acting both to inhibit ornithine decarboxylase (ODC) activity and to target it for degradation, as well as preventing polyamine uptake. The two transgenic lines had substantial, but different, levels of antizyme in the heart, as detected by Western blotting and by the ability of heart extracts to inhibit exogenous purified ODC. Despite the high levels of antizyme, endogenous ODC activity was not completely abolished, with 10– 39% remaining, depending on the transgenic line. Additionally, a relatively small decrease (30–32%) in cardiac spermidine content was observed, with levels of putrescine and spermine unaffected. Interestingly, although the two lines of transgenic mice had different antizyme expression levels, they had almost identical cardiac polyamine content. When treated with a single acute dose of isoprenaline (isoproterenol), cardiac ODC activity and putrescine content were substantially increased (by 14-fold and 4.7-fold respectively) in non-transgenic littermate mice, but these increases were completely prevented in the transgenic mice from both founder lines. Prolonged exposure to isoprenaline also caused increases in cardiac ODC activity and polyamine content, as well as an increase in cardiac growth, in non-transgenic mice. Although the increases in cardiac ODC activity and polyamine content were prevented in the transgenic mice from both founder lines, the increase in cardiac growth was unaffected. These transgenic mice thus provide a valuable model system in which to study the importance of polyamine levels in cardiac growth and electrophysiology in response to stress.

Abstract 1213: Cardiac Overexpression of Epac1 in Transgenic Mice Protects Heart from Lipopolysaccharide-induced Cardiac Dysfunction and Inhibits JAK-STAT Pathway

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Satoshi Okumura ◽  
Yunzhe Bai ◽  
Meihua Jin ◽  
Sayaka Suzuki ◽  
Akiko Kuwae ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cyclic Amp ◽  
Transgenic Mice ◽  
Cardiac Function ◽  
Proinflammatory Cytokines ◽  
Cardiac Dysfunction ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Ventricular Ejection Fraction ◽  
Stat Pathway

The sympathetic nervous system and proinflammatory cytokines are believed to play independent roles in the pathophysiology of heart failure. However, the recent identification of Epac (exchange protein activated by cyclic AMP), a new cyclic AMP-binding protein that directly activates Rap1, have implicated that there may be a potential cross talk between the sympathetic and cytokine signals. In order to examine the role of Epac in cytokine signal to regulate cardiac function, we have generated transgenic mice expressing the human Epac1 gene under the control of alpha-cardiac myosin heavy chain promoter (Epac1-TG), and examined their response in lipopolysaccharide (LPS)-induced cardiac dysfunction, a well established model for sepsis-induced cardiac dysfunction. Sepsis-induced cardiac dysfunction results from the production of proinflammatory cytokines. At baseline, left ventricular ejection fraction (LVEF) was similar (TG vs. NTG, 67±1.7 vs. 69±2.1%, n =7–9). The degree of cardiac hypertrophy (LV(mg)/tibia(mm)) was also similar at 3 months old (TG vs. NTG 4.0±0.1 vs. 4.2±0.1, n =5–6), but it became slightly but significantly greater in Epac1-TG at 5 month old (TG vs. NTG 4.9±0.1 vs. 4.4±0.1, p< 0.05, n =5–7). LPS (5mg/kg) elicited a significant and robust reduction of LVEF in both Epac1-TG and NTG, but the magnitude of this decrease was much less in Epac1-TG at 6 hr after injection (TG vs. NTG 48±2.4 vs. 57±1.8%, p< 0.01, n =6–9). At 24 hr after injection, cardiac function was restored to the baseline in both Epac1-TG and NTG. We also examined the activation of JAK-STAT pathway at 24 hr after injection. The tyrosine phosphorylation of STAT1 (Tyr701) and STAT3 (Tyr705) in LV, which is an indicator of STAT activation, was reduced to a greater degree in Epac1-TG by 31±8.8% ( p< 0.05, n =4) and 29±5.9% ( p< 0.05, n =7), respectively, relative to that in NTG. Taken together, Epac1 protects the heart from the cytokine-induced cardiac dysfunction, at least in part, through the inhibition of the JAK-STAT pathway, suggesting the beneficial role played by sympathetic signal to antagonize proinflammatory cytokine signal in heart failure.

scholarly journals Changes in labial capillary density on ascent to and descent from high altitude

F1000Research ◽  
2016 ◽  
Vol 5 ◽  
pp. 2107 ◽  
Author(s):  
Edward Gilbert-Kawai ◽  
Jonny Coppel ◽  
Phillip Hennis ◽  
Michael Grocott ◽  
Can Ince ◽  
...  
Keyword(s):  
High Altitude ◽  
Correlation Coefficient ◽  
Prolonged Exposure ◽  
Haemoglobin Concentration ◽  
Capillary Density ◽  
Vessel Density ◽  
Field Of View ◽  
Rank Test ◽  
Simplified Method

Present knowledge of how the microcirculation is altered by prolonged exposure to hypoxia at high altitude is incomplete and modification of existing analytical techniques may improve our knowledge considerably. We set out to use a novel simplified method of measuring in vivo capillary density during an expedition to high altitude using a CytoCam incident dark field imaging video-microscope. The simplified method of data capture involved recording one-second images of the mucosal surface of the inner lip to reveal data about microvasculature density in ten individuals. This was done on ascent to, and descent from, high altitude. Analysis was conducted offline by two independent investigators blinded to the participant identity, testing conditions and the imaging site.  Additionally we monitored haemoglobin concentration and haematocrit data to see if we could support or refute mechanisms of altered density relating to vessel recruitment. Repeated sets of paired values were compared using Kruskall Wallis Analysis of Variance tests, whilst comparisons of values between sites was by related samples Wilcoxon Signed Rank Test. Correlation between different variables was performed using Spearman’s rank correlation coefficient, and concordance between analysing investigators using intra-class correlation coefficient. There was a significant increase in capillary density from London on ascent to high altitude; median capillaries per field of view area increased from 22.8 to 25.3 (p=0.021). There was a further increase in vessel density during the six weeks spent at altitude (25.3 to 32.5, p=0.017). Moreover, vessel density remained high on descent to Kathmandu (31.0 capillaries per field of view area), despite a significant decrease in haemoglobin concentration and haematocrit. Using a simplified technique, we have demonstrated an increase in capillary density on early and sustained exposure to hypobaric hypoxia at thigh altitude, and that this remains elevated on descent to normoxia. The technique is simple, reliable and reproducible.

scholarly journals Disruption of adenylyl cyclase type V does not rescue the phenotype of cardiac-specific overexpression of Gαq protein-induced cardiomyopathy

2010 ◽  
Vol 299 (5) ◽  
pp. H1459-H1467 ◽  
Author(s):  
Valeriy Timofeyev ◽  
Cliff A. Porter ◽  
Dipika Tuteja ◽  
Hong Qiu ◽  
Ning Li ◽  
...  
Keyword(s):  
Heart Failure ◽  
Protein Kinase C ◽  
Protein Kinase ◽  
Mouse Model ◽  
Transgenic Mice ◽  
Cardiac Function ◽  
Adenylyl Cyclase ◽  
Electrical Remodeling ◽  
Kinase C ◽  
Progressive Heart Failure

Adenylyl cyclase (AC) is the principal effector molecule in the β-adrenergic receptor pathway. ACV and ACVI are the two predominant isoforms in mammalian cardiac myocytes. The disparate roles among AC isoforms in cardiac hypertrophy and progression to heart failure have been under intense investigation. Specifically, the salutary effects resulting from the disruption of ACV have been established in multiple models of cardiomyopathy. It has been proposed that a continual activation of ACV through elevated levels of protein kinase C could play an integral role in mediating a hypertrophic response leading to progressive heart failure. Elevated protein kinase C is a common finding in heart failure and was demonstrated in murine cardiomyopathy from cardiac-specific overexpression of Gαq protein. Here we assessed whether the disruption of ACV expression can improve cardiac function, limit electrophysiological remodeling, or improve survival in the Gαq mouse model of heart failure. We directly tested the effects of gene-targeted disruption of ACV in transgenic mice with cardiac-specific overexpression of Gαq protein using multiple techniques to assess the survival, cardiac function, as well as structural and electrical remodeling. Surprisingly, in contrast to other models of cardiomyopathy, ACV disruption did not improve survival or cardiac function, limit cardiac chamber dilation, halt hypertrophy, or prevent electrical remodeling in Gαq transgenic mice. In conclusion, unlike other established models of cardiomyopathy, disrupting ACV expression in the Gαq mouse model is insufficient to overcome several parallel pathophysiological processes leading to progressive heart failure.

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