scholarly journals Targeting MEF2 acetylation improves myocardial recovery and overall survival in mice

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
N.H Bishopric ◽  
J.Q Wei ◽  
C Crowley ◽  
G Wang
Keyword(s):  
Myocardial Infarction ◽  
Heart Failure ◽  
Median Survival ◽  
Myocardial Infarct ◽  
Compensatory Hypertrophy ◽  
Gene Set Enrichment Analysis ◽  
Wall Thickening ◽  
Funding Source ◽  
Heart Research

Abstract Background Post-myocardial infarct remodeling is a complex process that is strongly associated with the eventual development of heart failure, and involves myocyte hypertrophy, specific alterations in gene expression and mitochondrial metabolism, myocyte death, fibrosis, and incursion of inflammatory mediators. Many of these alterations involve dynamic changes in lysine acetylation (KAc), a key regulatory post-transcriptional modification in the nucleus and cytosol, and can be blocked by small molecules with broad activity against histone deacetylases (HDACi). The downstream targets of HDACi and other KAc modulators remain to be established, and the safety of this class of agent for long-term administration in heart failure is similarly unknown. We recently reported that a small molecule probe (8MI) selectively blocking acetylation of transcription factor MEF2 is effective in preventing and reversing pressure overload hypertrophy in vivo, without altering overall histone acetylation. Hypothesis Treatment with a MEF2-selective KAc modulator will accelerate cardiac functional recovery after myocardial infarction. Methods The left coronary artery was permanently ligated (PCO) in 8–10 week C57BL/6J mice; controls underwent thoracotomy only (Sham). Within each group, half received 8MI (20–100mg/kg) by gavage daily, beginning at 30 min, and half received diluent only (DMSO). Treatment was continued for 31 days with weekly echocardiography. Mice from each group (n=3–6) were euthanized weekly for gross and histological analysis. Separately, mice were subjected to transverse aortic banding (TAC) +/− 8MI. Comparative LV RNASeq data were analysed using Gene Set Enrichment Analysis at 4 weeks, and median survival was determined. Results At 24 hours all PCO vs. Sham mice had reduced ejection fraction (62.1±1.08% vs. 80.9±1.08%), increased LV diastolic dimensions, and decreased systolic wall thickening (n =min. 8 per group, p < E-001). Over 4 weeks, heart weights progressively increased in PCO mice together with lung and liver congestion. 8MI dose-dependently improvedeach of these parameters, with near-normal function and organ weights at 4 weeks in higher-dose groups. 8MI also reduced infarct size, compensatory hypertrophy, and fibrosis at 4 weeks. In parallel, 8MI extended median survival by 1.67-fold after TAC (127.5 vs 76 days, p<0.0001, 8MI vs DMSO). RNASeq +GSEA analysis revealed that 8MI treatment blocked MEF2 target gene induction, while enriching for gene sets Oxidative Phosphorylation and Myc Targets (FDR q values 0.000 and 0.041) compared with DMSO. Conclusion An inhibitor of MEF2 acetylation promoted significant functional and pathological recovery in a mouse model of myocardial infarction, associated with suppression of MEF2-dependent transcription. These findings point to a novel approach to preventing myocardial functional decline, and improving survival, after myocardial injury. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): National Institutes of Health; Miami Heart Research Institute

scholarly journals Histidine triad nucleotide-binding protein 2 protects cardiomyocytes via maintaining NAD homeostasis in virto and in vivo

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
F Mengkang ◽  
Y.I.N Huang ◽  
J Qian
Keyword(s):  
Myocardial Infarction ◽  
Heart Failure ◽  
Molecular Docking ◽  
Nucleotide Binding ◽  
Metabolic Status ◽  
Funding Source ◽  
Targeted Metabolomics ◽  
Pet Ct

Abstract Background Heart failure (HF) is the end-stage of most heart diseases with poor clinical outcomes. The mitochondrial dysfunction is a critical therapeutic target in HF, and the histidine triad nucleotide-binding (HINT2) protein has been shown to enhance energy metabolism in liver. However, the role of HINT2 in HF remains unclear. Purpose To explore the role of the histidine triad nucleotide-binding 2 (HINT2) protein in heart failure. Methods Neonatal mouse ventricle myocytes (NMVMs) and myocardial infarction-induced heart failure mice were used for in vitro or in vivo experiments. Adenovirus (ADV) and adeno-associated virus serum type 9 (AAV9) vectors were used to regulate HINT2 expression. The expression of HINT2 was determined by quantifying the mRNA and protein levels. Cell survival was analysed using the CCK-8 kit and TUNEL staining. Mitochondrial function was determined by the mitochondrial membrane potential and oxygen consumption rates. AAV9-HINT2 was injected 24 h post myocardial infarction following which transthoracic echocardiography and histological analyses were performed after 4 weeks. Positron emission tomography tomography-computed tomography (PET/CT) and targeted metabolomics analyses were used to explore the metabolic status in vivo. NAD levels were measured using a colorimetric kit. Computer-simulated rigid body molecular docking was performed using AUTODOCK4. Molecule binding kinetics assays were performed using biolayer interferometry. Results After 12 hours hypoxia stimuli, HINT2 was down regulated. ADV-HINT2 induced HINT2 overexpression improved NMVMs survival and reduced apoptosis after hypoxia. MMP was reduced in ADV-shHINT2 group and was preserved in ADV-HINT2 group under hypoxia. HINT2 overexpressed NMVMs showed less reduction in basal, ATP-linked and maximum OCR after hypoxia stimuli. In vivo experiment, showed that cardiac function and metabolic status was preserved by HINT2 overexpression. PET/CT displayed glucose uptake ability was significantly reduced in in failing heart, which was preserved by overexpression of HINT2. Targeted metabolomics analysis showed that nicotinate and nicotinamide metabolism pathway was regulated by HINT2, in which oxidized state NAD (NAD+) and redox state NAD (NADH) was increased in AAV9-HINT2 group. NAD concentration was detected in NMVMs. HINT2 can improve total NAD level rather than ratio of NAD+/NADH, and its effect was limited into mitochondria.HINT2 overexpression restored mitochondrial NAD levels; this was dependent on nicotinamide mononucleotide (NMN). Using computer-simulated molecular docking analysis and biolayer interferometry, we observed that HINT2 potentially binds and associates with NMN. Conclusion In summary, these findings demonstrate that the HINT2 is beneficial to preserve the heart function and metabolism in the HF murine model after acute MI, and this positive effect may due to the maintenance of mitochondrial NAD homeostasis. Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): National Natural Science Foundation of China (Grant Nos: 81970295, 81870267)

ADAM10 inhibition improves survival and augments cardiac function after myocardial infarction

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
E Klapproth ◽  
S Kuenzel ◽  
M Guenscht ◽  
K Lorenz ◽  
S Weber ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Heart Failure ◽  
Overall Survival ◽  
Cardiac Function ◽  
Elevated Serum ◽  
Functional Improvement ◽  
Funding Source ◽  
Heart Research ◽  
Neprilysin Inhibitor

Abstract Background and purpose Following myocardial infarction (MI), adverse fibrotic remodeling with extensive deposition of extracellular matrix (ECM) components has substantial consequences for the contractility of the ventricle finally leading to terminal heart failure (HF). Recently, inhibition of ECM-remodeling enzymes is discussed as potential treatment option for HF, especially following MI. The metalloprotease ADAM10 plays a crucial role in the development of the cardiovascular system and HF patients show elevated serum levels of the ADAM10 substrates CXCL16 and FasL. However, the causal role of ADAM10 in cardiovascular diseases has not been investigated. Here we evaluate the so far unknown role of ADAM10 in heart failure and after MI. Methods and results Our study capitalized from human atrial tissue biopsies, a cardiomyocyte-specific ADAM10 knockout (ADAM10 KO) mouse model as well as pharmacological ADAM10 inhibition following MI. ADAM10 expression analysis revealed elevated protein levels in HF patients compared to non-failing hearts. Upon MI, ADAM10 KO and pharmacological ADAM10 inhibition (GI254023X) significantly improved overall survival, significantly enhanced cardiac function (fractional area shortening - FAS, ejection fraction - EF) and significantly reduced infarct sizes. Compared to the high potential angiotensin receptor neprilysin inhibitor (ARNi) LCZ696, ADAM10 inhibition and combined ADAM10i/LCZ696 treatment resulted in preservation of cardiac function that was superior to sole LCZ696 treatment. Mechanistically, this functional improvement was due to reduced shedding of the ADAM10 substrate Notch1, induction of angiogenesis and an ADAM10-dependend inactivation of the NLRP3 inflammasome Conclusion Our data suggest that ADAM10 targeting is highly efficient for improving post-infarction cardiac function. Due to its overexpression in heart tissue of HF patients, ADAM10 could be a potential molecular target to improve therapy after MI. In terms of overall survival and pathophysiological remodeling following MI, our data suggest a greater potential of the ADAM10i/LCZ696 combinatorial therapy than sole LCZ696 treatment. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): German Heart Foundation/ German Foundation of Heart Research

A translational model of chronic heart failure in rats

2018 ◽  
pp. 136-148
Author(s):  
С.А. Крыжановский ◽  
И.Б. Цорин ◽  
Е.О. Ионова ◽  
В.Н. Столярук ◽  
М.Б. Вититнова ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Heart Failure ◽  
Chronic Heart Failure ◽  
Left Ventricular ◽  
Compensatory Hypertrophy ◽  
Experimental Myocardial Infarction ◽  
Left Ventricular Ejection ◽  
Translational Model ◽  
Innovative Drug ◽  
Ventricular Ejection Fraction

Цель исследования - разработка трансляционной модели хронической сердечной недостаточности (ХСН) у крыс, позволяющей, с одной стороны, изучить тонкие механизмы, лежащие в основе данной патологии, а с другой стороны, выявить новые биомишени для поиска и изучения механизма действия инновационных лекарственных средств. Методика. Использован комплекс эхокардиографических, морфологических, биохимических и молекулярно-биологических исследований, позволяющий оценивать и дифференцировать этапы формирования ХСН. Результаты. Динамические эхокардиографические исследования показали, что ХСН формируется через 90 дней после воспроизведения переднего трансмурального инфаркта миокарда. К этому времени у животных основной группы отмечается статистически значимое по сравнению со 2-ми сут. после воспроизведения экспериментального инфаркта миокарда снижение ФВ левого желудочка сердца (соответственно 55,9 ± 1,4 и 63,9 ± 1,6%, р = 0,0008). Снижение насосной функции сердца (на 13% по сравнению со 2-ми сут. после операции и на ~40% по сравнению с интактными животными) сопровождается увеличением КСР и КДР (соответственно с 2,49 ± 0,08 до 3,91 ± 0,17 мм, р = 0,0002, и с 3,56 ± 0,11 до 5,20 ± 0,19 мм, р = 0,0001), то есть к этому сроку развивается сердечная недостаточность. Результаты эхокардиографических исследований подтверждены данными морфометрии миокарда, продемонстрировавшими дилатацию правого и левого желудочков сердца. Параллельно проведенные гистологические исследования свидетельствуют о наличии патогномоничных для данной патологии изменений миокарда (постинфарктный кардиосклероз, компенсаторная гипертрофия кардиомиоцитов, очаги исчезновения поперечной исчерченности мышечных волокон и т.д.) и признаков венозного застоя в легких и печени. Биохимические исследования выявили значимое увеличение концентрации в плазме крови биохимического маркера ХСН - мозгового натрийуретического пептида. Данные молекулярно-биологических исследований позволяют говорить о наличии гиперактивности ренин-ангиотензин-альдостероновой и симпатоадреналовой систем, играющих ключевую роль в патогенезе ХСН. Заключение. Разработана трансляционная модель ХСН у крыс, воспроизводящая основные клинико-диагностические критерии этого заболевания. Показано наличие корреляции между морфометрическими, гистологическими, биохимическими и молекулярными маркерами прогрессирующей ХСН и эхокардиографическими диагностическими признаками, что позволяет использовать неинвазивный метод эхокардиографии, характеризующий состояние внутрисердечной гемодинамики, в качестве основного критерия оценки наличия/отсутствия данной патологии. Aim. Development of a translational model for chronic heart failure (CHF) in rats to identify new biotargets for finding and studying mechanisms of innovative drug effect in this disease. Methods. A set of echocardiographic, morphological, biochemical, and molecular methods was used to evaluate and differentiate stages of CHF development. Results. Dynamic echocardiographic studies showed that CHF developed in 90 days after anterior transmural myocardial infarction. By that time, left ventricular ejection fraction was significantly decreased in animals of the main group compared with rats studied on day 2 after experimental myocardial infarction (55.9 ± 1.4% vs . 63.9 ± 1.6%, respectively, p<0.0008). The decrease in heart’s pumping function (by 13% compared with day 2 after infarction and by approximately 40% compared to intact animals) was associated with increased ESD and EDD (from 2.49 ± 0.08 to 3.91 ± 0.17 mm, p = 0.0002, and from 3.56 ± 0.11 to 5.20 ± 0.19 mm, respectively, p = 0.0001); therefore, heart failure developed by that time. The results of echocardiographic studies were confirmed by myocardial morphometry, which demonstrated dilatation of both right and left ventricles. Paralleled histological studies indicated presence of the changes pathognomonic for this myocardial pathology (postinfarction cardiosclerosis, compensatory hypertrophy of cardiomyocytes, foci of disappeared transverse striation of muscle fibers, etc.) and signs of venous congestion in lungs and liver. Biochemical studies demonstrated a significant increase in plasma concentration of brain natriuretic peptide, a biochemical marker of CHF. Results of molecular studies suggested hyperactivity of the renin-angiotensin-aldosterone and sympathoadrenal systems, which play a key role in the pathogenesis of CHF. Conclusions. A translational model of CHF in rats was developed, which reproduced major clinical and diagnostic criteria for this disease. Morphometric, histological, biochemical, and molecular markers for progressive CHF were correlated with echocardiographic diagnostic signs, which allows using this echocardiographic, noninvasive method characterizing the intracardiac hemodynamics as a major criterion for the presence / absence of this pathology.

Long-term impact of new-onset atrial fibrillation complicating acute myocardial infarction on heart failure: insights from the NOAFCAMI-SH registry

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
S.L Xu ◽  
J Luo ◽  
H.Q Li ◽  
Z.Q Li ◽  
B.X Liu ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Heart Failure ◽  
Atrial Fibrillation ◽  
Acute Myocardial Infarction ◽  
Natural Science ◽  
Funding Source ◽  
Onset Atrial Fibrillation ◽  
New Onset

Abstract Background New-onset atrial fibrillation (NOAF) complicating acute myocardial infarction (AMI) has been associated with poor survival, but the clinical implication of NOAF on subsequent heart failure (HF) is still not well studied. We aimed to investigate the relationship between NOAF following AMI and HF hospitalization. Methods This retrospective cohort study was conducted between February 2014 and March 2018, using data from the New-Onset Atrial Fibrillation Complicating Acute Myocardial Infarction in ShangHai registry, where all participants did not have a documented AF history. Patients with AMI who discharged alive and had complete echocardiography and follow-up data were analyzed. The primary outcome was HF hospitalization, which was defined as a minimum of an overnight hospital stay of a participant who presented with symptoms and signs of HF or received intravenous diuretics. Results A total of 2075 patients were included, of whom 228 developed NOAF during the index AMI hospitalization. During up to 5 years of follow-up (median: 2.7 years), 205 patients (9.9%) experienced HF hospitalization and 220 patients (10.6%) died. The incidence rate of HF hospitalization among patients with NOAF was 18.4% per year compared with 2.8% per year for those with sinus rhythm. After adjustment for confounders, NOAF was significantly associated with HF hospitalization (hazard ratio [HR]: 3.14, 95% confidence interval [CI]: 2.30–4.28; p&lt;0.001). Consistent result was observed after accounting for the competing risk of all-cause death (subdistribution HR: 3.06, 95% CI: 2.18–4.30; p&lt;0.001) or performing a propensity score adjusted multivariable model (HR: 3.28, 95% CI: 2.39–4.50; p&lt;0.001). Furthermore, the risk of HF hospitalization was significantly higher in patients with persistent NOAF (HR: 5.81; 95% CI: 3.59–9.41) compared with that in those with transient NOAF (HR: 2.61; 95% CI: 1.84–3.70; p interaction = 0.008). Conclusion NOAF complicating AMI is strongly associated with an increased long-term risk of heart. Cumulative incidence of outcome Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): 1. National Natural Science Foundation of China, 2. Natural Science Foundation of Shanghai

miR-187 modulates cardiomyocyte apoptosis and oxidative stress in myocardial infarction mice via negatively regulating DYRK2

2021 ◽  
Keyword(s):  
Oxidative Stress ◽  
Myocardial Infarction ◽  
Protective Effect ◽  
Myocardial Infarct ◽  
Annexin V ◽  
Cardiomyocyte Apoptosis ◽  
Ros Generation ◽  
Downstream Target

Myocardial infarction is a serious representation of cardiovescular disease, MicroRNAs play a role in modifying I/R injury and myocardial infarct remodeling. The present study therefore examined the potential role of miR-187 in cardiac I/R injury and its underlying mechanisms. miR-187 was inhibited or overexpressed in cardiomyocytes H/R models by pretreatment with miR-187 mimic or inhibitor to confirm the function of miR-187 in H/R. DYRK2 was inhibited or overexpressed in cardiomyocytes H/R models by pretreatment with DYRK2 inhibitor. A myocardium I/R mouse model was established. Circulating levels of miR-187 or DYRK2 was detected by quantitative realtime PCR and protein expression was detected by western blotting. The cell viability in all groups was determined by MTT assay and the apoptosis ratio was detected by flow cytometry after staining with Annexin V-FITC. The effect of miR-187 on cellular ROS generation was examined by DCFH-DA. The level of lipid peroxidation and SOD expression were determined by MDA and SOD assay. The findings indicated that miR-187 may be a possible regulator in the protective effect of H/R-induced cardiomyocyte apoptosis, cellular oxidative stress and leaded to DYRK2 suppression at a posttranscriptional level. Moreover, the improvement of miR-187 on H/R-induced cardiomyocyte injury contributed to the obstruction of DYRK2 expression. In addition, these results identified DYRK2 as the functional downstream target of miR-187 regulated myocardial infarction and oxidative stress.These present work provided the first insight into the function of miR-187 in successfully protect cardiomyocyte both in vivo and in vitro, and such a protective effect were mediated through the regulation of DYRK2 expression.

(-)-Epigallocatechin Gallate Promotes MicroRNA 145 Expression against Myocardial Hypoxic Injury through Dab2/Wnt3a/β-catenin

2020 ◽  
Vol 48 (02) ◽  
pp. 341-356
Author(s):  
Chiu-Mei Lin ◽  
Wei-Jen Fang ◽  
Bao-Wei Wang ◽  
Chun-Ming Pan ◽  
Su-Kiat Chua ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Real Time ◽  
Real Time Pcr ◽  
Myocardial Infarct ◽  
Epigallocatechin Gallate ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Rat Cardiomyocytes

MicroRNA 145 (miR-145) is a critical modulator of cardiovascular diseases. The downregulation of myocardial miR-145 is followed by an increase in disabled-2 (Dab2) expression in cardiomyocytes. (-)-epigallocatechin gallate (EGCG) is a flavonoid that has been evaluated extensively due to its diverse pharmacological properties including anti-inflammatory effects. The aim of this study was to investigate the cardioprotective effects of EGCG under hypoxia-induced stress in vitro and in vivo. The hypoxic insult led to the suppression of miR-145 expression in cultured rat cardiomyocytes in a concentration-dependent manner. Western blotting and real-time PCR were performed. In rat myocardial infarction study, in situ hybridization, and immunofluorescent analyses were adopted. The western blot and real-time PCR data revealed that hypoxic stress with 2.5% O2 suppressed the expression of miR-145 and Wnt3a/[Formula: see text]-catenin in cultured rat cardiomyocytes but augmented Dab2. Treatment with EGCG attenuated Dab2 expression, but increased Wnt3a and [Formula: see text]-catenin in hypoxic cultured cardiomyocytes. Following in vivo myocardial infarction (MI) study, the data revealed the myocardial infarct area reduced by 48.5%, 44.6%, and 48.5% in EGCG (50[Formula: see text]mg/kg) or miR-145 dominant or Dab2 siRNA groups after myocardial infarction for 28 days, respectively. This study demonstrated that EGCG increased miR-145, Wnt3a, and [Formula: see text]-catenin expression but attenuated Dab2 expression. Moreover, EGCG ameliorated myocardial ischemia in vivo. The novel suppressive effect was mediated through the miR-145 and Dab2/Wnt3a/[Formula: see text]-catenin pathways.

scholarly journals Swiprosin-1/EFhD-2 Expression in Cardiac Remodeling and Post-Infarct Repair: Effect of Ischemic Conditioning

2020 ◽  
Vol 21 (9) ◽  
pp. 3359
Author(s):  
Zoltán Giricz ◽  
András Makkos ◽  
Rolf Schreckenberg ◽  
Jochen Pöling ◽  
Holger Lörchner ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Cardiac Remodeling ◽  
Myocardial Infarct ◽  
Ischemia Reperfusion ◽  
Common Mechanism ◽  
Structural Adaptation ◽  
Infarct Zone ◽  
Rat Cardiomyocytes ◽  
Ischemic Conditioning

Swiprosin-1 (EFhD2) is a molecule that triggers structural adaptation of isolated adult rat cardiomyocytes to cell culture conditions by initiating a process known as cell spreading. This process mimics central aspects of cardiac remodeling, as it occurs subsequent to myocardial infarction. However, expression of swiprosin-1 in cardiac tissue and its regulation in vivo has not yet been addressed. The expression of swiprosin-1 was analyzed in mice, rat, and pig hearts undergoing myocardial infarction or ischemia/reperfusion with or without cardiac protection by ischemic pre- and postconditioning. In mouse hearts, swiprosin-1 protein expression was increased after 4 and 7 days in myocardial infarct areas specifically in cardiomyocytes as verified by immunoblotting and histology. In rat hearts, swiprosin-1 mRNA expression was induced within 7 days after ischemia/reperfusion but this induction was abrogated by conditioning. As in cultured cardiomyocytes, the expression of swiprosin-1 was associated with a coinduction of arrestin-2, suggesting a common mechanism of regulation. Rno-miR-32-3p and rno-miR-34c-3p were associated with the regulation pattern of both molecules. Moreover, induction of swiprosin-1 and ssc-miR-34c was also confirmed in the infarct zone of pigs. In summary, our data show that up-regulation of swiprosin-1 appears in the postischemic heart during cardiac remodeling and repair in different species.

Transition from compensatory hypertrophy to dilated, failing left ventricles in Dahl salt-sensitive rats

1994 ◽  
Vol 267 (6) ◽  
pp. H2471-H2482 ◽  
Author(s):  
M. Inoko ◽  
Y. Kihara ◽  
I. Morii ◽  
H. Fujiwara ◽  
S. Sasayama
Keyword(s):  
Heart Failure ◽  
Systolic Pressure ◽  
Myocardial Necrosis ◽  
Compensatory Hypertrophy ◽  
High Salt ◽  
High Salt Diet ◽  
Tension Development ◽  
Salt Diet ◽  
The Right

To establish an experimental model for studying a specific transitional stage for compensatory hypertrophy to heart failure, we studied the pathophysiology of the left ventricle (LV) in Dahl salt-sensitive (DS) rats fed a high-salt diet. DS rats fed an 8% NaCl diet after the age of 6 wk developed concentric LV hypertrophy at 11 wk, followed by marked LV dilatation at 15-20 wk. During the latter stage, the DS rats showed labored respiration with LV global hypokinesis. All the DS rats died within 1 wk by massive pulmonary congestion. The dissected left ventricles revealed chamber dilatation and a marked increase in mass without myocardial necrosis. In contrast, corresponding Dahl salt-resistant (DR) rats fed the same diet showed neither mortality nor any of these pathological changes. The in vivo LV end-systolic pressure-volume relationship shifted to the right with a less steep slope in the failing DS rats compared with that in age-matched DR rats. Isometric contractions of LV papillary muscles isolated from these DS rats showed reduced tension development in the failing stage, but normal tension development in the hypertrophied stage. In conclusion, the DS rat fed a high-salt diet is a useful model showing rapidly developing congestive heart failure, in which the transition from compensatory hypertrophy to decompensatory dilatation of LV is easily and consistently manifested.

Cytokine signaling during myocardial infarction: sequential appearance of IL-1 beta and IL-6

1995 ◽  
Vol 269 (2) ◽  
pp. R229-R235 ◽  
Author(s):  
I. Guillen ◽  
M. Blanes ◽  
M. J. Gomez-Lechon ◽  
J. V. Castell
Keyword(s):  
Myocardial Infarction ◽  
Endothelial Cells ◽  
Protein Synthesis ◽  
Proinflammatory Cytokines ◽  
Early Stage ◽  
Myocardial Infarct ◽  
Cytokine Signaling ◽  
Target Cells ◽  
Necrosis Factor Alpha

The purpose of this study was to investigate the significance of the sequential changes in proinflammatory cytokines observed in the plasma of patients early after myocardial infarct: a rise in interleukin (IL)-1 beta (308 +/- 126 vs. 141 +/- 78 pg/ml, P < 0.01) between 0 and 2 h followed by an IL-6 peak (49 +/- 24 vs. 14.5 +/- 13 pg/ml, P < 0.01) 4-9 h later. No significant changes in tumor necrosis factor-alpha (TNF-alpha) were observed at this early stage. The linkage between IL-1 beta and IL-6 secretions is supported by 1) the ability of patient's plasma drawn early after myocardial infarction to induce IL-6 mRNA and protein synthesis in cells that may be potential targets in vivo (fibroblasts and endothelial cells), 2) suppression of this activity by antibodies against IL-1 beta, and 3) a delay between IL-1 beta and IL-6 peaks in vivo (4-9 h), which is similar to the time required for maximal IL-6 production in IL-1 beta stimulated target cells in vitro (6 h). This sequential signaling might serve as the basis for an amplification mechanism of proinflammatory cytokines. In fact, a much greater synthesis of C-reactive protein was observed in hepatocytes when stimulated with conditioned medium of fibroblasts or endothelial cells that had previously been incubated with plasma of patients. The results of our work strongly suggest that, by inducing IL-6 in potential target cells, IL-1 beta could act as the primary, but indirect, signal that stimulates acute-phase protein synthesis after myocardial injury.

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