scholarly journals Alteration of m6A RNA Methylation in Heart Failure With Preserved Ejection Fraction

2021 ◽  
Vol 8 ◽  
Author(s):  
Beijian Zhang ◽  
Yamei Xu ◽  
Xiaotong Cui ◽  
Hao Jiang ◽  
Wei Luo ◽  
...  
Keyword(s):  
Heart Failure ◽  
Ejection Fraction ◽  
Mouse Model ◽  
Rna Polymerase Ii ◽  
Peripheral Blood ◽  
Mononuclear Cells ◽  
Translation Regulation ◽  
Preserved Ejection Fraction ◽  
Rna Methylation ◽  
M6a Rna Methylation

Background: Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous disease, in which its pathogenesis is very complex and far from defined. Here, we explored the N6-methyladenosine (m6A) RNA methylation alteration in patients with HFpEF and mouse model of HFpEF.Methods: In this case–control study, peripheral blood mononuclear cells (PBMCs) were separated from peripheral blood samples obtained from 16 HFpEF patients and 24 healthy controls. The change of m6A regulators was detected by quantitative real-time PCR (RT-PCR). A “two-hit” mouse model of HFpEF was induced by a high-fat diet and drinking water with 0.5 g/L of Nω-nitro-l-arginine methyl ester (L-NAME). MeRIP-seq was used to map transcriptome-wide m6A in control mice and HFpEF mice, and the gene expression was high-throughput detected by RNA-seq.Results: The expression of m6A writers METTL3, METTL4, and KIAA1429; m6A eraser FTO; and reader YTHDF2 was up-regulated in HFpEF patients, compared with health controls. Furthermore, the expression of FTO was also elevated in HFpEF mice. A total of 661 m6A peaks were significantly changed by MeRIP-seq. Gene Ontology (GO) analysis revealed that protein folding, ubiquitin-dependent ERAD pathway, and positive regulation of RNA polymerase II were the three most significantly altered biological processes in HFpEF. The pathways including proteasome, protein processing in the endoplasmic reticulum, and PI3K-Akt signaling pathway were significantly changed in HFpEF by Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis.Conclusions: The expression pattern of m6A regulators and m6A landscape is changed in HFpEF. This uncovers a new transcription-independent mechanism of translation regulation. Therefore, our data suggest that the modulation of epitranscriptomic processes, such as m6A methylation, might be an interesting target for therapeutic interventions.

Abstract 14648: Interleukin-18 Blockade Prevents Diastolic Dysfunction in a Mouse Model of Heart Failure With Preserved Ejection Fraction

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Jessica A Regan ◽  
Adolofo G Mauro ◽  
Salvatore Carbone ◽  
Carlo Marchetti ◽  
Eleonora Mezzaroma ◽  
...  
Keyword(s):  
Heart Failure ◽  
Blood Pressure ◽  
Ejection Fraction ◽  
Mouse Model ◽  
Diastolic Dysfunction ◽  
Diastolic Function ◽  
Low Dose ◽  
Preserved Ejection Fraction ◽  
Interleukin 18 ◽  
Lv Diastolic Function

Background: Heart failure with preserved ejection fraction (HFpEF) is characterized by elevated left ventricular (LV) filling pressures due to impaired LV diastolic function. Low-dose infusion of angiotensin 2 (AT2) in the mouse induces a HFpEF phenotype without increasing blood pressure. AT2 infusion induces expression of Interleukin-18 (IL-18) in the heart. We therefore tested whether IL-18 mediated AT2-induced LV diastolic dysfunction in this model. Methods: We infused subcutaneously AT2 (0.2 mg/Kg/day) or a matching volume of vehicle via osmotic pumps surgically implanted in the interscapular space in adult wild-type (WT) male mice and IL-18 knock-out mice (IL-18KO). We also treated WT mice with daily intraperitoneal injections of recombinant murine IL-18 binding protein (IL-18bp, a naturally occurring IL-18 blocker) at 3 different doses (0.1, 0.3 and 1.0 mg/kg) or vehicle for 25 days starting on day 3. We performed a Doppler-echocardiography study before implantation and at 28 days to measure LV dimensions, mass, and systolic and diastolic function in all mice. LV catheterization was performed prior to sacrifice to measure LV end-diastolic pressure (LVEDP) using a Millar catheter. Results: AT2 induces a significant increase in isovolumetric relaxation time (IRT) and myocardial performance index (MPI) at Doppler echocardiography and elevation of LVEDP at catheterization, indicative of impaired LV diastolic function, in absence of any measurable effects on systolic blood pressure nor LV dimensions, mass, or systolic function. Mice with genetic deletion of IL-18 (IL-18 KO) or WT mice treated with IL-18bp had no significant increase in IRT, MPI or LVEDP with AT2 infusion. Conclusion: Genetic or pharmacologic IL-18 blockade prevent diastolic dysfunction in a mouse model of HFpEF induced by low dose AT2 infusion, suggesting a critical role of IL-18 in the pathophysiology of HFpEF.

Abstract P389: Free Fatty Acid Receptor 4 Is Necessary For An Adaptive Response Following Heart Failure Induced By Metabolic Syndrome In Mice

2021 ◽  
Vol 129 (Suppl_1) ◽  
Author(s):  
Naixin Zhang ◽  
Katherine A Murphy ◽  
Dylan J Gyberg ◽  
Timothy D O'Connell
Keyword(s):  
Heart Failure ◽  
Metabolic Syndrome ◽  
Fatty Acid ◽  
Free Fatty Acid ◽  
Ejection Fraction ◽  
Mouse Model ◽  
Diastolic Dysfunction ◽  
Preserved Ejection Fraction ◽  
Acid Receptor ◽  
Free Fatty Acid Receptor

Non-resolving inflammation is central to the pathogenesis of heart failure (HF). Heart failure preserved ejection fraction (HFpEF) is a type of HF that is particularly associated with inflammation provoked by metabolic syndrome (MetS). The G-protein coupled receptor, free fatty acid receptor 4 (Ffar4), is a receptor for medium and long chain fatty acids (FA) that regulates metabolism and attenuates inflammation. Ffar4 is expressed in the human heart, and downregulated in heart failure. Furthermore, polymorphisms in Ffar4 have been associated with eccentric remodeling in a patient cohort. Previously, Ffar4 was shown to protect the heart from pathologic stress by attenuating oxidative stress in a mouse model of pressure overload. Here, we tested the hypothesis that Ffar4 would attenuate the development of heart failure using a mouse model of MetS-induced HFpEF. Metabolic syndrome was induced in mice by feeding a high-fat, high-sucrose diet (42% fat, 30% sucrose) to produce obesity and delivering the nitric oxide synthase inhibitor, L-NAME, in the drinking water to induce hypertension. The combined intervention (referred to as HFpEF diet) resulted in mice developing excessive adiposity, glucose intolerance (in males only), and mild hypertension. After 20 weeks on the HFpEF diet, both male and female WT mice, developed diastolic dysfunction (increased E/A and E/e’) and preserved ejection fraction (EF), consistent with clinical HFpEF. In Ffar4KO male mice HFpEF diet induced a greater degree of diastolic dysfunction compared to WT mice, despite equivalent metabolic parameters. Female Ffar4KO mice fed the HFpEF diet had a greater increase in weight gain and adiposity compared to WT female mice. Surprisingly, diastolic function was equivalent between WT and FFAR4KO female mice, suggesting a sex-based difference in FFAR4 cardioprotection. Our data show that Ffar4 attenuates HFpEF secondary to MetS.

Abstract MP227: Single Cell RNA Sequencing Analysis Reveals Insulin Signaling Defects In Cardiomyocytes Derived From A Novel Mouse Model Of Heart Failure With Preserved Ejection Fraction

2021 ◽  
Vol 129 (Suppl_1) ◽  
Author(s):  
Jijun Huang ◽  
Zhaojun Xiong ◽  
Shuxun Ren ◽  
Nancy Cao ◽  
Jianfang Liu ◽  
...  
Keyword(s):  
Heart Failure ◽  
Insulin Resistance ◽  
Ejection Fraction ◽  
Mouse Model ◽  
Rna Sequencing ◽  
Insulin Signaling ◽  
Mitochondrial Gene ◽  
Cell Types ◽  
Sequencing Analysis ◽  
Preserved Ejection Fraction

Heart failure with preserved ejection fraction (HFpEF) is an emerging form of heart failure worldwide with no effective therapies in contrast with heart failure with reserved ejection fraction (HFrEF). To simulate multiple risk-factors associated with HFpEF in clinic, we developed a HFpEF mouse model by introducing cardiac hypertrophy with transverse aortic constriction (TAC) in ObOb ( Lep ob/ob ) mice, which has intrinsic systemic metabolic dysfunctions including obesity and insulin resistance. We first validated pathological changes in diastolic but not systolic parameters in the Ob-TAC vs. Ob-sham mice up to 10 weeks post-TAC by echocardiography. To evaluate the global transcriptome change in difference cell types, we conducted single nuclei RNA sequencing (snRNA-seq) from whole hearts of lean mice (c57), ObOb, and Ob-TAC mice (male only). 10x genomic 3’ GEM kit was used to generate the cDNA library and sequencing was done by Novaseq SP platform. A total of 13k nuclei were recovered from QC, nFeature RNA (&lt 2500) and mitochondrial gene (&lt 5%) filtering. By UMAP dimension reduction analysis, we annotated major cardiac cell types in the integrated snRNA-seq dataset, including 3 clusters of Cardiomyocytes (CMs). By pathway analysis of the differentially expressed genes in each CM clusters, we found that insulin resistance and glucagon pathway were enriched among the up regulated genes in CMs in HFpEF vs. lean control, while cell migration, signal transduction including insulin substrates were down regulated. Thus, we hypothesized that the altered crosstalk between glucagon and insulin signaling might contribute to the development of HFpEF in this mouse modal. This hypothesis was validated in a proof-of-concept study showing significant improvement of HFpEF features by inhibiting the glucagon receptors post-TAC with injection of a glucagon receptor antagonist.

scholarly journals Endothelial Senescence Contributes to Heart Failure With Preserved Ejection Fraction in an Aging Mouse Model

2017 ◽  
Vol 10 (6) ◽  
Author(s):  
Andreas B. Gevaert ◽  
Hadis Shakeri ◽  
Arthur J. Leloup ◽  
Cor E. Van Hove ◽  
Guido R.Y. De Meyer ◽  
...  
Keyword(s):  
Heart Failure ◽  
Ejection Fraction ◽  
Mouse Model ◽  
Preserved Ejection Fraction ◽  
Aging Mouse

Abstract 56: Growth Hormone Releasing Hormone Improves Sarcomere Relaxation and Calcium Decline in Cardiomyocyte From a Mouse Model of Heart Failure With Preserved Ejection Fraction

2016 ◽  
Vol 119 (suppl_1) ◽  
Author(s):  
Raul A Dulce ◽  
Rosemeire M Kanashiro-Takeuchi ◽  
Lauro M Takeuchi ◽  
Wayne Balkan ◽  
Renzhi Cai ◽  
...  
Keyword(s):  
Heart Failure ◽  
Growth Hormone ◽  
Ejection Fraction ◽  
Mouse Model ◽  
Sarcomere Length ◽  
Growth Hormone Releasing Hormone ◽  
Preserved Ejection Fraction ◽  
Ang Ii ◽  
Calcium Decline ◽  
Ghrh Receptor

Heart failure with preserved ejection fraction (HFpEF) is characterized by impaired relaxation, ventricular stiffening and fibrosis. Growth hormone releasing hormone (GHRH) agonists reduce fibrosis in rat and swine models of ischemic myocardial injury. However, their effect on cardiomyocytes is not known. We hypothesized that activation of GHRH receptor signaling improves impaired cardiomyocyte relaxation in a mouse model of HFpEF. C57BL6N mice (n=4-5) were implanted with a mini-osmotic pump to deliver angiotensin-II (Ang-II: 0.8 mg/kg/day) for 4 weeks and received daily injections of GHRH-Agonist (GHRH-A [MR-409]: 100 μg/kg) or vehicle (DMSO+propylene-glycol). Cardiomyocytes were isolated and calcium and sarcomere shortening assessed. Ang-II-treated cardiomyocytes exhibited reduced sarcomere length, indicating an inability to completely relax, despite lower resting calcium. These cardiomyocytes also exhibited impaired ability to contract with no changes in calcium transient amplitude, deficient relaxation and delayed calcium decay. MR-409 treatment restored resting calcium and resting sarcomere length; improved sarcomere shortening and completely abrogated Ang-II-induced delay in calcium decline and relaxation (see figure 1). Our findings demonstrate that chronic administration of Ang-II mediates structural and functional changes consistent with HFpEF and suggest that activation of the GHRH receptor signaling pathways prevents HFpEF-associated cardiomyocyte performance alterations.

Abstract MP03: Immunophenotyping A Heart Failure With Preserved Ejection Fraction (HFpEF) Mouse Model With Cellular Indexing Of Transcriptomes And Epitopes (CITE)-seq

Hypertension ◽  
2020 ◽  
Vol 76 (Suppl_1) ◽  
Author(s):  
Charles D Smart ◽  
Vineet Agrawal ◽  
Anna R Hemnes ◽  
Meena S Madhur
Keyword(s):  
Heart Failure ◽  
Ejection Fraction ◽  
Mouse Model ◽  
Diastolic Dysfunction ◽  
Gene Set Enrichment Analysis ◽  
Heart Weight ◽  
Time To Exhaustion ◽  
Type I ◽  
Preserved Ejection Fraction ◽  
Pulmonary Congestion

Deoxycorticosterone acetate (DOCA)-salt is a common hypertension model in mice and has recently been used to study heart failure with preserved ejection fraction (HFpEF) in rats. Our goal was to validate DOCA-salt as a mouse model of HFpEF and determine how DOCA-salt alters the cardiac immunological landscape to identify novel therapeutic targets for this disease. DOCA-salt mice underwent uninephrectomy, implantion of a DOCA pellet, and supplementation of the drinking water with 1% NaCl water for three weeks. Control mice underwent a sham procedure and received normal water. Compared to control mice, DOCA-salt mice exhibited elevated systolic BP, increased heart weight to body weight ratios (5.6 vs 7.1), increased lung wet to dry weight ratios (4.4 vs 4.8) indicative of pulmonary congestion, and decreased time to exhaustion upon treadmill exercise testing (23.0 vs. 18.5 seconds). On conscious echocardiography, DOCA-salt mice exhibited a preserved ejection fraction. Invasive hemodynamic studies revealed an increased tau constant (5.7 vs 8.2) and increased end-diastolic pressures in DOCA-salt mice (1.7 vs 2.6), consistent with diastolic dysfunction. CITE-seq, a novel technique to obtain transcriptomic and surface marker expression on single cells, was performed on a total of 4,359 and 7,600 cells sorted live CD45+ leukocytes from four sham and four DOCA-salt left ventricles, respectively. Unsupervised computational analysis revealed 29 clusters of immune cells. Six clusters containing natural killer, T lymphocyte and myeloid cell populations were overrepresented and five B cell clusters were underrepresented in DOCA-salt samples. Differential expression analysis of CD11b+CD64+ cardiac macrophages revealed transcriptional changes between groups with 146 significantly upregulated and 111 downregulated genes. Gene set enrichment analysis showed upregulation of leukocyte migration, response to type I interferon, and cytokine-mediated signaling pathways in DOCA-salt macrophages. In conclusion, the DOCA-salt mouse model recapitulates key features of HFpEF including diastolic dysfunction with preserved ejection fraction, cardiac hypertrophy, and pulmonary congestion and is associated with an altered cardiac immune cell profile.

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