Activation of Oxytocin Neurons Improves Cardiac Function in a Pressure-Overload Model of Heart Failure

Abstract Aims Chronic heart failure is becoming increasingly prevalent and is still associated with a high mortality rate. Myocardial hypertrophy and fibrosis drive cardiac remodelling and heart failure, but they are not sufficiently inhibited by current treatment strategies. Furthermore, despite increasing knowledge on cardiomyocyte intracellular signalling proteins inducing pathological hypertrophy, therapeutic approaches to target these molecules are currently unavailable. In this study, we aimed to establish and test a therapeutic tool to counteract the 22 kDa calcium and integrin binding protein (CIB) 1, which we have previously identified as nodal regulator of pathological cardiac hypertrophy and as activator of the maladaptive calcineurin/NFAT axis. Methods and results Among three different sequences, we selected a shRNA construct (shCIB1) to specifically down-regulate CIB1 by 50% upon adenoviral overexpression in neonatal rat cardiomyocytes (NRCM), and upon overexpression by an adeno-associated-virus (AAV) 9 vector in mouse hearts. Overexpression of shCIB1 in NRCM markedly reduced cellular growth, improved contractility of bioartificial cardiac tissue and reduced calcineurin/NFAT activation in response to hypertrophic stimulation. In mice, administration of AAV-shCIB1 strongly ameliorated eccentric cardiac hypertrophy and cardiac dysfunction during 2 weeks of pressure overload by transverse aortic constriction (TAC). Ultrastructural and molecular analyses revealed markedly reduced myocardial fibrosis, inhibition of hypertrophy associated gene expression and calcineurin/NFAT as well as ERK MAP kinase activation after TAC in AAV-shCIB1 vs. AAV-shControl treated mice. During long-term exposure to pressure overload for 10 weeks, AAV-shCIB1 treatment maintained its anti-hypertrophic and anti-fibrotic effects, but cardiac function was no longer improved vs. AAV-shControl treatment, most likely resulting from a reduction in myocardial angiogenesis upon downregulation of CIB1. Conclusions Inhibition of CIB1 by a shRNA-mediated gene therapy potently inhibits pathological cardiac hypertrophy and fibrosis during pressure overload. While cardiac function is initially improved by shCIB1, this cannot be kept up during persisting overload.

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Distinct roles of resident and nonresident macrophages in nonischemic cardiomyopathy

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1720065115 ◽

2018 ◽

Vol 115 (20) ◽

pp. E4661-E4669 ◽

Cited By ~ 35

Author(s):

Xudong Liao ◽

Yuyan Shen ◽

Rongli Zhang ◽

Keiki Sugi ◽

Neelakantan T. Vasudevan ◽

...

Keyword(s):

Heart Failure ◽

Cardiac Function ◽

Late Phase ◽

Myeloid Cells ◽

Pressure Overload ◽

Genetic Mutations ◽

Nonischemic Cardiomyopathy ◽

Resident Macrophage ◽

Temporal And Spatial

Nonischemic cardiomyopathy (NICM) resulting from long-standing hypertension, valvular disease, and genetic mutations is a major cause of heart failure worldwide. Recent observations suggest that myeloid cells can impact cardiac function, but the role of tissue-intrinsic vs. tissue-extrinsic myeloid cells in NICM remains poorly understood. Here, we show that cardiac resident macrophage proliferation occurs within the first week following pressure overload hypertrophy (POH; a model of heart failure) and is requisite for the heart’s adaptive response. Mechanistically, we identify Kruppel-like factor 4 (KLF4) as a key transcription factor that regulates cardiac resident macrophage proliferation and angiogenic activities. Finally, we show that blood-borne macrophages recruited in late-phase POH are detrimental, and that blockade of their infiltration improves myocardial angiogenesis and preserves cardiac function. These observations demonstrate previously unappreciated temporal and spatial roles for resident and nonresident macrophages in the development of heart failure.

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GW28-e0941 Increasing fatty acid utilization improves cardiac function through OPA1-mediated mitochondrial fusion in pressure overload-induced heart failure

Journal of the American College of Cardiology ◽

10.1016/j.jacc.2017.07.225 ◽

2017 ◽

Vol 70 (16) ◽

pp. C66

Author(s):

Yongzheng Guo ◽

Xing Zhang ◽

Feng Gao

Keyword(s):

Heart Failure ◽

Fatty Acid ◽

Cardiac Function ◽

Pressure Overload ◽

Mitochondrial Fusion ◽

Fatty Acid Utilization

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Osteopontin RNA aptamer can prevent and reverse pressure overload-induced heart failure

Cardiovascular Research ◽

10.1093/cvr/cvx016 ◽

2017 ◽

Vol 113 (6) ◽

pp. 633-643 ◽

Cited By ~ 21

Author(s):

Jihe Li ◽

Keyvan Yousefi ◽

Wen Ding ◽

Jayanti Singh ◽

Lina A. Shehadeh

Keyword(s):

Heart Failure ◽

Cardiac Function ◽

Cardiac Dysfunction ◽

Cardiac Fibrosis ◽

Cardiac Myocyte ◽

Pressure Overload ◽

Cardiomyocyte Hypertrophy ◽

Therapeutic Effects ◽

Rna Aptamer ◽

Myocyte Hypertrophy

Aims Cardiac myocyte hypertrophy, the main compensatory response to chronic stress in the heart often progresses to a state of decompensation that can lead to heart failure. Osteopontin (OPN) is an effector for extracellular signalling that induces myocyte growth and fibrosis. Although increased OPN activity has been observed in stressed myocytes and fibroblasts, the detailed and long term effects of blocking OPN signalling on the heart remain poorly defined. Targeting cardiac OPN protein by an RNA aptamer may be beneficial for tuning down OPN pathologic signalling. We aimed to demonstrate the therapeutic effects of an OPN RNA aptamer on cardiac dysfunction. Methods and results In vivo, we show that in a mouse model of pressure overload, treating at the time of surgeries with an OPN aptamer prevented cardiomyocyte hypertrophy and cardiac fibrosis, blocked OPN downstream signalling (PI3K and Akt phosphorylation), reduced expression of extracellular matrix (Lum, Col3a1, Fn1) and hypertrophy (Nppa, Nppb) genes, and prevented cardiac dysfunction. Treating at two months post-surgeries with the OPN aptamer reversed cardiac dysfunction and fibrosis and myocyte hypertrophy. While genetic homozygous deletion of OPN reduced myocardial wall thickness, surprisingly cardiac function and myocardial fibrosis, specifically collagen deposition and myofibroblast infiltration, were worse compared with wild type mice at three months of pressure overload. Conclusion Taken together, these data demonstrate that tuning down cardiac OPN signalling by an OPN RNA aptamer is a novel and effective approach for preventing cardiac hypertrophy and fibrosis, improving cardiac function, and reversing pressure overload-induced heart failure.

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Chronic Benzene Exposure Aggravates Pressure Overload-Induced Cardiac Dysfunction

10.1101/2021.08.31.458367 ◽

2021 ◽

Author(s):

Igor N Zelko ◽

Sujith Dassanayaka ◽

Marina V Malovichko ◽

Caitlin M Howard ◽

Lauren F Garrett ◽

...

Keyword(s):

Heart Failure ◽

Endothelial Cells ◽

Cardiac Function ◽

Cardiac Tissue ◽

Pressure Overload ◽

Endothelial Activation ◽

Air Exposure ◽

Benzene Exposure ◽

Increased Risk

Benzene is a ubiquitous environmental pollutant abundant in household products, petrochemicals and cigarette smoke. Benzene is a well-known carcinogen in humans and experimental animals; however, little is known about the cardiovascular toxicity of benzene. Recent population-based studies indicate that benzene exposure is associated with an increased risk for heart failure. Nonetheless, it is unclear whether benzene exposure is sufficient to induce and/or exacerbate heart failure. We examined the effects of benzene (50 ppm, 6 h/day, 5 days/week, 6 weeks) or HEPA-filtered air exposure on transverse aortic constriction (TAC)-induced pressure overload in male C57BL/6J mice. Our data show that benzene exposure had no effect on cardiac function in the Sham group; however, it significantly compromised cardiac function as depicted by a significant decrease in fractional shortening and ejection fraction, as compared with TAC/Air-exposed mice. RNA-seq analysis of the cardiac tissue from the TAC/benzene-exposed mice showed a significant increase in several genes associated with adhesion molecules, cell-cell adhesion, inflammation, and stress response. In particular, neutrophils were implicated in our unbiased analyses. Indeed, immunofluorescence studies showed that TAC/benzene exposure promotes infiltration of CD11b+/S100A8+/myeloperoxidase+-positive neutrophils in the hearts by 3-fold. In vitro, the benzene metabolites, hydroquinone and catechol, induced the expression of P-selectin in cardiac microvascular endothelial cells by 5-fold and increased the adhesion of neutrophils to these endothelial cells by 1.5-2.0-fold. Benzene metabolite-induced adhesion of neutrophils to the endothelial cells was attenuated by anti-P-selectin antibody. Together, these data suggest that benzene exacerbates heart failure by promoting endothelial activation and neutrophil recruitment.

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Abstract 50: Therapeutic Silencing of miRNA-652 Restores Cardiac Function and Attenuates Pathological Remodeling in a Mouse Model of Pressure Overload

Circulation Research ◽

10.1161/res.115.suppl_1.50 ◽

2014 ◽

Vol 115 (suppl_1) ◽

Author(s):

Bianca C Bernardo ◽

Sally S Nguyen ◽

Catherine E Winbanks ◽

Xiao-Ming Gao ◽

Esther J Boey ◽

...

Keyword(s):

Heart Failure ◽

Mouse Model ◽

Cardiac Function ◽

Cardiac Dysfunction ◽

Heart Function ◽

Pressure Overload ◽

Post Treatment ◽

Locked Nucleic Acid ◽

Luciferase Assay ◽

Sham Operation

Introduction: Targeting microRNAs differentially regulated in settings of stress and protection could represent a new approach for the treatment of heart failure. miR-652 expression increased in hearts of a cardiac stress mouse model and was downregulated in a model of cardiac protection. Aim: To assess the therapeutic potential of silencing miR-652 in a mouse model with established pathological hypertrophy and cardiac dysfunction due to pressure overload. Methods: Mice were subjected to a sham operation (n=10) or transverse aortic constriction (TAC, n=14) for 4 weeks to induce hypertrophy and cardiac dysfunction. Mice were subcutaneously administered a locked nucleic acid (LNA)-antimiR-652 or LNA-control. Cardiac function was assessed by echocardiography before and 8 weeks post treatment, followed by molecular and histological analyses. Results: Expression of miR-652 increased in hearts subjected to pressure overload compared to sham operated mice (2.9 fold, n=3-5, P<0.05), but was silenced in hearts of mice administered LNA-antimiR-652 (95% decrease, n=3-7, P<0.05). In mice subjected to pressure overload, inhibition of miR-652 improved cardiac function (29±1% at 4 weeks post TAC compared to 35±1% post treatment, n=7, P<0.001) and attenuated cardiac hypertrophy. Functional and morphologic improvements in hearts of treated mice were associated with reduced cardiac fibrosis, apoptosis, cardiomyocyte size; decreased B-type natriuretic peptide gene expression; and preserved angiogenesis (all P<0.05, n=4-7/group). Mechanistically, we identified Jagged1, a Notch1 ligand, as a direct target of miR-652 by luciferase assay. Jagged1 and Notch1 mRNA were upregulated in hearts of TAC treated mice (1.2-1.7 fold, n=7, P<0.05). Importantly, chronic knockdown of miR-652 was not associated with any notable toxicity in other tissues. Conclusion: Therapeutic silencing of miR-652 protects the heart against pathological cardiac remodeling and improves heart function via mechanisms that are associated with preserved angiogenesis, decreased fibrosis and upregulation of a miR-652 target, Jagged1. These studies provide the first evidence that targeted inhibition of miR-652 could represent an attractive approach for the treatment of heart failure.

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Abstract 211: Intercellular Adhesion Molecule 1 Regulates Cardiac Remodeling and Function and T Cell Recruitment to the Heart in Pressure Overload Induced Heart Failure

Circulation Research ◽

10.1161/res.117.suppl_1.211 ◽

2015 ◽

Vol 117 (suppl_1) ◽

Author(s):

Ane Miren Salvador ◽

Tania Nevers ◽

Mark Aronovitz ◽

Robert Blanton ◽

Pilar Alcaide

Keyword(s):

Heart Failure ◽

T Cell ◽

Cardiac Function ◽

Adhesion Molecule ◽

Cardiac Remodeling ◽

Pressure Overload ◽

Leukocyte Recruitment ◽

Cell Infiltration ◽

Cell Recruitment ◽

T Cell Infiltration

Background: Left ventricular (LV) dysfunction and Heart Failure (HF) are associated in humans with systemic inflammation, including increased circulating levels of pro-inflammatory cytokines and soluble intercellular cell adhesion molecule-1 (ICAM-1). Endothelial ICAM-1 regulates leukocyte recruitment into tissues, which in the heart can result in altered cardiac function. We hypothesize that ICAM-1 regulates cardiac remodeling by mediating leukocyte recruitment to the LV and thus contributing to worsening of cardiac function during pressure overload induced HF. Methods and results: We used the mouse model of Thoracic Aortic Constriction (TAC) to induce LV remodeling and HF in WT and ICAM-1 deficient mice (ICAM-1 -/- ). Immunohistochemistry, flow cytometry, qPCR, echocardiography and hemodynamics were used to investigate leukocyte infiltration into the LV, cardiac function, hypertrophy and fibrosis mechanisms taking place in response to TAC. Endothelial ICAM-1 was upregulated in WT mice in response to TAC as compared to Sham, correlating with LV T cell infiltration. In contrast, CD3+ and CD4+ T cell recruitment into the LV was significantly reduced in response to TAC in ICAM-1 -/- mice as compared to WT mice. Further, indices of sistolic and diastolic function were preserved in ICAM-1 -/- mice (dP/dt max = WT TAC 5,627±549 vs. ICAM-1 -/- TAC 8,396±1,495 ; dP/dt min = WT TAC -5,614±1,195 vs. ICAM- 1-/- TAC -8,832±2,274) and the End Diastolic Pressure was significantly lower than in WT TAC mice (31.0±7.0mmHg in WT TAC vs 8.1±7.8mmHg in ICAM-1 -/- TAC). Despite increased LV weight, ICAM-1 -/- did not develop fibrosis in response to TAC, with blunted collagen deposition and lack of mRNA upregulation of fibrotic markers Collagen-I, TGFβ and SMAα four and ten weeks after TAC when dilated cardiomiopathy is established in WT mice. Conclusion: Our data indicate that ICAM-1 regulates LV T cell infiltration, cardiac function and fibrosis in HF induced by TAC. Further studies will determine whether ICAM-1 contributes to HF pathogenesis exclusively by regulating T cell interactions with the LV endothelium or participating in novel mechanisms regulating cardiac cell function, which could represent new targets for the treatment of this deadly syndrome.

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Abstract 407: Overexpression of the Valosin-containing Protein in vivo Prevents Cardiac Hypertrophy and Heart Failure by Chronic Pressure Overload via Suppressing the Activation of mTORC1 Pathway

Circulation Research ◽

10.1161/res.119.suppl_1.407 ◽

2016 ◽

Vol 119 (suppl_1) ◽

Author(s):

Ning Zhou ◽

Ben Ma ◽

Tristen T Hays ◽

Hongyu Qiu

Keyword(s):

Heart Failure ◽

Cardiac Hypertrophy ◽

Cardiac Function ◽

Pressure Overload ◽

Significant Inhibition ◽

Cardiac Structure ◽

Lung Weight ◽

Cross Sectional ◽

Mtorc1 Signaling

Aims: Pressure overload induced cardiac hypertrophy is a key risk factor for heart failure. Although several defined interventions result in a significant inhibition of cardiac hypertrophy, the functional consequences are controversial. Identification of novel targets modulating the cardiac hypertrophy without adversely affecting cardiac function is particularly crucial to the treatment of heart failure. Here we test our hypothesis that the valosin-containing protein (VCP) is a novel mediator of cardiac protection against cardiac hypertrophy and heart failure by pressure overload. Methods and Results: Pressure overload was induced by transverse aortic constriction (TAC) in a mouse model to mimic the progression of cardiac hypertrophy and heart failure. Cardiac structure and function were measured by echocardiography and hemodynamic analysis. VCP expression was significantly reduced in wild type (WT) mice after 2 weeks TAC at both the mRNA and protein levels by 40% and 45 % respectively and even more markedly reduced after 5 weeks TAC (68% in mRNA and 73% in protein, all, P <0.01 vs sham). Cardiac overexpression of VCP in a transgenic (TG) mouse did not alter either cardiac structure or function at baseline condition. However, compared to 2 week TAC WT mice, VCP TG mice showed a significant repression of cardiac hypotrophy, evidenced by a significant reduction in the ratio of left ventricle (LV) /tibial length (TL) by 36%, LV posterior wall thickness by 20%, and cardiomyocyte cross sectional area by 39% (all P <0.05 vs WT). After 5 weeks of TAC, while WT mice progressed to cardiac failure, VCP TG mice exhibited preservation of cardiac function in terms of ejection function (EF,72±1% vs 52±4.1% in WT) and Lung weight /TL ratio (8.0±0.8mg/mm vs 9.8±0.8 mg/mm in WT) ( P <0.05 vs WT). Induction of fetal cardiac genes in TAC WT, e.g. ANP and BNP, was significant suppressed in VCP TG mice ( P <0.05 vs WT). TAC induced activation of mammalian target of rapamycin complex 1 (mTORC1), e.g., an increase of phosphorylation of mTOR and S6K1, was significantly blunted in VCP TG mice vs WT after TAC ( P <0.05 vs WT). Conclusion: Overexpression of VCP in vivo prevents the progression of cardiac hypertrophy and dysfunction upon pressure overload by modulating mTORC1 signaling pathways.

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Abstract 87: Alterations to Cardiac Mechanics Do Not Preserve Normal Cardiac Function in a Novel Ossabaw Swine Model of Heart Failure with Preserved Ejection Fraction

Circulation Research ◽

10.1161/res.121.suppl_1.87 ◽

2017 ◽

Vol 121 (suppl_1) ◽

Author(s):

Jenna C Edwards ◽

Madeleine Dionne ◽

T. D Olver ◽

Jan R Ivey ◽

Pamela K Thorne ◽

...

Keyword(s):

Heart Failure ◽

Ejection Fraction ◽

Cardiac Function ◽

Strain Rate ◽

Pressure Overload ◽

Left Ventricular ◽

Volume Index ◽

Lv Function ◽

Swine Model ◽

Preserved Ejection Fraction

Introduction: Heart failure with preserved ejection fraction (HFpEF) is clinically characterized by an increased incidence in females and many comorbidities including type 2 diabetes (T2D) and obesity. Animal models accurately representing clinical HFpEF are lacking; thus, the purpose of this study was to examine left ventricular (LV) mechanics in a novel Ossabaw swine model of chronic pressure-overload (aortic-banding; AB) and T2D (Western diet; WD) using two dimensional speckle tracking echocardiography (2D-STE). We hypothesized that global LV strain would be decreased primarily in the longitudinal direction in WD-AB animals. Methods: Female Ossabaws were randomly divided into 2 groups: CON (n=5) and WD-AB (n=5). LV function and strain were measured at 1 year of age after 6 mo. of AB and 9 mo. of WD via pressure-volume relations and 2D-STE. Significance was set at P < 0.05 using t-test vs. CON. Results: In the WD-AB group, ejection fraction (EF%) and end diastolic volume were normal (>50%), and observed in parallel with increased LV weight, lung weight, and LV diastolic wall thickness (i.e. concentric hypertrophy). WD-AB group had increased HOMA-IR and body surface area, two common features in T2D. In WD-AB animals, although global longitudinal systolic strain rate and end systolic displacement were increased, stroke volume index was decreased. Early diastolic rotation rate was decreased, while global longitudinal late diastolic strain rate was increased in the WD-AB group. These changes, considered in parallel with an increased end diastolic pressure-volume relationship in WD-AB animals, are consistent with diastolic dysfunction. In contrast, longitudinal, radial, and circumferential early diastolic strain rates increased in the WD-AB group. Conclusion: Contrary to our hypothesis, LV longitudinal strain was increased during both systole and diastole, and observed in parallel with decreased early diastolic untwisting in WD-AB animals. Our results suggest alterations to LV mechanics do not preserve normal systolic and diastolic cardiac function, despite normal resting EF%, in this novel translational model of pressure-overload HF with potential relevance to human HFpEF including associated clinical comorbidities (sex, obesity, and T2D).

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Abstract 069: Mitochondrial Mechanisms Of Reverse Remodeling In Heart Failure

Circulation Research ◽

10.1161/res.113.suppl_1.a069 ◽

2013 ◽

Vol 113 (suppl_1) ◽

Author(s):

Preeti Ahuja ◽

William R MacLellan ◽

Yibin Wang

Keyword(s):

Heart Failure ◽

Cardiac Function ◽

Cardiac Myocyte ◽

Pressure Overload ◽

Left Ventricular ◽

Reverse Remodeling ◽

Ventricular Assist ◽

Hypertrophic Response ◽

Mtdna Deletions ◽

And Function

Enhancement of myocardial mitochondrial (mt) function resulting in efficient energy production by means of Left ventricular assist device (LVAD) has been suggested in heart failure (HF) which could have important clinical implications and may represent a novel therapeutic target. However, the basis for this improvement remains unknown. To characterize mt biogenesis, mt genomic integrity and mitophagy in reversing pathological remodeling, we investigated LV tissue from post-LVAD human hearts and after reversal of transaortic constriction (TAC) in mice. In Post-LVAD human hearts there was increased expression of mt fusion and biogenesis, mtDNA levels were normalized and deletion mutation rates were significantly reduced with reverse remodeling and these changes were associated with enhancement of mt ETC complex I and II activities and improved cardiac-myocyte morphology. To better understand the mechanisms underlying mt repair/remodeling with LVAD support, we developed a model of aortic banding (AB) and debanding (DB) in mice. C57BL/6 mice were subjected to 2 weeks of AB and subsequent DB for period of 1 to 20 days and cardiac function and hypertrophy were evaluated by echocardiography and real-time PCR, respectively. Compared with control animals, mice that had undergone banding had a robust hypertrophic response with decline in cardiac function. These parameters were reversed following removal of pressure overload by DB. Even 1 day of unloading led to significant increase in the expression of mt fusion and biogenesis genes. Hearts from AB (2 weeks) mice showed a 3.7-fold (P<0.05) increase in frequency of mtDNA deletions. However, mtDNA deletions were significantly reduced in frequency with DB when compared with AB hearts alone. Increase in expression of autophagy related genes could also be observed after hemodynamic unloading in mouse failing hearts. Removal of pressure overload by DB led to 2.58-fold (P<0.05) increase in expression of LC3B when compared to sham and AB mice. Thus, our data strongly suggest that protective effect of enhanced mt biogenesis, fusion/mtDNA repair and removal of damaged mitochondria by mitophagy could play an important role in maintaining mt integrity and function in the adult heart with reverse remodeling.

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