Homoarginine Treatment of Rats Improves Cardiac Function and Remodeling in Response to Pressure Overload

Abstract Purpose Low serum concentrations of the amino acid homoarginine (HA) are associated with increased cardiovascular mortality by incompletely understood mechanisms. This study sought to assess the influence of HA on myocardial function and remodeling in rats undergoing aortic banding or given the nitric oxide synthesis inhibitor Nω-Nitro-L-arginine methyl ester hydrochloride (L-NAME). Methods Male Wistar rats (n = 136) underwent sham operation (SH) or aortic banding (AB) and were equally divided into fourteen subgroups, receiving different doses of HA alone or in combination with either lisinopril, spironolactone or L-NAME over a 4-week period. Results HA treatment in AB animals resulted in a dose-dependent improvement of cardiac function up to a concentration of 800 mg·kg− 1·day− 1. Combining 800 mg·kg− 1·day− 1 HA with spironolactone or lisinopril yielded synergistic effects, showing a positive correlation with LV ejection fraction (+ 27%, p < 0.05), fractional shortening (+ 37%, p < 0.05) and an inverse association with collagen area fraction (-56%, p < 0.05), myocyte cross-sectional area (-22%, p < 0.05) and the molecular markers atrial natriuretic factor (-78%, p = 0.04), brain natriuretic peptide (-28%, p = 0.22), beta-myosin heavy chain (-42%, p = 0.19) and collagen type V alpha 1 chain (-73%, p = 0.06) compared to placebo treated AB animals. Even co-administration of HA and L-NAME was found to attenuate cardiac remodeling and to prevent NO-deficient hypertension following AB. Conclusion HA treatment has led to a dose-dependent improvement of myocardial function and marked histological and molecular changes of cardiac remodeling following AB. Combining HA with standard heart failure medication resulted in synergistic beneficial effects boosting the direct impact of HA on heart failure pathophysiology.

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Effects of Combination of ACE Inhibitor and Angiotensin Receptor Blocker on Cardiac Remodeling, Cardiac Function, and Survival in Rat Heart Failure

Circulation ◽

10.1161/01.cir.103.1.148 ◽

2001 ◽

Vol 103 (1) ◽

pp. 148-154 ◽

Cited By ~ 106

Author(s):

Shokei Kim ◽

Minoru Yoshiyama ◽

Yasukatsu Izumi ◽

Hitomi Kawano ◽

Manabu Kimoto ◽

...

Keyword(s):

Heart Failure ◽

Cardiac Function ◽

Cardiac Remodeling ◽

Rat Heart ◽

Angiotensin Receptor Blocker ◽

Ace Inhibitor ◽

Receptor Blocker ◽

Angiotensin Receptor

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Qiliqiangxin Attenuates Cardiac Remodeling via Inhibition of TGF-β1/Smad3 and NF-κB Signaling Pathways in a Rat Model of Myocardial Infarction

Cellular Physiology and Biochemistry ◽

10.1159/000487871 ◽

2018 ◽

Vol 45 (5) ◽

pp. 1797-1806 ◽

Cited By ~ 22

Author(s):

Anbang Han ◽

Yingdong Lu ◽

Qi Zheng ◽

Jian Zhang ◽

YiZhou Zhao ◽

...

Keyword(s):

Myocardial Infarction ◽

Heart Failure ◽

Cardiac Function ◽

Signaling Pathways ◽

Rat Model ◽

Cardiac Remodeling ◽

Left Ventricular ◽

Protective Effects ◽

Tnf Α ◽

Tgf Β1

Background/Aims: Qiliqiangxin (QL), a traditional Chinese medicine, has been demonstrated to be effective and safe for the treatment of chronic heart failure. Left ventricular (LV) remodeling causes depressed cardiac performance and is an independent determinant of morbidity and mortality after myocardial infarction (MI). Our previous studies have shown that QL exhibits cardiac protective effects against heart failure after MI. The objective of this study was to explore the effects of QL on myocardial fibrosis in rats with MI and to investigate the underlying mechanism of these effects. Methods: A rat model of acute myocardial infarction was induced by ligating the left anterior descending coronary artery. The rats were treated with QL (1.0 g/kg/day) for 4 weeks after surgery. Echocardiography and histology examination were performed to evaluate heart function and fibrosis, respectively. Protein levels of transforming growth factor-β1 (TGF-β1), phosphorylated Smad3 (p-Smad3), phosphorylated Smad7 (p-Smad7), collagen I (Col- I), alpha smooth muscle actin (a-SMA), tumor necrosis factor-α (TNF-α), interleukin 6 (IL-6), nuclear factor κB (NF-κB), and phosphorylated inhibitor of kappa B alpha (p-IκBα) were measured by western blot analysis. Results: QL treatment ameliorated adverse cardiac remodeling 8 weeks after AMI, including better preservation of cardiac function, decreased inflammation, and reduced fibrosis. In addition, QL treatment reduced Col-I, a-SMA, TGF-β1, and p-Smad3 expression levels but increased p-Smad7 levels in postmyocardial infarct rat hearts. QL administration also reduced the elevated levels of cardiac inflammation mediators, such as TNF-α and IL-6, as well as NF-κB and p-IκBα expression. Conclusions: QL therapy exerted protective effects against cardiac remodeling potentially by inhibiting TGF-β1/Smad3 and NF-κB signaling pathways, thereby preserving cardiac function, as well as reducing myocardial inflammation and fibrosis.

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Proteasome inhibition decreases cardiac remodeling after initiation of pressure overload

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00532.2008 ◽

2008 ◽

Vol 295 (4) ◽

pp. H1385-H1393 ◽

Cited By ~ 68

Author(s):

Nadia Hedhli ◽

Paulo Lizano ◽

Chull Hong ◽

Luke F. Fritzky ◽

Sunil K. Dhar ◽

...

Keyword(s):

Heart Failure ◽

Ejection Fraction ◽

Cardiac Remodeling ◽

Ventricular Remodeling ◽

Pressure Overload ◽

Proteasome Inhibition ◽

Aortic Banding ◽

Lung Weight ◽

Cross Sectional ◽

Myocyte Apoptosis

We tested the possibility that proteasome inhibition may reverse preexisting cardiac hypertrophy and improve remodeling upon pressure overload. Mice were submitted to aortic banding and followed up for 3 wk. The proteasome inhibitor epoxomicin (0.5 mg/kg) or the vehicle was injected daily, starting 2 wk after banding. At the end of the third week, vehicle-treated banded animals showed significant ( P < 0.05) increase in proteasome activity (PA), left ventricle-to-tibial length ratio (LV/TL), myocyte cross-sectional area (MCA), and myocyte apoptosis compared with sham-operated animals and developed signs of heart failure, including increased lung weight-to-TL ratio and decreased ejection fraction. When compared with that group, banded mice treated with epoxomicin showed no increase in PA, a lower LV/TL and MCA, reduced apoptosis, stabilized ejection fraction, and no signs of heart failure. Because overload-mediated cardiac remodeling largely depends on the activation of the proteasome-regulated transcription factor NF-κB, we tested whether epoxomicin would prevent this activation. NF-κB activity increased significantly upon overload, which was suppressed by epoxomicin. The expression of NF-κB-dependent transcripts, encoding collagen types I and III and the matrix metalloprotease-2, increased ( P < 0.05) after banding, which was abolished by epoxomicin. The accumulation of collagen after overload, as measured by histology, was 75% lower ( P < 0.05) with epoxomicin compared with vehicle. Myocyte apoptosis increased by fourfold in hearts submitted to aortic banding compared with sham-operated hearts, which was reduced by half upon epoxomicin treatment. Therefore, we propose that proteasome inhibition after the onset of pressure overload rescues ventricular remodeling by stabilizing cardiac function, suppressing further progression of hypertrophy, repressing collagen accumulation, and reducing myocyte apoptosis.

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Serial Assessment of Cardiac Function during and following Mitoxantrone Infusion in 30 Consecutive Patients with Multiple Sclerosis

Multiple Sclerosis International ◽

10.1155/2010/351045 ◽

2010 ◽

Vol 2010 ◽

pp. 1-4

Author(s):

Damian Franzen ◽

Angelika Haus ◽

Martin Hellmich

Keyword(s):

Multiple Sclerosis ◽

Heart Failure ◽

Cardiac Function ◽

Low Dose ◽

Therapeutic Option ◽

Clinical Signs ◽

Cardiac Effect ◽

Left Ventricular ◽

History Taking ◽

Dose Dependent

Immunosuppressive therapy is an established therapeutic option in patients suffering from multiple sclerosis (MS). In an open nonrandomized study we serially assessed cardiac function in 30 consecutive patients with MS before, during, and after mitoxantrone therapy. Mitoxantrone (12 mg/m2) was administered intravenously at 3-month intervals. Before each infusion, cardiac function was assessed by history taking, resting electrocardiogram, and echocardiography. Whereas no patient experienced clinical signs of heart failure, left ventricular pump function decreased continuously during mitoxantrone therapy and did not recover after cessation. The presented data suggest a dose-dependent and long-lasting toxic cardiac effect of low-dose mitoxantrone therapy in MS.

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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 16434: Temporal Metabolomic and Transcriptomic Changes in a Large-Animal Model of Hfpef

Circulation ◽

10.1161/circ.142.suppl_3.16434 ◽

2020 ◽

Vol 142 (Suppl_3) ◽

Author(s):

Andrew A Gibb ◽

Emma K Murray ◽

Deborah M Eaton ◽

Anh T Huynh ◽

Dhanendra Tomar ◽

...

Keyword(s):

Cardiac Function ◽

Disease Progression ◽

Mitochondrial Function ◽

Pulmonary Mechanics ◽

Pathway Enrichment Analysis ◽

Sham Operation ◽

Large Animal ◽

Aortic Banding ◽

Metabolomics Data ◽

Lipid Species

Heart failure with preserved ejection fraction (HFpEF) accounts for ~50% of HF cases, with no effective treatments. We previously reported that a feline aortic banding model recapitulates many of the multi-factorial features of HFpEF, including: LV hypertrophy, left atrial enlargement, elevated LV filling pressures, impaired pulmonary mechanics and fibrosis. Importantly, this model lacks obesity and hypertension enabling the discovery of cardiac centric targets independent of comorbidities. We examined early changes in metabolism and transcription to gain mechanistic insight into HFpEF development. Male short-hair kittens (2mo old) underwent aortic banding or sham operation. Cardiac function was assessed at baseline and 1mo post-banding prior to tissue collection and downstream analyses. Following banding, we observed significant cardiac hypertrophy and initiation of LV fibrosis in the absence of changes in cardiac function. We observed LV mitochondrial dysfunction, indicated by impaired complex-I and -II respiration prompting the examination of cardiac metabolism by unbiased metabolomics. 82 metabolites were significantly different (≥ 1.25 fold, p ≤ 0.1) between 1mo banded and sham hearts, with an overrepresentation of amino acid (aa) and lipid species. Pathway enrichment analysis highlighted an increase in aa metabolism (e.g. serine, proline) that is associated with ECM remodeling and tissue fibrosis. Additionally, an increase in lipid species (i.e. acyl-carnitines) suggests reduced fatty acid utilization and a shift towards glycolysis. Correlations of metabolomics data with mitochondrial function and cardiac phenotyping revealed strong associations between mitochondrial function and the cardiac energy state, as well as aa and LV fibrosis. RNA-seq and enrichment analyses revealed a significant inflammatory response early in disease progression and a decrease in protein/histone acetylation. Collectively, this systems-based approach provides new insights into the cellular biology underlying HFpEF-like disease progression. The metabolic and transcriptional signature that precede the clinical features of HFpEF, will provide new pre-clinical research directions and may yield novel therapeutic targets.

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Mechanical work and energetic analysis of eccentric cardiac remodeling in a volume overload heart failure in rats

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.01120.2008 ◽

2009 ◽

Vol 296 (4) ◽

pp. H1117-H1124 ◽

Cited By ~ 16

Author(s):

Yoshiaki Takewa ◽

Elie R. Chemaly ◽

Miyako Takaki ◽

Li Fan Liang ◽

Hongwei Jin ◽

...

Keyword(s):

Heart Failure ◽

Cardiac Remodeling ◽

Sham Group ◽

Group Versus ◽

Volume Overload ◽

Left Ventricular ◽

Mechanical Work ◽

Energy Utilization ◽

Male Rats ◽

Sham Operation

Eccentric cardiac remodeling seen in dilated cardiomyopathy or regurgitant valvular disease is a well-known process of heart failure progression, but its mechanoenergetic profile has not been yet established. We made a volume overload (VO) heart failure model in rats and for the first time investigated left ventricular (LV) mechanical work and energetics in cross-circulated whole heart preparations. Laparotomy was performed in 14 Wistar male rats, and abdominal aortic-inferior vena caval shunt was created in seven rats (VO group). Another seven rats underwent a sham operation without functional shunt (Sham group). LV dimensions changes were followed with weekly transthoracic echocardiography. Three months after surgery, we measured LV pressure and volume and myocardial O2 consumption in isolated heart cross circulation. LV internal dimensions in both systolic and diastolic phases were significantly increased in the VO group versus the Sham group ( P < 0.05). LV pressure was markedly decreased in the VO group versus in the Sham group ( P < 0.05). LV end-systolic pressure-volume relation shifted downward, and myocardial O2 consumption related to Ca2+ handling significantly decreased. The contractile response to Ca2+ infusion was attenuated. Nevertheless, the increase in Ca2+ handling-related O2 consumption per unit change in LV contractility in the VO group was significantly higher than that in the Sham group ( P < 0.05). The levels of sarco(endo)plasmic reticulum Ca2+-ATPase 2a protein were reduced in the VO group ( P < 0.01). In conclusion, VO failing rat hearts had a character of marked contractile dysfunction accompanied with less efficient energy utilization in the Ca2+ handling processes. These results suggest that restoring Ca2+ handling in excitation-contraction coupling would improve the contractility of the myocardium after eccentric cardiac remodeling.

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Myocardial tumor necrosis factor-α secretion in hypertensive and heart failure-prone rats

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1999.277.2.h543 ◽

1999 ◽

Vol 277 (2) ◽

pp. H543-H550 ◽

Cited By ~ 12

Author(s):

Marina R. Bergman ◽

Ruey H. Kao ◽

Sylvia A. McCune ◽

Bethany J. Holycross

Keyword(s):

Heart Failure ◽

Tumor Necrosis Factor ◽

Cardiac Function ◽

Cardiac Remodeling ◽

Tumor Necrosis ◽

Left Ventricular ◽

Sprague Dawley ◽

Spontaneously Hypertensive ◽

Tnf Α ◽

Necrosis Factor

Acute increases in blood pressure (BP) increase myocardial tumor necrosis factor (TNF)-α production, but it is not known whether chronic hypertensive stress elevates myocardial TNF-α production, possibly contributing to cardiac remodeling, decreased cardiac function, and faster progression to heart failure. BP, cardiac function, and size were evaluated in normotensive [Sprague-Dawley (SD)], spontaneously hypertensive (SHR), and spontaneously hypertensive heart failure-prone (SHHF) rats at 6, 12, 15, and 18 mo of age and in failing SHHF. Left ventricular tissues were evaluated for secretion of bioactive TNF-α and inhibition of TNF-α secretion by phosphodiesterase inhibitors. All ventricles secreted bioactive and immunoreactive TNF-α, but secretion decreased with age. SHR and SHHF rats secreted more TNF-α than SD rats at 6 mo of age, but only failing SHHF rats secreted significantly more TNF-α at 18 mo. Amrinone inhibited TNF-α secretion in all rats and was less potent but more efficacious than RO-201724 in all strains. TNF-α secretion correlated with BP and left ventricular mass in 6-mo-old rats, but this relationship disappeared with age. Results suggest that hypertension and/or cardiac remodeling is associated with elevated myocardial TNF-α, and, although hypertension, per se, did not maintain elevated cardiac TNF-α levels, SHHF rats increase TNF-α production during the end stages of failure.

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