Transgenic Expression of Matrix Metalloproteinase-1 Inhibits Myocardial Fibrosis and Prevents the Transition to Heart Failure in a Pressure Overload Mouse Model

Aims: With aging and stresses, the myocardium undergoes structural remodeling and often leading to fibrosis. Main Methods: To examine whether lumican, one of the class II small leucine-rich proteoglycans, has a role in cardiac remodeling and fibrosis, we analyzed the basic cardiac phenotypes of lumican-null (Lum-/-) mice in both youth and elder, and then used the isoproterenol-induced cardiac fibrosis model to study the roles of extra-cellular matrix and apoptosis in cardiac remodeling. Key Findings: Higher mortality resulted from significantly impaired systolic function, and an increase of atrial natriuretic peptide secreted by the ventricles in response to excessive stretching of myocytes of Lum-/- mice in comparison to wild type littermates. In addition, Lum-/- mice exhibited higher level of TGF-β, collagen I/III, and membrane-type matrix metalloproteinase-1 (MT1-MMP, or MMP-14) during cardiac remodeling. Significance: Our data implicates that the lumican protein plays an important role in the pathogenesis of cardiac fibrosis.

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3057Relation of atrial remodeling to circulating biomarkers of myocardial fibrosis and apoptotic microparticles in patients with atrial fibrillation and heart failure with preserved ejection fraction

European Heart Journal ◽

10.1093/eurheartj/ehz745.0024 ◽

2019 ◽

Vol 40 (Supplement_1) ◽

Author(s):

M S Dzeshka ◽

E Shantsila ◽

V A Snezhitskiy ◽

G Y H Lip

Keyword(s):

Heart Failure ◽

Atrial Fibrillation ◽

Ejection Fraction ◽

Matrix Metalloproteinase ◽

Myocardial Fibrosis ◽

Univariate Analysis ◽

Volume Index ◽

Atrial Remodeling ◽

Preserved Ejection Fraction ◽

Circulating Biomarkers

Abstract Introduction Left atrial (LA) remodeling is a mainstay for atrial fibrillation (AF) occurrence. AF further promotes structural changes in LA, as fibrosis and stretching, followed by AF progression to its permanent form. Many profibrotic pathways have been studied, and circulating microparticles (MPs) may have a role. MPs are extracellular submicron anucleoid phospholipid vesicles released from different cells. Annexin V-binding (AnV+) MPs were suggested as a marker of apoptosis. Purpose To evaluate association of circulating biomarkers of myocardial fibrosis and MPs subsets with LA remodeling in patients with AF and heart failure with preserved ejection fraction. Methods We studied 274 patients (median age 62 years, 37% females). Paroxysmal AF was diagnosed in 150 patients (55%) and non-paroxysmal AF (persistent or permanent) in 124 (45%). Median CHA2DS2-VASc score was 3 in males and 4 in females. Patients with valvular AF, recent (<6 months) thromboembolic or hemorrhagic event, advanced chronic kidney or hepatic dysfunction, malignancy or active inflammatory disorders were excluded. Transthoracic echocardiography was performed. LA maximum volume index (LAVi) was measured as an index of LA structural remodeling in AF. Average values from ten consecutive cardiac cycles were calculated. Blood levels of galectin 3, interleukin-1 receptor-like 1 (ST2), transforming growth factor beta 1 (TGF-β1), procollagen type III aminoterminal propeptide (PIIINP), matrix metalloproteinase 9 (MMP-9), tissue inhibitor of matrix metalloproteinase 1 (TIMP-1), angiotensin II and aldosterone were assayed as surrogate biomarkers of myocardial fibrosis with ELISA. Using microflow cytometry (Figure), numbers of platelet-derived (CD42b+), monocyte-derived (CD14+), endothelial (CD144+), and apoptotic MPs (AnV+) were quantified in plasma samples. Linear regression was used to reveal parameters associated with LAVi. Raw data were normalized with Box-Cox transformation. Results Median LAVi in studied patients was 48 (39–59) ml/m2 and increased from patients with paroxysmal AF (42 [35–51] ml/m2) to persistent AF (53 [43–62] ml/m2) and permanent AF (57 [46–69] ml/m2), p<0.001. On univariate analysis male gender (β=0.11, p=0.04); history of hypertension (β=0.18, p=0.03); AF type, i.e. progression from paroxysmal to permanent (β=0.38, p<0.001); AnV+ MPs (β=0.19, p=0.005); ST2 (β=0.15, p=0.02); and early mitral inflow velocity (E)/early mitral annular diastolic velocity (E/E') averaged for LV septal and lateral basal regions (β=0.18, p=0.005) were associated with LAVi. Using stepwise multivariate regression AnV+ MPs (β=0.14, p=0.03); AF type (β=0.35, p<0.001); and E/E' ratio (β=0.11, p=0.04) remained significant predictors of LAVi (adjusted for age and gender). Apoptotic MPs detection with microFCM Conclusion Level of circulating apoptotic MPs is associated with LAVi in AF patients with HFpEF, and may be involved in remodeling process or could represent surrogate markers of myocardial damage in AF. Acknowledgement/Funding ESC Research Grant, EHRA Academic Research Fellowship Programme

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Cytosolic H2O2 mediates hypertrophy, apoptosis, and decreased SERCA activity in mice with chronic hemodynamic overload

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00084.2014 ◽

2014 ◽

Vol 306 (10) ◽

pp. H1453-H1463 ◽

Cited By ~ 32

Author(s):

Fuzhong Qin ◽

Deborah A. Siwik ◽

David R. Pimentel ◽

Robert J. Morgan ◽

Andreia Biolo ◽

...

Keyword(s):

Oxidative Stress ◽

Heart Failure ◽

Cardiac Myocyte ◽

Pressure Overload ◽

Left Ventricular ◽

Transgenic Expression ◽

Myocardial Oxidative Stress ◽

Plasmic Reticulum ◽

Oxidative Modifications ◽

Hemodynamic Overload

Oxidative stress in the myocardium plays an important role in the pathophysiology of hemodynamic overload. The mechanism by which reactive oxygen species (ROS) in the cardiac myocyte mediate myocardial failure in hemodynamic overload is not known. Accordingly, our goals were to test whether myocyte-specific overexpression of peroxisomal catalase (pCAT) that localizes in the sarcoplasm protects mice from hemodynamic overload-induced failure and prevents oxidation and inhibition of sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA), an important sarcoplasmic protein. Chronic hemodynamic overload was caused by ascending aortic constriction (AAC) for 12 wk in mice with myocyte-specific transgenic expression of pCAT. AAC caused left ventricular hypertrophy and failure associated with a generalized increase in myocardial oxidative stress and specific oxidative modifications of SERCA at cysteine 674 and tyrosine 294/5. pCAT overexpression ameliorated myocardial hypertrophy and apoptosis, decreased pathological remodeling, and prevented the progression to heart failure. Likewise, pCAT prevented oxidative modifications of SERCA and increased SERCA activity without changing SERCA expression. Thus cardiac myocyte-restricted expression of pCAT effectively ameliorated the structural and functional consequences of chronic hemodynamic overload and increased SERCA activity via a post-translational mechanism, most likely by decreasing inhibitory oxidative modifications. In pressure overload-induced heart failure cardiac myocyte cytosolic ROS play a pivotal role in mediating key pathophysiologic events including hypertrophy, apoptosis, and decreased SERCA activity.

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Retraction: Transgenic expression of human matrix metalloproteinase-1 attenuates pulmonary arterial hypertension in mice

Clinical Science ◽

10.1042/cs20160295ret ◽

2016 ◽

Vol 131 (1) ◽

pp. 25-25 ◽

Cited By ~ 1

Author(s):

Joseph George ◽

Jie Sun ◽

Jeanine D'Armiento

Keyword(s):

Pulmonary Arterial Hypertension ◽

Matrix Metalloproteinase ◽

Arterial Hypertension ◽

Transgenic Expression ◽

Matrix Metalloproteinase 1 ◽

Pulmonary Arterial

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P3789Circulating biomarkers of myocardial fibrosis and cellular apoptosis in patients with atrial fibrillation and heart failure with preserved ejection fraction

European Heart Journal ◽

10.1093/eurheartj/ehz745.0635 ◽

2019 ◽

Vol 40 (Supplement_1) ◽

Author(s):

M S Dzeshka ◽

E Shantsila ◽

V A Snezhitskiy ◽

G Y H Lip

Keyword(s):

Heart Failure ◽

Atrial Fibrillation ◽

Angiotensin Ii ◽

Ejection Fraction ◽

Matrix Metalloproteinase ◽

Diastolic Dysfunction ◽

Diastolic Function ◽

Myocardial Fibrosis ◽

Volume Index ◽

Preserved Ejection Fraction

Abstract Introduction Atrial fibrillation (AF) and heart failure with preserved ejection fraction (HFpEF) commonly coexist. AF is associated with left atrial (LA) and ventricular (LV) myocardial fibrosis, contributing to diastolic dysfunction in HFpEF. Many profibrotic pathways have been studied in AF and HFpEF, but scarce data are available on the role of circulating microparticles (MPs). Purpose To evaluate association of circulating biomarkers of fibrosis and MPs subsets with Doppler-derived parameters of diastolic function in AF and HFpEF. Methods We studied 274 patients with non-valvular AF and HFpEF (median age 62 years, 37% females). Paroxysmal AF was diagnosed in 150 patients (55%) and non-paroxysmal AF (persistent or permanent) in 124 (45%). Median CHA2DS2-VASc score was 3 in males and 4 in females. Transthoracic echocardiography was performed to assess LV diastolic function, including early mitral inflow velocity (E), E/A velocities ratio (on sinus rhythm), early mitral annular diastolic velocity (E') for LV septal and lateral basal regions, E/E' ratio, LA maximum volume index (LAVi), E-wave velocity deceleration time (DT), flow propagation velocity (Vp). Average values from ten consecutive cardiac cycles were calculated. E/E' ratio was chosen as valid and reproducible index of diastolic function in AF patients for regression analysis. Blood levels of galectin 3, interleukin-1 receptor-like 1 (ST2), transforming growth factor beta 1 (TGF-β1), procollagen type III aminoterminal propeptide (PIIINP), matrix metalloproteinase 9 (MMP-9), tissue inhibitor of matrix metalloproteinase 1 (TIMP-1), angiotensin II and aldosterone level were assayed as surrogate biomarkers of myocardial fibrosis and profibrotic signaling. Using microflow cytometry, numbers of platelet-derived (CD42b+), monocyte-derived (CD14+), endothelial (CD144+), and apoptotic MPs (Annexin V+) were quantified in plasma samples. Linear regression was used to reveal parameters associated with diastolic function assessed as E/E' ratio. Data were normalized with Box-Cox transformation. Results Grade I diastolic dysfunction was found in 149 (54%); 94 (34%), and 31 (11%) patients had grade II and grade III diastolic dysfunction, respectively. On univariate analysis, age (β=0.23, p=0.0001); male gender (β=-0.19, p=0.02); history of hypertension (β=0.15, p=0.02); AF type, i.e. progression from paroxysmal to permanent (β=0.14, p=0.02); AnV+ MPs (β=0.19, p=0.01); angiotensin II (β=0.13, p=0.04); ST2 (β=0.1, p=0.04); and TIMP-1 (β=0.13, p=0.03) were associated with E/E' ratio. Using stepwise multivariate regression, AnV+ MPs (β=0.15, p=0.01) and TIMP-1 (β=0.3, p=0.04) remained significant predictors of E/E' ratio, adjusted for age, gender, hypertension and AF type. Relation of E/E' to TIMP-1 and AnV+ MPs Conclusion Apoptotic (AnV+) MPs and TIMP-1 were independently associated with diastolic dysfunction in AF and HFpEF. These may contribute to the pathophysiology of AF and HFpEF, and complications related to the presence of both. Acknowledgement/Funding ESC Research Grant, EHRA Academic Research Fellowship Programme

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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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