scholarly journals Moderate Loss of the Extracellular Matrix Proteoglycan Lumican Attenuates Cardiac Fibrosis in Mice Subjected to Pressure Overload

Cardiology ◽  
2020 ◽  
Vol 145 (3) ◽  
pp. 187-198 ◽  
Author(s):  
Naiyereh Mohammadzadeh ◽  
Arne Olav Melleby ◽  
Sheryl Palmero ◽  
Ivar Sjaastad ◽  
Shukti Chakravarti ◽  
...  
Keyword(s):  
Heart Failure ◽  
Extracellular Matrix ◽  
Diastolic Dysfunction ◽  
Cardiac Fibrosis ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Cross Linking ◽  
Myocardial Remodeling ◽  
Functional Changes ◽  
Collagen Cross Linking

Introduction: The heart undergoes myocardial remodeling during progression to heart failure following pressure overload. Myocardial remodeling is associated with structural and functional changes in cardiac myocytes, fibroblasts, and the extracellular matrix (ECM) and is accompanied by inflammation. Cardiac fibrosis, the accumulation of ECM molecules including collagens and collagen cross-linking, contributes both to impaired systolic and diastolic function. Insufficient mechanistic insight into what regulates cardiac fibrosis during pathological conditions has hampered therapeutic so­lutions. Lumican (LUM) is an ECM-secreted proteoglycan known to regulate collagen fibrillogenesis. Its expression in the heart is increased in clinical and experimental heart failure. Furthermore, LUM is important for survival and cardiac remodeling following pressure overload. We have recently reported that total lack of LUM increased mortality and left ventricular dilatation, and reduced collagen expression and cross-linking in LUM knockout mice after aortic banding (AB). Here, we examined the effect of LUM on myocardial remodeling and function following pressure overload in a less extreme mouse model, where cardiac LUM level was reduced to 50% (i.e., moderate loss of LUM). Methods and Results: mRNA and protein levels of LUM were reduced to 50% in heterozygous LUM (LUM+/–) hearts compared to wild-type (WT) controls. LUM+/– mice were subjected to AB. There was no difference in survival between LUM+/– and WT mice post-AB. Echocardiography revealed no striking differences in cardiac geometry between LUM+/– and WT mice 2, 4, and 6 weeks post-AB, although markers of diastolic dysfunction indicated better function in LUM+/– mice. LUM+/– hearts revealed reduced cardiac fibrosis assessed by histology. In accordance, the expression of collagen I and III, the main fibrillar collagens in the heart, and other ECM molecules central to fibrosis, i.e. including periostin and fibronectin, was reduced in the hearts of LUM+/– compared to WT 6 weeks post-AB. We found no differences in collagen cross-linking between LUM+/– and WT mice post-AB, as assessed by histology and qPCR. Conclusions: Moderate lack of LUM attenuated cardiac fibrosis and improved diastolic dysfunction following pressure overload in mice, adding to the growing body of evidence suggesting that LUM is a central profibrotic molecule in the heart that could serve as a potential therapeutic target.

scholarly journals A Porcine Model of Heart Failure With Preserved Ejection Fraction Induced by Chronic Pressure Overload Characterized by Cardiac Fibrosis and Remodeling

2021 ◽  
Vol 8 ◽  
Author(s):  
Weijiang Tan ◽  
Xiang Li ◽  
Shuang Zheng ◽  
Xiaohui Li ◽  
Xiaoshen Zhang ◽  
...  
Keyword(s):  
Gene Expression ◽  
Heart Failure ◽  
Ejection Fraction ◽  
Cardiac Fibrosis ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Pathological Examination ◽  
Type I ◽  
Preserved Ejection Fraction

Heart failure is induced by multiple pathological mechanisms, and current therapies are ineffective against heart failure with preserved ejection fraction (HFpEF). As there are limited animal models of HFpEF, its underlying mechanisms have not yet been elucidated. Here, we employed the descending aortic constriction (DAC) technique to induce chronic pressure overload in the left ventricles of Tibetan minipigs for 12 weeks. Cardiac function, pathological and cellular changes, fibrotic signaling activation, and gene expression profiles were explored. The left ventricles developed concentric hypertrophy from weeks 4 to 6 and transition to dilation starting in week 10. Notably, the left ventricular ejection fraction was maintained at >50% in the DAC group during the 12-week period. Pathological examination, biochemical analyses, and gene profile analysis revealed evidence of inflammation, fibrosis, cell death, and myofilament dephosphorylation in the myocardium of HFpEF model animals, together with gene expression shifts promoting cardiac remodeling and downregulating metabolic pathways. Furthermore, we noted the activation of several signaling proteins that impact cardiac fibrosis and remodeling, including transforming growth factor-β/SMAD family members 2/3, type I/III/V collagens, phosphatidylinositol 3-kinase, extracellular signal-regulated kinase, matrix metalloproteinases 2 and 9, tissue inhibitor of metalloproteinases 1 and 2, interleukins 6 and 1β, and inhibitor of κBα/nuclear factor-κB. Our findings demonstrate that this chronic pressure overload-induced porcine HFpEF model is a powerful tool to elucidate the mechanisms of this disease and translate preclinical findings.

A tangled tale of microRNA and cardiac fibrosis

2019 ◽  
Vol 133 (21) ◽  
pp. 2217-2220 ◽  
Author(s):  
Mark Chandy
Keyword(s):  
Heart Failure ◽  
Extracellular Matrix ◽  
Wound Healing ◽  
Cardiac Fibrosis ◽  
Pressure Overload ◽  
Clinical Science ◽  
Therapeutic Options ◽  
Diagnostic Modalities

Abstract Cardiac fibrosis is important for wound healing, regeneration and producing the extracellular matrix (ECM) that provides the scaffold for cells. In pathological situations, fibroblasts are activated and remodel the ECM. In volume 133, issue 17 of Clinical Science, Yang et al. discovered that the miR-214-3p/NLRC5 axis is important for fibroblast-to-myofibroblast transition (FMT) and ECM remodelling in a pressure overload model of fibrosis [Clin. Sci. (2019) 133(17), 1845–1856]. This discovery helps to explain the complicated regulation of cardiac fibrosis. It also underscores the need for more investigation into the mechanisms of cardiac fibrosis to develop better diagnostic modalities and therapeutic options in heart failure.

Abstract P300: Cardiac Ly6C high Monocyte Accumulation and Remodeling Depend on the Mineralocorticoid Receptor in Endothelial Cells

Hypertension ◽  
2016 ◽  
Vol 68 (suppl_1) ◽  
Author(s):  
Achim Lother ◽  
Aurelia Hübner ◽  
Ingo Hilgendorf ◽  
Tilman Schnick ◽  
Martin Moser ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Diastolic Dysfunction ◽  
Mineralocorticoid Receptor ◽  
Cardiac Fibrosis ◽  
Ventricular Remodeling ◽  
Interstitial Fibrosis ◽  
Left Ventricular Remodeling ◽  
Marker Gene ◽  
Pressure Overload ◽  
Left Ventricular

Introduction: Inflammation is a key driver for the development of cardiac fibrosis and diastolic dysfunction. Aldosterone promotes the expression of adhesion molecules and vascular inflammation. Thus, the goal of the present study was to examine the significance of endothelial MR for pressure overload induced cardiac inflammation and remodeling. Methods and results: Mice with endothelial cell-specific deletion of the mineralocorticoid receptor (MR Cdh5Cre ) were generated using the Cre/loxP system. MR Cdh5Cre and Cre-negative littermates (MR wildtype ) underwent transverse aortic constriction (TAC, n=5-7 per group). After two weeks of pressure overload echocardiography revealed diastolic dysfunction in MR wildtype (mitral valve E acceleration time TAC 15.7 ± 0.5 vs. sham 12.8 ± 0.4 ms, P<0.05) but not in MR Cdh5Cre mice (TAC 11.2 ± 0.6 vs. sham 12.2 ± 0.9 ms, n.s.). Cardiac hypertrophy (ventricle weight 143.2 ± 5.2 vs. MR wildtype 167.3 ± 6.7 mg, P<0.001) and interstitial fibrosis (sirius red stained area 8.2 ± 4.7 vs. MR wildtype 13.5 ± 4.5 %, P<0.05) following TAC were attenuated in MR Cdh5Cre mice. mRNA expression of atrial natriuretic peptide ( Nppa , 2429 ± 1230 vs. MR wildtype 7051 ± 3182 copies/10 4 copies Rps29 , P<0.01) or the fibrosis marker gene collagen 1a1 ( Col1a1 , 256 ± 89 vs. MR wildtype 432 ± 165 copies/10 4 copies Rps29 , P<0.05) as determined by qRT-PCR confirmed these findings. Cardiac leukocytes were quantitatively analyzed by fluorescence assisted cell sorting using specific antibodies. Numbers of CD45 + leukocytes were similarly increased after TAC in the hearts of both genotypes (MR Cdh5Cre 3840 ± 443 vs. MR wildtype 4051 ± 385 /mg tissue, n.s.). Subtype analysis revealed a shift towards CD45 + CD11b + F4/80 low Ly6C high monocytes vs. CD45 + CD11b + F4/80 high Ly6C low macrophages in the heart of MR wildtype (TAC 20 ± 6 vs. sham 4 ± 1 % of CD45 + CD11b + , P<0.05) but not of MR Cdh5Cre mice (TAC 6 ± 2 vs. sham 3 ± 1 % of CD45 + CD11b + , n.s.). Conclusion: MR deletion from endothelial cells ameliorates left ventricular remodeling and diastolic dysfunction after pressure overload. The protective effect of endothelial MR deletion is associated with a shift towards less pro-inflammatory Ly6C high monocytes and more reparative Ly6C low macrophages.

Differential regulation of extracellular matrix constituents in myocardial remodeling with and without heart failure following pressure overload

2013 ◽  
Vol 32 (2) ◽  
pp. 133-142 ◽  
Author(s):  
Biljana Skrbic ◽  
Johannes L. Bjørnstad ◽  
Henriette S. Marstein ◽  
Cathrine R. Carlson ◽  
Ivar Sjaastad ◽  
...  
Keyword(s):  
Heart Failure ◽  
Extracellular Matrix ◽  
Pressure Overload ◽  
Differential Regulation ◽  
Myocardial Remodeling

scholarly journals Phosphodiesterase 2 inhibition preferentially promotes NO/guanylyl cyclase/cGMP signaling to reverse the development of heart failure

2018 ◽  
Vol 115 (31) ◽  
pp. E7428-E7437 ◽  
Author(s):  
Reshma S. Baliga ◽  
Michael E. J. Preedy ◽  
Matthew S. Dukinfield ◽  
Sandy M. Chu ◽  
Aisah A. Aubdool ◽  
...  
Keyword(s):  
Heart Failure ◽  
Guanylyl Cyclase ◽  
Cardiac Fibrosis ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Treatment Modalities ◽  
Pharmacodynamic Profile ◽  
Cgmp Signaling ◽  
Synthase Inhibitor ◽  
And Function

Heart failure (HF) is a shared manifestation of several cardiovascular pathologies, including hypertension and myocardial infarction, and a limited repertoire of treatment modalities entails that the associated morbidity and mortality remain high. Impaired nitric oxide (NO)/guanylyl cyclase (GC)/cyclic guanosine-3′,5′-monophosphate (cGMP) signaling, underpinned, in part, by up-regulation of cyclic nucleotide-hydrolyzing phosphodiesterase (PDE) isozymes, contributes to the pathogenesis of HF, and interventions targeted to enhancing cGMP have proven effective in preclinical models and patients. Numerous PDE isozymes coordinate the regulation of cardiac cGMP in the context of HF; PDE2 expression and activity are up-regulated in experimental and human HF, but a well-defined role for this isoform in pathogenesis has yet to be established, certainly in terms of cGMP signaling. Herein, using a selective pharmacological inhibitor of PDE2, BAY 60-7550, and transgenic mice lacking either NO-sensitive GC-1α (GC-1α−/−) or natriuretic peptide-responsive GC-A (GC-A−/−), we demonstrate that the blockade of PDE2 promotes cGMP signaling to offset the pathogenesis of experimental HF (induced by pressure overload or sympathetic hyperactivation), reversing the development of left ventricular hypertrophy, compromised contractility, and cardiac fibrosis. Moreover, we show that this beneficial pharmacodynamic profile is maintained in GC-A−/− mice but is absent in animals null for GC-1α or treated with a NO synthase inhibitor, revealing that PDE2 inhibition preferentially enhances NO/GC/cGMP signaling in the setting of HF to exert wide-ranging protection to preserve cardiac structure and function. These data substantiate the targeting of PDE2 in HF as a tangible approach to maximize myocardial cGMP signaling and enhancing therapy.

scholarly journals Sotagliflozin, a Dual SGLT1/2 Inhibitor, Improves Cardiac Outcomes in a Normoglycemic Mouse Model of Cardiac Pressure Overload

2021 ◽  
Vol 12 ◽  
Author(s):  
Sophia L. Young ◽  
Lydia Ryan ◽  
Thomas P. Mullins ◽  
Melanie Flint ◽  
Sarah E. Steane ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Fibrosis ◽  
Cardiac Injury ◽  
Pressure Overload ◽  
Tween 80 ◽  
Left Ventricular ◽  
Normal Diet ◽  
Whole Body ◽  
High Fat ◽  
Cardiac Outcomes

Selective SGLT2 inhibition reduces the risk of worsening heart failure and cardiovascular death in patients with existing heart failure, irrespective of diabetic status. We aimed to investigate the effects of dual SGLT1/2 inhibition, using sotagliflozin, on cardiac outcomes in normal diet (ND) and high fat diet (HFD) mice with cardiac pressure overload. Five-week-old male C57BL/6J mice were randomized to receive a HFD (60% of calories from fat) or remain on ND for 12 weeks. One week later, transverse aortic constriction (TAC) was employed to induce cardiac pressure-overload (50% increase in right:left carotid pressure versus sham surgery), resulting in left ventricular hypertrophic remodeling and cardiac fibrosis, albeit preserved ejection fraction. At 4 weeks post-TAC, mice were treated for 7 weeks by oral gavage once daily with sotagliflozin (10 mg/kg body weight) or vehicle (0.1% tween 80). In ND mice, treatment with sotagliflozin attenuated cardiac hypertrophy and histological markers of cardiac fibrosis induced by TAC. These benefits were associated with profound diuresis and glucosuria, without shifts toward whole-body fatty acid utilization, increased circulating ketones, nor increased cardiac ketolysis. In HFD mice, sotagliflozin reduced the mildly elevated glucose and insulin levels but did not attenuate cardiac injury induced by TAC. HFD mice had vacuolation of proximal tubular cells, associated with less profound sotagliflozin-induced diuresis and glucosuria, which suggests dampened drug action. We demonstrate the utility of dual SGLT1/2 inhibition in treating cardiac injury induced by pressure overload in normoglycemic mice. Its efficacy in high fat-fed mice with mild hyperglycemia and compromised renal morphology requires further study.

scholarly journals Regulation and impact of cardiac lymphangiogenesis in pressure-overload-induced heart failure

2021 ◽  
Author(s):  
C Heron ◽  
A Dumesnil ◽  
M Houssari ◽  
S Renet ◽  
A Lebon ◽  
...  
Keyword(s):  
Heart Failure ◽  
Dilated Cardiomyopathy ◽  
Cardiac Fibrosis ◽  
Immune Cell ◽  
Pressure Overload ◽  
Wall Stress ◽  
Myocardial Edema ◽  
Selective Inhibition ◽  
Left Ventricular ◽  
Ventricular Dilation

AbstractRationaleLymphatics are essential for cardiac health, and insufficient lymphatic expansion (lymphangiogenesis) contributes to development of heart failure (HF) after myocardial infarction. However, the regulation and impact of lymphatics in non-ischemic cardiomyopathy induced by pressure-overload remains to be determined.ObjectiveInvestigate cardiac lymphangiogenesis following transverse aortic constriction (TAC) in adult male or female C57Bl/6J or Balb/c mice, and in patients with end-stage HF.Methods & ResultCardiac function was evaluated by echocardiography, and cardiac hypertrophy, lymphatics, inflammation, edema, and fibrosis by immunohistochemistry, flow cytometry, microgravimetry, and gene expression analysis, respectively. Treatment with neutralizing anti-VEGFR3 antibodies was applied to inhibit cardiac lymphangiogenesis in mice.The gender- and strain-dependent mouse cardiac hypertrophic response to TAC, especially increased ventricular wall stress, led to lymphatic expansion in the heart. Our experimental findings that ventricular dilation triggered cardiac lymphangiogenesis was mirrored by observations in clinical HF samples, with increased lymphatic density found in patients with dilated cardiomyopathy. Surprisingly, the striking lymphangiogenesis observed post-TAC in Balb/c mice, linked to increased cardiac Vegfc, did not suffice to resolve myocardial edema, and animals progressed to dilated cardiomyopathy and HF. Conversely, selective inhibition of the essentially Vegfd-driven capillary lymphangiogenesis observed post-TAC in male C57Bl/6J mice did not significantly aggravate cardiac edema. However, cardiac immune cell levels were increased, notably myeloid cells at 3 weeks and T lymphocytes at 8 weeks. Moreover, while the TAC-triggered development of interstitial cardiac fibrosis was unaffected by anti-VEGFR3, inhibition of lymphangiogenesis increased perivascular fibrosis and accelerated the development of left ventricular dilation and cardiac dysfunction.ConclusionsWe demonstrate for the first time that endogenous cardiac lymphangiogenesis limits pressure-overload-induced cardiac inflammation and perivascular fibrosis, thus delaying HF development. While these findings remain to be confirmed in a larger study of HF patients, we propose that under settings of pressure-overload poor cardiac lymphangiogenesis may accelerate HF development.

scholarly journals IL-18 induction of osteopontin mediates cardiac fibrosis and diastolic dysfunction in mice

2009 ◽  
Vol 297 (1) ◽  
pp. H76-H85 ◽  
Author(s):  
Qianli Yu ◽  
Randy Vazquez ◽  
Elham Vali Khojeini ◽  
Chirag Patel ◽  
Raj Venkataramani ◽  
...  
Keyword(s):  
Diastolic Dysfunction ◽  
Cardiac Fibrosis ◽  
Interstitial Fibrosis ◽  
Cardiac Fibroblasts ◽  
Pressure Overload ◽  
Volume Overload ◽  
Left Ventricular Pressure ◽  
Neutralizing Antibody ◽  
Left Ventricular ◽  
Fibrotic Process

Osteopontin (OPN), a key component of the extracellular matrix, is associated with the fibrotic process during tissue remodeling. OPN and the cytokine interleukin (IL)-18 have been shown to be overexpressed in an array of human cardiac pathologies. In the present study, we determined the role of IL-18 in the regulation of cardiac OPN expression and the subsequent interstitial fibrosis and diastolic dysfunction. We demonstrated parallel increases in IL-18, OPN expression, and interstitial fibrosis in murine models of left ventricular pressure and volume overload. Exogenous recombinant (r)IL-18 administered for 2 wk increased cardiac OPN expression, interstitial fibrosis, and diastolic dysfunction. Stimulation of the T helper (Th)1 lymphocyte phenotype with a selective toll-like receptor (TLR)9 agonist induced cardiac IL-18 and OPN expression, which was associated with increased cardiac fibrillar collagen concentrations and interstitial fibrosis resulting in diastolic dysfunction. rIL-18 induced OPN expression and protein levels in primary of cardiac fibroblast cultures. Conditioned media from TLR9-stimulated T lymphocyte cultures induced IL-18 and OPN expression in cardiac fibroblasts, while blockade of the IL-18 receptor with a neutralizing antibody abolished the increase in OPN expression. Furthermore, a mutation in the transcriptional factor interferon regulatory factor (IRF)1 or IRF1 small interfering RNA (siRNA) resulted in the decreased expression of IL-18 and OPN in cardiac fibroblasts. With pressure overload, IRF1-mutant mice showed downregulation of IL-18 and OPN expression in cardiac tissue, reduced cardiac fibrotic development, and increased left ventricular function compared with wild type. These results provide direct evidence that the induction of IL-18 regulates OPN-mediated cardiac fibrosis and diastolic dysfunction.

PLK2 is a novel regulator of osteopontin-driven fibrosis and diastolic dysfunction in permanent atrial fibrillation

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
S Kuenzel ◽  
E Klapproth ◽  
K Kuenzel ◽  
C Piorkowski ◽  
M Mayr ◽  
...  
Keyword(s):  
Heart Failure ◽  
Atrial Fibrillation ◽  
Diastolic Dysfunction ◽  
Cardiac Fibrosis ◽  
Cardiac Fibroblasts ◽  
Diastolic Heart Failure ◽  
Left Ventricular Diastolic Dysfunction ◽  
Left Ventricular ◽  
Knockout Mouse Model ◽  
Ventricular Diastolic Dysfunction

Abstract Background and aim Atrial fibrillation (AF) is frequently accompanied by cardiac fibrosis and diastolic heart failure. Due to the heterogeneous nature and complexity of fibrosis, the knowledge of the underlying pathomechanisms is limited. Thus, effective antifibrotic pharmacotherapy is missing. The objective of this study was to decipher the role of polo-like kinase 2 (PLK2) in the pathogenesis of cardiac fibrosis and left ventricular diastolic dysfunction. We put particular emphasis on the identification of profibrotic downstream targets of PLK2, which can serve as therapeutic targets. Methods and results This study was based on human atrial tissue biopsies and peripheral blood samples, a PLK2 knockout mouse model, a canine tachy-pacing model and specific pharmacological interventions on cardiac fibroblasts. In human atrial AF tissue samples, PLK2 was 50% downregulated by hypoxia-induced promoter methylation compared to sinus rhythm (SR) control. Confirmatory analysis of a canine tachy-pacing model showed PLK2 downregulation exclusively in the atria but not in the ventricles. Specific pharmacological inhibition as well as genetic deletion of PLK2 led to a striking myofibroblast phenotype. Discovery proteomics revealed that the global knockout of PLK2 resulted in de novo secretion of the inflammatory cytokine osteopontin (OPN) in cardiac fibroblasts and concomitant ventricular fibrosis in the PLK2 knockout mouse model. An ELISA analysis of peripheral blood samples of AF patients with electrophysiologically proven fibrosis, confirmed significantly increased OPN plasma concentrations compared to SR and non-fibrosis AF controls. Consequently, echocardiography on PLK2 KO mice revealed left ventricular diastolic dysfunction, tachycardia and fibrosis-typical surface ECG anomalies (PQ and QRS prolongation). Mechanistically, we identified the ERK1/2 signaling pathway as the molecular link between reduced expression of PLK2 and elevated osteopontin transcription. In a reverse translational attempt, we successfully tested the capability of 5-amino-salicylic acid (5-ASA) to inhibit osteopontin transcription and to reverse a TGF-β-induced myofibroblast phenotype in vitro. Currently the long-term administration of 5-ASA is tested in PLK2 knockout mice to evaluate the therapeutic potential to prevent cardiac fibrosis and diastolic heart failure development. Conclusion and clinical impact We identified PLK2 as an epigenetically regulated kinase involved in the pathophysiology of fibrosis in AF. PLK2 knockout mice can serve as a model of diastolic heart failure wherein OPN is a promising therapeutic target. Our results strengthen the current hypothesis that atrial fibrillation is not only an ion channel disease but a complex systemic disorder. Restoration of physiological PLK2 expression and blockade of osteopontin release with 5-ASA may constitute valuable new drug targets for the prevention and treatment of fibrosis and diastolic heart failure in AF. Funding Acknowledgement Type of funding source: Public Institution(s). Main funding source(s): Faculty of Medicine, Carl Gustav Carus, Dresden, “MeDDrive Start” Grant

Female sex and estrogen receptor-β attenuate cardiac remodeling and apoptosis in pressure overload

2010 ◽  
Vol 298 (6) ◽  
pp. R1597-R1606 ◽  
Author(s):  
Daniela Fliegner ◽  
Carola Schubert ◽  
Adam Penkalla ◽  
Henning Witt ◽  
George Kararigas ◽  
...  
Keyword(s):  
Heart Failure ◽  
Estrogen Receptor ◽  
Cardiac Fibrosis ◽  
Pressure Overload ◽  
Transcriptional Response ◽  
Left Ventricular ◽  
Estrogen Receptor Β ◽  
Female Sex ◽  
Microarray Profiling ◽  
Eccentric Hypertrophy

We investigated sex differences and the role of estrogen receptor-β (ERβ) on myocardial hypertrophy in a mouse model of pressure overload. We performed transverse aortic constriction (TAC) or sham surgery in male and female wild-type (WT) and ERβ knockout (ERβ−/−) mice. All mice were characterized by echocardiography and hemodynamic measurements and were killed 9 wk after surgery. Left ventricular (LV) samples were analyzed by microarray profiling, real-time RT-PCR, and histology. After 9 wk, WT males showed more hypertrophy and heart failure signs than WT females. Notably, WT females developed a concentric form of hypertrophy, while males developed eccentric hypertrophy. ERβ deletion augmented the TAC-induced increase in cardiomyocyte diameter in both sexes. Gene expression profiling revealed that WT male hearts had a stronger induction of matrix-related genes and a stronger repression of mitochondrial genes than WT female hearts. ERβ−/− mice exhibited a different transcriptional response. ERβ−/−/TAC mice of both sexes exhibited induction of proapoptotic genes with a stronger expression in ERβ−/− males. Cardiac fibrosis was more pronounced in male WT/TAC than in female mice. This difference was abolished in ERβ−/− mice. The number of apoptotic nuclei was increased in both sexes of ERβ−/−/TAC mice, most prominent in males. Female sex offers protection against ventricular chamber dilation in the TAC model. Both female sex and ERβ attenuate the development of fibrosis and apoptosis, thus slowing the progression to heart failure.

Sign in / Sign up

Export Citation Format

Share Document