scholarly journals Phenotypic characterization of primary cardiac fibroblasts from patients with HFpEF

PLoS ONE ◽  
2022 ◽  
Vol 17 (1) ◽  
pp. e0262479
Author(s):  
Yuhua Zhang ◽  
An O. Van Laer ◽  
Catalin F. Baicu ◽  
Lily S. Neff ◽  
Stanley Hoffman ◽  
...  

Heart failure is a leading cause of hospitalizations and mortality worldwide. Heart failure with a preserved ejection fraction (HFpEF) represents a significant clinical challenge due to the lack of available treatment modalities for patients diagnosed with HFpEF. One symptom of HFpEF is impaired diastolic function that is associated with increases in left ventricular stiffness. Increases in myocardial fibrillar collagen content is one factor contributing to increases in myocardial stiffness. Cardiac fibroblasts are the primary cell type that produce fibrillar collagen in the heart. However, relatively little is known regarding phenotypic changes in cardiac fibroblasts in HFpEF myocardium. In the current study, cardiac fibroblasts were established from left ventricular epicardial biopsies obtained from patients undergoing cardiovascular interventions and divided into three categories: Referent control, hypertension without a heart failure designation (HTN (-) HFpEF), and hypertension with heart failure (HTN (+) HFpEF). Biopsies were evaluated for cardiac myocyte cross-sectional area (CSA) and collagen volume fraction. Primary fibroblast cultures were assessed for differences in proliferation and protein expression of collagen I, Membrane Type 1-Matrix Metalloproteinase (MT1-MMP), and α smooth muscle actin (αSMA). Biopsies from HTN (-) HFpEF and HTN (+) HFpEF exhibited increases in myocyte CSA over referent control although only HTN (+) HFpEF exhibited significant increases in fibrillar collagen content. No significant changes in proliferation or αSMA was detected in HTN (-) HFpEF or HTN (+) HFpEF cultures versus referent control. Significant increases in production of collagen I was detected in HF (-) HFpEF fibroblasts, whereas significant decreases in MT1-MMP levels were measured in HTN (+) HFpEF cells. We conclude that epicardial biopsies provide a viable source for primary fibroblast cultures and that phenotypic differences are demonstrated by HTN (-) HFpEF and HTN (+) HFpEF cells versus referent control.

2012 ◽  
Vol 303 (2) ◽  
pp. H234-H240 ◽  
Author(s):  
Catalin F. Baicu ◽  
Yuhua Zhang ◽  
An O. Van Laer ◽  
Ludivine Renaud ◽  
Michael R. Zile ◽  
...  

Cardiac interstitial fibrillar collagen accumulation, such as that associated with chronic pressure overload (PO), has been shown to impair left ventricular diastolic function. Therefore, insight into cellular mechanisms that mediate excessive collagen deposition in the myocardium is pivotal to this important area of research. Collagen is secreted as a soluble procollagen molecule with NH2- and COOH (C)-terminal propeptides. Cleavage of these propeptides is required for collagen incorporation to insoluble collagen fibrils. The C-procollagen proteinase, bone morphogenic protein 1, cleaves the C-propeptide of procollagen. Procollagen C-endopeptidase enhancer (PCOLCE) 2, an enhancer of bone morphogenic protein-1 activity in vitro, is expressed at high levels in the myocardium. However, whether the absence of PCOLCE2 affects collagen content at baseline or after PO induced by transverse aortic constriction (TAC) has never been examined. Accordingly, in vivo procollagen processing and deposition were examined in wild-type (WT) and PCOLCE2-null mice. No significant differences in collagen content or myocardial stiffness were detected in non-TAC (control) PCOLCE2-null versus WT mice. After TAC-induced PO, PCOLCE2-null hearts demonstrated a lesser collagen content (PCOLCE2-null TAC collagen volume fraction, 0.41% ± 0.07 vs. WT TAC, 1.2% ± 0.3) and lower muscle stiffness compared with WT PO hearts [PCOLCE2-null myocardial stiffness (β), 0.041 ± 0.002 vs. WT myocardial stiffness, 0.065 ± 0.001]. In addition, in vitro, PCOLCE2-null cardiac fibroblasts exhibited reductions in efficiency of C-propeptide cleavage, as demonstrated by increases in procollagen α1(I) and decreased levels of processed collagen α1(I) versus WT cardiac fibroblasts. Hence, PCOLCE2 is required for efficient procollagen processing and deposition of fibrillar collagen in the PO myocardium. These results support a critical role for procollagen processing in the regulation of collagen deposition in the heart.


Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Yuksel Cavusoglu ◽  
Omer Kozan ◽  
Ahmet Temizhan ◽  
Serdar Kucukoglu

Purpose: Resting heart rate (HR), health related quality of life (HQoL) and NYHA functional capacity are referred as important determinants of prognosis and targets of therapy in heart failure (HF). REALITY HF (Resting Heart Rate and Real Life Treatment Modality in Outpatients with Left Ventricular Systolic Dysfunction) study data were analyzed for the evaluation of any relationship of resting HR with HQoL assessed by Kansas City Cardiomyopathy Questionnaire (KCCQ) and NYHA functional class. Methods: REALITY HF was a multicenter, prospective registry designed to evaluate HF patients’ characteristics and effects of treatment modalities on resting HR and enrolled 1057 patients (age 61±12 years) with LVEF <40%. 781 (74%) patients in sinus rhythm were included in this analysis. Patients were classified into 4 groups according to the quartiles of HR: Q1:<68 bpm (n=234), Q2:69-75 bpm (n=189), Q3:76-87 bpm (n=194) and Q4:>87 bpm (n=164). KCCQ was completed in a random sample of 320 (Q1:n=27, Q2:n=99, Q3:n=125, Q4:n=69) patients, in which higher scores show better patient’s health status. Results: During enrollment, 82% of patients were receiving ≥2 drugs including ACE[[Unable to Display Character: &#304;]]/ARB, beta blocker, aldosterone blocker, diuretic or digoxin. Resting HR was 76±14 bpm and 68% of patients had a resting HR ≥70 bpm. KCCQ overall summary score (OSC) was found to be 75.7±13.2 in those in Q1, 65.5±20.8 in Q2, 64.4±20.6 in Q3 and 58.3±21.2 in Q4 (p=0.004) and KCCQ clinical summary score (CSS) was 80.4±15.7 in those in Q1, 70.0±22.4 in Q2, 69.9±21.9 in Q3 and 63.8±23.3 in Q4 (p=0.016). Also, there was a significant negative correlation between resting HR and OSC (p=0.008) or CSS (p=0.031). The distribution of NYHA-I patients for Q1, Q2, Q3 and Q4 were 40.7%, 22.8%, 23.8% and 12.7%, NYHA-II patients-30.8%, 23.1%, 27.2% and 18.9%, NYHA-III patients-21.2%, 23.9%, 24.3% and 30.6% and NYHA-IV patients-22.7%, 34.1%, 22.7% and 20.5%, respectively (p<0.001). Also, resting HR were found to gradually and significantly increase across NYHA categories (72.8±12 bpm in NYHA-I, 76.1±13 bpm in NYHA-II, 80.2±15 bpm in NYHA-III and 78.9±16 bpm in NYHA-IV, p<0.001). Conclusions: These results suggest that elevated resting HR in HF patients is associated with impaired HQoL and worse NYHA functional capacity.


2016 ◽  
Vol 119 (suppl_1) ◽  
Author(s):  
Elke Dworatzek ◽  
Shokoufeh Mahmoodzadeh ◽  
Christina Westphal ◽  
Daniela Fliegner ◽  
Vera Regitz-Zagrosek

Objectives: Female pressure-overloaded hearts show less fibrosis compared with males. 17β-Estradiol (E2) attenuates cardiac fibrosis in female mice. Whether this is mediated by direct E2-effects on collagen synthesis is still unknown. Therefore, we investigated the role of E2 and estrogen receptors (ER) on collagen I and III expression and analyzed involved mechanisms. Methods: Female C57BL/6J mice (7 weeks) underwent sham operation, ovariectomy (OVX), OVX with E2-supplementation (390mg E2-containing pellets) or placebo. After 2 weeks, animals underwent transverse aortic constriction (TAC) or sham surgery. Mice were sacrificed after 9 weeks. Collagen amount, collagen I and III protein in left ventricular tissue were detected by Sirius Red and antibody staining, respectively. Gene and protein expression were determined by quantitative Real-Time PCR and Western blot. Adult female rat cardiac fibroblasts were treated with E2 (10 -8 M), vehicle, ERα- and β-agonists (10 -7 M) for 24h or pre-treated with PD98059 for 1h. ER binding to the collagen I and III promoter was analyzed by chromatin immunoprecipitation assays. Findings: In female OVX mice, undergoing TAC surgery, E2-supplementation significantly reduced collagen deposition, collagen I and III mRNA and protein levels in comparison with mice without E2. In female rat cardiac fibroblasts, E2 significantly down-regulated collagen I and III mRNA and protein level. Specific ER-agonist-treatment showed that E2-mediated regulation of collagen I and III expression was mediated via activation of ERα, but not ERβ. Further, upon E2-treatment, ERα was phosphorylated at Ser118, which occurred by E2-induced activation of ERK1/2 signaling. Furthermore, we could show that ERα and ERβ bind to two putative half-palindromic estrogen response elements within the collagen I and III promoter in female cardiac fibroblasts. Conclusion: E2 inhibits cardiac collagen I and III mRNA and protein in female mice under pressure overload. Data from rat female cardiac fibroblasts suggest that this is mediated via E2-activated ERK1/2 signaling and ERα, which binds with ERβ to the collagen I and III promoter. Understanding of how E2/ER attenuate collagen I and III expression in pathological hypertrophy may improve therapy.


2020 ◽  
Author(s):  
Lin Wang ◽  
Bo Deng ◽  
Ran Zhang ◽  
Xingxing Hu ◽  
Yang Li ◽  
...  

Abstract Background: Heart failure (HF) is one of the major serious diseases to do harm to human health. Drugs, interventional treatment and heart transplantation are currently the main methods to treat HF. However, they fail to improve the patient's condition. Mesenchymal stem cells (MSCs) can regenerate functional cardiomyocytes and are promising to become a new therapeutic measure to treat heart failure. We assumed that Rehmannia glutinosa oligosaccharide (RGOs) has the synergistic effect with Nkx2.5 transfected MSCs (Nkx2.5) transplantation in treatment heart failure. Methods: MSCs and Nkx2.5 were preconditioned by RGOs. The apoptosis rate was detected by flow cytometry and the expressions of cardiac specific genes were analyzed with quantitative real-time PCR and Western blot in vitro. Heart failure models were duplicated by injecting doxorubicin (total dose of 15mg/kg) intraperitoneally in male SD rats. When the models were prepared, rats were randomly divided into 6 groups: Control (CON), HF, MSCs, Nkx2.5, RGOs and RGOs combined with Nkx2.5 (RGOs+Nkx2.5) group. Echocardiography was used to detect cardiac function in rats. HE staining was used to observe the pathological changes of myocardium, and Masson staining was used to calculate the collagen volume fraction to detect the degree of myocardial fibrosis. The total mRNA was extracted to detect the following genes including cTnI, CX43, TGF-β1, Collagen I, MEF2 and GATA4 by Q-PCR. Protein of myocardial tissue was extracted to detect the expression of cTnI, CX43, MEF2 and GATA4, by western blot. Results: RGOs could not enhance cardiac specific gene expressions including CK, α-MHC, however it improved the survival of Nkx2.5 induced by H2O2 in vitro. In rat heart failure models, RGOs alone improved the heart pumping function and decreased collagen volume fraction (CVF), TGF-β1 and collagen I expression, and increased MEF2 and GATA4 mRNA expression. Moreover, RGOs cooperated with Nkx2.5 in improving left ventricular end-diastolic volume (LVEDV) and left ventricular end-systolic volume (LVESV). Furthermore, RGOs and Nkx2.5 combination also increased CX43 expression, whereas decreased CVF and collagen I expression. Conclusion: RGOs has the synergistic effect with Nkx2.5 gene transfected MSCs transplantation in treatment with heart failure through decreasing myocardial fibrosis, inhibiting ventricular remodeling, and increasing the expressions of GATA4, MEF2.


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 ◽  
...  

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.


Author(s):  
Javier Barallobre-Barreiro ◽  
Tamás Radovits ◽  
Marika Fava ◽  
Ursula Mayr ◽  
Wen-Yu Lin ◽  
...  

Background: Remodelling of the extracellular matrix (ECM) is a hallmark of heart failure (HF). Our previous analysis of the secretome of murine cardiac fibroblasts returned ADAMTS5 (a disintegrin and metalloproteinase with thrombospondin motifs 5) as one of the most abundant proteases. ADAMTS5 cleaves chondroitin sulphate proteoglycans (CSPGs) such as versican. The contribution of ADAMTS5 and its substrate versican to HF is unknown. Methods: Versican remodelling was assessed in mice lacking the catalytic domain of ADAMTS5 (Adamts5 △Cat ). Proteomics was applied to study ECM remodelling in left ventricular samples from HF patients, with a particular focus on the effects of common medications used for the treatment of HF. Results: Versican and versikine, an ADAMTS-specific versican cleavage product, accumulated in ischemic HF patients. Versikine was also elevated in a porcine model of cardiac ischemia/reperfusion injury and in murine hearts after angiotensin II (Ang II) infusion. In Adamts5 △Cat mice, Ang II infusion resulted in an aggravated versican build-up and hyaluronic acid disarrangement, accompanied by reduced levels of integrin beta 1, filamin A and connexin 43. Echocardiographic assessment of Adamts5 △Cat mice revealed a reduced ejection fraction and an impaired global longitudinal strain upon Ang II infusion. Cardiac hypertrophy and collagen deposition, however, were similar to littermate controls. In a proteomics analysis of a larger cohort of cardiac explants from ischemic HF patients (n=65), the use of β-blockers was associated with a reduction in ECM deposition, with versican being among the most pronounced changes. Subsequent experiments in cardiac fibroblasts confirmed that β1-adrenergic receptor stimulation increased versican expression. Despite similar clinical characteristics, HF patients treated with β-blockers had a distinct cardiac ECM profile. Conclusions: Our results in animal models and patients suggest that ADAMTS proteases are critical for versican degradation in the heart, and that versican accumulation is associated with impaired cardiac function. A comprehensive characterisation of the cardiac ECM in ischemic HF patients revealed that β−blockers may have a previously unrecognized beneficial effect on the cardiac CSPG content.


Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Dirk Westermann ◽  
Mario Kasner ◽  
Olga Lettau ◽  
Micheal Noutsias ◽  
Heinz-Peter Schultheiss ◽  
...  

Aims: One of the hemodynamic mechanisms underlying heart failure with normal EF (HFNEF) is increased LV stiffness. In order to clarify the pathological changes leading to increased stiffness we investigated the left ventricular (LV) function using pressure-volume loops under basal conditions and during atrial pacing and investigated endomyocardial biopsies of patients with HFNEF. Methods: In 36 patients with HFNEF and 8 controls pressure volume loops were measured under basal conditions and during atrial pacing. Furthermore, endomyocardial biopsies were analyzed for changes in the extracellular matrix regulation, cardiac inflammation and changes in the titin isoforms. Results: Patients with HFNEF had an increased LV diastolic stiffness (+350%) compared to controls. During atrial pacing, stroke volume decreased (−35%) due to a leftward shift of the PV loops. This was associated with increased collagen content in cardiac biopsies (+380%), which blunted their cardiac output response to enhanced cardiac demand. This may explain the exercise intolerance in HFNEF patients. The total collagen correlated with cardiac stiffness in the HFNEF group (r2=0.69). This was associated with increased mRNA levels of the pro fibrotic TGF-b. Furthermore, the collagenase matrix metalloproteinases (MMP) 1 was not changed while TIMP-1 was increased (+150%), which supposes a decrease in collagen degradation in HFNEF. Nevertheless, MMP 2 was increased (+160%). This MMP is also associated with inflammation, and coherently, we investigated cardiac inflammation. We documented increased cardiac inflammation by an increment of adhesion molecules (ICAM +55%) and invading cells (CD11b cells +250%) in the cardiac tissue of HFNEF patients compared to controls. Interestingly, there was no change in titin isoforms between both groups. Conclusion: Patients with HFNEF have increased diastolic stiffness leading to an impairment of the Frank-Starling mechanism during atrial pacing. Since increased stiffness correlated with the cardiac collagen content, changes in the ECM regulation might be important for the development of HFNEF and invading cells triggering cardiac inflammation might further participate in this pathophysiology.


2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
K.M Herum ◽  
G Gilles ◽  
A Romaine ◽  
A.O Melleby ◽  
G Christensen ◽  
...  

Abstract Introduction Activation of cardiac fibroblasts (CFB) is a key step in development of fibrosis in the heart. It was recently shown that, in addition to the well-studied myofibroblast (myoFB) phenotype, activated cardiac fibroblasts can adopt a newly defined matrifibrocyte phenotype, characterized by expression of extracellular matrix (ECM) genes associated with bone, cartilage and tendon development. However, it is unknown whether matrifibrocytes exists in the pressure-overloaded fibrotic and failing heart, and whether substrate stiffness drives differentiation. Hypothesis Matrifibrocyte differentiation occurs in vitro during culturing of primary cardiac fibroblasts, and in vivo in response to left ventricular pressure overload. Methods Left ventricular pressure overload induced by o-ring aortic banding (ORAB) induced cardiac phenotypes of concentric hypertrophic remodelling and congestive heart failure. Primary CFB from adult mice were cultured on plastic or soft polyacrylamide hydrogels (4.5 kPa) for various times. mRNA expression of phenotypic markers were measured by RT-PCR. Presence of smooth muscle α-actin (SMA) fibers was determined by immunocytochemistry. Results ECM genes normally expressed in bone and cartilage (COMP, CILP-2, OPG and SCX) were upregulated in hypertrophic left ventricles of mice with congestive heart failure. The myoFB marker acta2 was increased 2 weeks after ORAB, returned to baseline at 4 weeks and increased again at 20 weeks when the left ventricle was dilating and failing, indicating that the myoFB phenotype is not permanent. In vitro, primary CFB upregulated bone/cartilage-associated ECM genes after 12 days of culturing on plastic. Acta2 mRNA and SMA protein levels peaked after 9 days in culture whereafter they declined, indicating a shift in phenotype. Culturing primary CFB on soft (4.5 kPa) hydrogels delayed, but did not prevent, myoFB differentiation while expression of bone/cartilage ECM genes was absent or low, indicating that high stiffness is a driver of the matrifibrocyte phenotype. Blockers of mechanotransduction, SB431542 (TGFβRI inhibitor), Y27623 (ROCK inhibitor) and cyclosporine A (calcineurin inhibitor), completely inhibited myoFB differentiation but upregulated several matrifibrocyte markers, indicating that distinct signaling pathways regulate myoFB and matrifibrocyte differentiation. Removing inhibitors re-induced myofibroblast markers in cells on plastic but not on soft gels consistent with high stiffness promoting myofibroblast differentiation. Conclusion Primary cardiac fibroblasts acquire characteristics of matrifibrocytes in vitro when cultured for long time on plastic and in vivo in left ventricles of mice with pressure overload-induced congestive heart failure. Funding Acknowledgement Type of funding source: Public grant(s) – EU funding. Main funding source(s): Marie Sklodowska-Curie Individual Fellowship


Amino Acids ◽  
2021 ◽  
Author(s):  
Jinshuang Li ◽  
Hao Ding ◽  
Yong Li ◽  
Hao Zhou ◽  
Wanhong Wang ◽  
...  

AbstractThe present study was to explore whether alarin could alleviate heart failure (HF) and attenuate cardia fibrosis via inhibiting oxidative stress. The fibrosis of cardiac fibroblasts (CFs) was induced by angiotensin (Ang) II. HF models were induced by ligation of the left anterior descending artery to cause ischemia myocardial infarction (MI) in Sprague–Dawley rats. Alarin (1.0 nM/kg/d) was administrated by intraperitoneal injection for 28 days. The decreases of left ventricular (LV) ejection fraction (EF), fractional shortening (FS), the maximum of the first differentiation of LV pressure (LV ± dp/dtmax) and LV systolic pressure (LVSP), and the increases of LV volume in systole (LVVS), LV volume in diastole (LVVD), LV end-systolic diameter (LVESD) and LV end-diastolic diameter (LVEDD) in MI rats were improved by alarin treatment. The increases in the expression levels of collagen I, collagen III, and transforming growth factor (TGF)-β were inhibited by alarin treatment in CFs and in the hearts of MI rats. The levels of NADPH oxidase (Nox) activity, superoxide anions and malondialdehyde (MDA) levels were increased, and the level of superoxide dismutase (SOD) activity was reduced in Ang II-treated CFs, which were reversed by alarin. Nox1 overexpression reversed the effects of alarin on attenuating the increases of collagen I, collagen III and TGF-β expression levels induced by Ang II in CFs. These results indicated that alarin improved HF and cardiac fibrosis via inhibiting oxidative stress in HF rats. Nox1 played important roles in the regulation of alarin effects on attenuating CFs fibrosis induced by Ang II.


2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
S Kuenzel ◽  
E Klapproth ◽  
K Kuenzel ◽  
C Piorkowski ◽  
M Mayr ◽  
...  

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


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