Pericardial fluid (PF) has been suggested as a reservoir of molecular targets that can be modulated for efficient repair after myocardial infarction (MI). Here, we set out to address the content of this biofluid after MI, namely in terms of microRNAs (miRs) that are important modulators of the cardiac pathological response. PF was collected during coronary artery bypass grafting (CABG) from two MI cohorts, patients with non-ST-segment elevation MI (NSTEMI) and patients with ST-segment elevation MI (STEMI), and a control group composed of patients with stable angina and without previous history of MI. The PF miR content was analyzed by small RNA sequencing, and its biological effect was assessed on human cardiac fibroblasts. PF accumulates fibrotic and inflammatory molecules in STEMI patients, namely causing the soluble suppression of tumorigenicity 2 (ST-2), which inversely correlates with the left ventricle ejection fraction. Although the PF of the three patient groups induce similar levels of fibroblast-to-myofibroblast activation in vitro, RNA sequencing revealed that PF from STEMI patients is particularly enriched not only in pro-fibrotic miRs but also anti-fibrotic miRs. Among those, miR-22-3p was herein found to inhibit TGF-β-induced human cardiac fibroblast activation in vitro. PF constitutes an attractive source for screening diagnostic/prognostic miRs and for unveiling novel therapeutic targets in cardiac fibrosis.

• Klíčová slova
• cardiac fibroblasts, fibrosis, miR-22-3p, miRNAs, myocardial infarction, pericardial fluid,
• MeSH
• fibroblasty metabolismus   MeSH
• fibróza * MeSH
• infarkt myokardu s elevacemi ST úseků metabolismus   patologie   genetika   MeSH
• infarkt myokardu * metabolismus   genetika   patologie   MeSH
• interleukin-1 receptor-like 1 protein metabolismus   genetika   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mikro RNA * genetika   metabolismus   MeSH
• myokard metabolismus   patologie   MeSH
• perikardiální tekutina * metabolismus   MeSH
• senioři MeSH
• transformující růstový faktor beta metabolismus   MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• IL1RL1 protein, human MeSH Prohlížeč
• interleukin-1 receptor-like 1 protein MeSH
• mikro RNA * MeSH
• MIRN22 microRNA, human MeSH Prohlížeč
• transformující růstový faktor beta MeSH

BACKGROUND: Dilated cardiomyopathy (DCM) is a major cause of heart failure and carries a high mortality rate. Myocardial recovery in DCM-related heart failure patients is highly variable, with some patients having little or no response to standard drug therapy. A genome-wide association study may agnostically identify biomarkers and provide novel insight into the biology of myocardial recovery in DCM. METHODS: A genome-wide association study for change in left ventricular ejection fraction was performed in 686 White subjects with recent-onset DCM who received standard pharmacotherapy. Genome-wide association study signals were subsequently functionally validated and studied in relevant cellular models to understand molecular mechanisms that may have contributed to the change in left ventricular ejection fraction. RESULTS: The genome-wide association study identified a highly suggestive locus that mapped to the 5'-flanking region of the CDCP1 (CUB [complement C1r/C1s, Uegf, and Bmp1] domain containing protein 1) gene (rs6773435; P=7.12×10-7). The variant allele was associated with improved cardiac function and decreased CDCP1 transcription. CDCP1 expression was significantly upregulated in human cardiac fibroblasts (HCFs) in response to the PDGF (platelet-derived growth factor) signaling, and knockdown of CDCP1 significantly repressed HCF proliferation and decreased AKT (protein kinase B) phosphorylation. Transcriptomic profiling after CDCP1 knockdown in HCFs supported the conclusion that CDCP1 regulates HCF proliferation and mitosis. In addition, CDCP1 knockdown in HCFs resulted in significantly decreased expression of soluble ST2 (suppression of tumorigenicity-2), a prognostic biomarker for heart failure and inductor of cardiac fibrosis. CONCLUSIONS: CDCP1 may play an important role in myocardial recovery in recent-onset DCM and mediates its effect primarily by attenuating cardiac fibrosis.

• Klíčová slova
• cardiomyopathy, dilated, fibrosis, genetics, genome-wide association study, heart failure, humans, ventricular remodeling,
• MeSH
• antigeny nádorové terapeutické užití   MeSH
• celogenomová asociační studie MeSH
• dilatační kardiomyopatie * metabolismus   MeSH
• fibróza MeSH
• funkce levé komory srdeční MeSH
• lidé MeSH
• molekuly buněčné adheze metabolismus   MeSH
• srdeční selhání * MeSH
• tepový objem MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• antigeny nádorové MeSH
• CDCP1 protein, human MeSH Prohlížeč
• molekuly buněčné adheze MeSH

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia associated with a two-fold increase in mortality caused by a higher risk of stroke and heart failure. Currently, AF is present in ~ 2 % of the general population, and its incidence and prevalence are increasing. Obesity, hypertension, diabetes mellitus, obstructive sleep apnea, and alcohol consumption increase the risk of AF. Each unit of increase in BMI increases the risk of AF by 3 %, and intensive weight loss is also associated with reduced AF recurrence. Hypertension increases the risk of AF by 50 % in men and by 40 % in women, and explains ~ 20 % of new AF cases. Patients with obstructive sleep apnea are at four times higher risk of developing AF than subjects without sleep apnea. Higher concentrations of pro-inflammatory cytokines, higher amounts of epicardial adipose tissue, and a higher degree of ventricular diffuse myocardial fibrosis are present in AF patients and patients with the aforementioned metabolic disorders. Several prospective cohort studies and randomized trials have been initiated to show whether weight loss and treatment of other risk factors will be associated with a reduction in AF recurrences.

• MeSH
• diabetes mellitus * MeSH
• fibrilace síní * diagnóza   epidemiologie   MeSH
• hypertenze * komplikace   epidemiologie   MeSH
• lidé MeSH
• obezita komplikace   diagnóza   epidemiologie   MeSH
• prospektivní studie MeSH
• rizikové faktory MeSH
• syndromy spánkové apnoe * komplikace   diagnóza   epidemiologie   MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

Current knowledge on the renin-angiotensin system (RAS) indicates its central role in the pathogenesis of cardiovascular remodelling via both hemodynamic alterations and direct growth and the proliferation effects of angiotensin II or aldosterone resulting in the hypertrophy of cardiomyocytes, the proliferation of fibroblasts, and inflammatory immune cell activation. The noncoding regulatory microRNAs has recently emerged as a completely novel approach to the study of the RAS. A growing number of microRNAs serve as mediators and/or regulators of RAS-induced cardiac remodelling by directly targeting RAS enzymes, receptors, signalling molecules, or inhibitors of signalling pathways. Specifically, microRNAs that directly modulate pro-hypertrophic, pro-fibrotic and pro-inflammatory signalling initiated by angiotensin II receptor type 1 (AT1R) stimulation are of particular relevance in mediating the cardiovascular effects of the RAS. The aim of this review is to summarize the current knowledge in the field that is still in the early stage of preclinical investigation with occasionally conflicting reports. Understanding the big picture of microRNAs not only aids in the improved understanding of cardiac response to injury but also leads to better therapeutic strategies utilizing microRNAs as biomarkers, therapeutic agents and pharmacological targets.

• Klíčová slova
• RAS, cardiac fibrosis, cardiac hypertrophy, cardiac remodelling, miRNA,
• MeSH
• fibróza MeSH
• kardiomegalie genetika   metabolismus   patologie   MeSH
• lidé MeSH
• mikro RNA genetika   metabolismus   MeSH
• myokard metabolismus   patologie   MeSH
• nemoci srdce genetika   metabolismus   patologie   MeSH
• renin-angiotensin systém * MeSH
• signální transdukce * MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• mikro RNA MeSH

The increased production of reactive oxygen species and oxidative stress are important factors contributing to the development of diseases of the cardiovascular and central nervous systems. Molecular hydrogen is recognized as an emerging therapeutic, and its positive effects in the treatment of pathologies have been documented in both experimental and clinical studies. The therapeutic potential of hydrogen is attributed to several major molecular mechanisms. This review focuses on the effects of hydrogen on the cardiovascular and central nervous systems, and summarizes current knowledge about its actions, including the regulation of redox and intracellular signaling, alterations in gene expressions, and modulation of cellular responses (e.g., autophagy, apoptosis, and tissue remodeling). We summarize the functions of hydrogen as a regulator of nuclear factor erythroid 2-related factor 2 (Nrf2)-mediated redox signaling and the association of hydrogen with mitochondria as an important target of its therapeutic action. The antioxidant functions of hydrogen are closely associated with protein kinase signaling pathways, and we discuss possible roles of the phosphoinositide 3-kinase/protein kinase B (PI3K/Akt) and Wnt/β-catenin pathways, which are mediated through glycogen synthase kinase 3β and its involvement in the regulation of cellular apoptosis. Additionally, current knowledge about the role of molecular hydrogen in the modulation of autophagy and matrix metalloproteinases-mediated tissue remodeling, which are other responses to cellular stress, is summarized in this review.

• Klíčová slova
• autophagy, matrix metalloproteinases, molecular hydrogen, oxidative stress,
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

Cardiac fibrosis is a final common pathology in inherited and acquired heart diseases that causes cardiac electrical and pump failure. Here, we use systems genetics to identify a pro-fibrotic gene network in the diseased heart and show that this network is regulated by the E3 ubiquitin ligase WWP2, specifically by the WWP2-N terminal isoform. Importantly, the WWP2-regulated pro-fibrotic gene network is conserved across different cardiac diseases characterized by fibrosis: human and murine dilated cardiomyopathy and repaired tetralogy of Fallot. Transgenic mice lacking the N-terminal region of the WWP2 protein show improved cardiac function and reduced myocardial fibrosis in response to pressure overload or myocardial infarction. In primary cardiac fibroblasts, WWP2 positively regulates the expression of pro-fibrotic markers and extracellular matrix genes. TGFβ1 stimulation promotes nuclear translocation of the WWP2 isoforms containing the N-terminal region and their interaction with SMAD2. WWP2 mediates the TGFβ1-induced nucleocytoplasmic shuttling and transcriptional activity of SMAD2.

• MeSH
• dospělí MeSH
• extracelulární matrix - proteiny metabolismus   MeSH
• fibróza genetika   metabolismus   MeSH
• genetická predispozice k nemoci * genetika   MeSH
• genové regulační sítě * MeSH
• kardiomyopatie genetika   metabolismus   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• myši transgenní MeSH
• myši MeSH
• nemoci srdce genetika   metabolismus   MeSH
• protein - isoformy MeSH
• protein Smad2 genetika   metabolismus   MeSH
• regulace genové exprese MeSH
• senioři MeSH
• transformující růstový faktor beta metabolismus   MeSH
• ubikvitinligasy genetika   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• myši MeSH
• senioři MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• betaIG-H3 protein MeSH Prohlížeč
• extracelulární matrix - proteiny MeSH
• protein - isoformy MeSH
• protein Smad2 MeSH
• Smad2 protein, mouse MeSH Prohlížeč
• transformující růstový faktor beta MeSH
• ubikvitinligasy MeSH
• Wwp2 protein, mouse MeSH Prohlížeč