| 1. |
- Sandstedt, Joakim, et al.
(författare)
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Markedly reduced myocardial expression of γ-protocadherins and long non-coding RNAs in patients with heart disease.
- 2021
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Ingår i: International journal of cardiology. - : Elsevier BV. - 1874-1754 .- 0167-5273. ; 344, s. 149-159
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Tidskriftsartikel (refereegranskat)abstract
- Adverse cardiac remodeling and tissue damage following heart disease is strongly associated with chronic low grade inflammation. The mechanisms underlying persisting inflammatory signals are not fully understood, but may involve defective and/or non-responsive transcriptional and post-transcriptional regulatory mechanisms. In the current study, we aimed to identify novel mediators and pathways involved in processes associated with inflammation in the development and maintenance of cardiac disease.We performed RNA sequencing analysis of cardiac tissue from patients undergoing coronary artery bypass grafting (CABG) or aortic valve replacement (AVR) and compared with control tissue from multi-organ donors. Our results confirmed previous findings of a marked upregulated inflammatory state, but more importantly, we found pronounced reduction of non-protein coding genes, particularly long non-coding RNAs (lncRNA), including several lncRNAs known to be associated with inflammation and/or cardiovascular disease. In addition, Gene Set Enrichment Analysis revealed markedly downregulated microRNA pathways, resulting in aberrant expression of other genes, particularly γ-protocadherins.Our data suggest that aberrant expression of non-coding gene regulators comprise crucial keys in the progression of heart disease, and may be pivotal for chronic low grade inflammation associated with cardiac dysfunction. By unmasking atypical γ-protocadherin expression as a prospective genetic biomarker of myocardial dysfunction, our study provides new insight into the complex molecular framework of heart disease. Creating new approaches to modify non-coding gene regulators, such as those identified in the current study, may define novel strategies to shift γ-protocadherin expression, thereby normalizing part of the molecular architecture associated with heart disease.
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| 2. |
- Sandstedt, Joakim, et al.
(författare)
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Metagenomic sequencing of human cardiac tissue reveals Microbial RNA which correlates with Toll-like receptor-associated inflammation in patients with heart disease
- 2023
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Ingår i: Scientific Reports. - 2045-2322. ; 13:1
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Tidskriftsartikel (refereegranskat)abstract
- Cardiovascular disease (CVD) is strongly associated with chronic low-grade inflammation, involving activated Toll-like receptors and their downstream cellular machinery. Moreover, CVD and other related inflammatory conditions are associated with infiltration of bacteria and viruses originating from distant body sites. Thus, in this study we aimed to map the presence of microbes in the myocardium of patients with heart disease that we previously found to display upregulated Toll-like receptor signaling. We performed metagenomics analysis of atrial cardiac tissue from patients undergoing coronary artery bypass grafting (CABG) or aortic valve replacement (AVR) and compared with atrial cardiac tissue from organ donors. A total of 119 species of bacteria and seven species of virus were detected in the cardiac tissue. RNA expression of five bacterial species were increased in the patient group of which L. kefiranofaciens correlated positively with cardiac Toll-like receptor-associated inflammation. Interaction network analysis revealed four main gene set clusters involving cell growth and proliferation, Notch signaling, G protein signaling and cell communication in association with L.kefiranofaciens RNA expression. Taken together, intracardial expression of L. kefiranofaciens RNA correlates with pro-inflammatory markers in the diseased cardiac atrium and may have an effect on specific signaling processes important for cell growth, proliferation and cell communication.
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| 3. |
- Sjölin, Jacob, et al.
(författare)
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Expression of Stem Cell Niche-Related Biomarkers at the Base of the Human Tricuspid Valve
- 2023
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Ingår i: Stem Cells and Development. - : Mary Ann Liebert Inc. - 1547-3287 .- 1557-8534. ; 32:5-6, s. 140-151
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Tidskriftsartikel (refereegranskat)abstract
- Stem cell niches have been thoroughly investigated in tissue with high regenerative capacity but not in tissues where cell turnover is slow, such as the human heart. The left AtrioVentricular junction (AVj), the base of the mitral valve, has previously been proposed as a niche region for cardiac progenitors in the adult human heart. In the present study, we explore the right side of the human heart, the base of the tricuspid valve, to investigate the potential of this region as a progenitor niche. Paired biopsies from explanted human hearts were collected from multi-organ donors (N = 12). The lateral side of the AVj, right atria (RA), and right ventricle (RV) were compared for the expression of stem cell niche-related biomarkers using RNA sequencing. Gene expression data indicated upregulation of genes related to embryonic development and extracellular matrix (ECM) composition in the proposed niche region, that is, the AVj. In addition, immunohistochemistry showed high expression of the fetal cardiac markers MDR1, SSEA4, and WT1 within the same region. Nuclear expression of HIF1 alpha was detected suggesting hypoxia. Rare cells were found with the co-staining of the proliferation marker PCNA and Ki67 with cardiomyocyte nuclei marker PCM1 and cardiac Troponin T (cTnT), indicating proliferation of small cardiomyocytes. WT1+/cTnT+ and SSEA4+/cTnT+ cells were also found, suggesting cardiomyocyte-specific progenitors. The expression of the stem cell markers gradually decreased with distance from the tricuspid valve. No expression of these markers was observed in the RV tissue. In summary, the base of the tricuspid valve is an ECM-rich region containing cells with expression of several stem cell niche-associated markers. Co-expression of stem cell markers with cTnT indicates cardiomyocyte-specific progenitors. We previously reported similar data from the base of the mitral valve and thus propose that human adult cardiomyocyte progenitors reside around both atrioventricular valves.
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