Sex differences in the development of the normal heart and the prevalence of cardiomyopathies have been reported. The molecular basis of these differences remains unclear. Sex differences in the human heart might be related to patterns of gene expression. Recent studies have shown that sex specific differences in gene expression in tissues including the brain, kidney, skeletal muscle, and liver. Similar data is limited for the heart. Herein we address this issue by analyzing donor and post-mortem adult human heart samples originating from 46 control individuals to study whole-genome gene expression in the human left ventricle. Using data from the genotype tissue expression (GTEx) project, we compared the transcriptome expression profiles of male and female hearts. We found that genes located on sex chromosomes were the most abundant ones among the sexually dimorphic genes. The majority of differentially expressed autosomal genes were those involved in the regulation of inflammation, which has been found to be an important contributor to left ventricular remodeling. Specifically, genes on autosomal chromosomes encoding chemokines with inflammatory functions (e.g. CCL4, CX3CL1, TNFAIP3) and a gene that regulates adhesion of immune cells to the endothelium (e.g., VCAM1) were identified with sex-specific expression levels. This study underlines the relevance of sex as an important modifier of cardiac gene expression. These results have important implications in the understanding of the differences in the physiology of the male and female heart transcriptome and how they may lead to different sex specific difference in human cardiac health and its control.
Background: Once considered primarily a disorder of lipid deposition, coronary artery disease is an incurable, life-threatening disease that is now also characterized by chronic inflammation notable for the buildup of atherosclerotic plaques containing immune cells in various states of activation and differentiation. Understanding how these immune cells contribute to disease progression may lead to the development of novel therapeutic strategies. Methods: We used single-cell technology and in vitro assays to interrogate the immune microenvironment of human coronary atherosclerotic plaque at different stages of maturity. Results: In addition to macrophages, we found a high proportion of αβ T cells in the coronary plaques. Most of these T cells lack high expression of CCR7 and L-selectin , indicating that they are primarily antigen-experienced, memory cells. Notably, nearly one-third of these cells express the HLA-DRA surface marker, signifying activation through their TCRs (T-cell receptors). Consistent with this, TCR repertoire analysis confirmed the presence of activated αβ T cells (CD4<CD8), exhibiting clonal expansion of specific TCRs. Interestingly, we found that these plaque T cells had TCRs specific for influenza, coronavirus, and other viral epitopes, which share sequence homologies to proteins found on smooth muscle cells and endothelial cells, suggesting potential autoimmune-mediated T-cell activation in the absence of active infection. To better understand the potential function of these activated plaque T cells, we then interrogated their transcriptome at the single-cell level. Of the 3 T-cell phenotypic clusters with the highest expression of the activation marker HLA-DRA identified by the Seurat algorithm, 2 clusters express a proinflammatory and cytolytic signature characteristic of CD8 cells, while the other expresses AREG (amphiregulin), which promotes smooth muscle cell proliferation and fibrosis, and, thus, contributes to plaque progression. Conclusions: Taken together, these findings demonstrate that plaque T cells are clonally expanded potentially by antigen engagement, are potentially reactive to self-epitopes, and may interact with smooth muscle cells and macrophages in the plaque microenvironment.
Objectives To evaluate whether radiation exposure from cardiac computed tomographic angiography is associated with DNA damage and whether damage leads to programmed cell death and activation of genes involved in apoptosis and DNA repair. Background Exposure to radiation from medical imaging has become a public health concern, but whether it causes significant cell damage remains unclear. Methods We conducted a prospective cohort study in 67 patients undergoing cardiac computed tomographic angiography (CTA) between January 2012 and December 2013 in two US medical centers. Median blood radiation exposure was estimated using phantom dosimetry. Biomarkers of DNA damage and apoptosis were measured by flow cytometry, whole genome sequencing, and single cell polymerase chain reaction. Results The median DLP was 1535.3 mGy·cm (969.7 – 2674.0 mGy·cm). The median radiation dose to the blood was 29.8 milliSieverts (18.8 – 48.8 mSv). Median DNA damage increased 3.39% (1.29 – 8.04%, P<0.0001) post-radiation. Median apoptosis increased 3.1-fold (1.4 – 5.1-fold, P<0.0001) post-radiation. Whole genome sequencing revealed changes in the expression of 39 transcription factors involved in the regulation of apoptosis, cell cycle, and DNA repair. Genes involved in mediating apoptosis and DNA repair were significantly changed post-radiation, including DDB2 [1.9-fold (1.5 – 3.0-fold), P<0.001], XRCC4 [3.0-fold (1.1 – 5.4-fold), P=0.005], and BAX [1.6-fold (0.9 – 2.6-fold), P<0.001]. Exposure to radiation was associated with DNA damage [OR: 1.8 (1.2 – 2.6), P=0.003]. DNA damage was associated with apoptosis [OR: 1.9 (1.2 – 5.1), P<0.0001] and gene activation [OR: 2.8 (1.2 – 6.2), P=0.002]. Conclusions Patients exposed to radiation from cardiac CTA had evidence of DNA damage, which was associated with programmed cell death and activation of genes involved in apoptosis and DNA repair.
Background Although single photon emission computed tomography myocardial perfusion imaging (SPECT MPI) has improved the diagnosis and risk stratification of patients with suspected coronary artery disease, it remains a primary source of low dose radiation exposure for cardiac patients. To determine the biological effects of low dose radiation from SPECT MPI, we measured the activation of the DNA damage response pathways using quantitative flow cytometry and single cell gene expression profiling. Methods and Results Blood samples were collected from patients before and after SPECT MPI (n=63). Overall, analysis of all recruited patients showed no marked differences in the phosphorylation of proteins (H2AX, p53, and ATM) following SPECT. The majority of patients also had either down-regulated or unchanged expression in DNA damage response genes at both 24 and 48 hours post-SPECT. Interestingly, a small subset of patients with increased phosphorylation also had significant up-regulation of genes associated with DNA damage, whereas those with no changes in phosphorylation had significant down-regulation or no difference, suggesting that some patients may potentially be more sensitive to low dose radiation exposure. Conclusions Our findings showed that SPECT MPI resulted in a variable activation of the DNA damage response pathways. Although only a small subset of patients had increased protein phosphorylation and elevated gene expression post-imaging, continued care should be taken to reduce radiation exposure to both patients and operators.
Although it is well-known that sex and age are important factors regulating endothelial cell (EC) function, the impact of sex and age on the gene expression of ECs has not been systematically analyzed at the single cell level. In this study, we performed an integrated characterization of the EC transcriptome of five major organs (e.g., fat, heart-aorta, lung, limb muscle, and kidney) isolated from male and female C57BL/6 mice at 3 and 18 months of age. A total of 590 and 252 differentially expressed genes (DEGS) were identified between females and males in the 3- and 18-month subgroups, respectively. Within the younger and older group, there were 177 vs. 178 DEGS in fat, 305 vs. 469 DEGS in heart/aorta, 22 vs. 37 DEGS in kidney, 26 vs. 439 DEGS in limb muscle, and 880 vs. 274 DEGS in lung. Interestingly, LARS2, a mitochondrial leucyl tRNA synthase, involved in the translation of mitochondrially encoded genes was differentially expressed in all organs in males compared to females in the 3-month group while S100a8 and S100a9, which are calcium binding proteins that are increased in inflammatory and autoimmune states, were upregulated in all organs in males at 18 months. Importantly, findings from RNAseq were confirmed by qPCR and Western blot. Gene enrichment analysis found genes enriched in protein targeting, catabolism, mitochondrial electron transport, IL 1- and IL 2- signaling, and Wnt signaling in males vs. angiogenesis and chemotaxis in females at 3 months. In contrast, ECs from males and females at 18-months had up-regulation in similar pathways involved in inflammation and apoptosis. Taken together, our findings suggest that gene expression is largely similar between males and females in both age groups. Compared to younger mice, however, older mice have increased expression of genes involved in inflammation in endothelial cells, which may contribute to the development of chronic, non-communicable diseases like atherosclerosis, hypertension, and Alzheimer's disease with age.
Molecular probes provide imaging signal and contrast for the visualization, characterization, and measurement of biological processes at the molecular level. These probes can be designed to target the cell or tissue of interest and must be retained at the imaging site until they can be detected by the appropriate imaging modality. In this article, we will discuss the basic design of molecular probes, differences among the various types of probes, and general strategies for their evaluation of cardiovascular disease.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.