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Endothelial cells play a critical role in the adaptation of tissues to injury. Tissue ischemia induced by infarction leads to profound changes in endothelial cell functions and can induce transition to a mesenchymal state. Here we explore the kinetics and individual cellular responses of endothelial cells after myocardial infarction by using single cell RNA sequencing. This study demonstrates a time dependent switch in endothelial cell proliferation and inflammation associated with transient changes in metabolic gene signatures. Trajectory analysis reveals that the majority of endothelial cells 3 to 7 days after myocardial infarction acquire a transient state, characterized by mesenchymal gene expression, which returns to baseline 14 days after injury. Lineage tracing, using the Cdh5-CreERT2;mT/mG mice followed by single cell RNA sequencing, confirms the transient mesenchymal transition and reveals additional hypoxic and inflammatory signatures of endothelial cells during early and late states after injury. These data suggest that endothelial cells undergo a transient mes-enchymal activation concomitant with a metabolic adaptation within the first days after myocardial infarction but do not acquire a long-term mesenchymal fate. This mesenchymal activation may facilitate endothelial cell migration and clonal expansion to regenerate the vascular network.
Cardiovascular diseases (CVDs) remain the leading cause of death worldwide. Many studies have provided evidence that both genetic and environmental factors induce atherosclerosis, leading thus to cardiovascular complications. Atherosclerosis is an inflammatory disease, and aging is strongly associated with the development of atherosclerosis. Recent experimental evidence suggests that clonal hematopoiesis (CH) is an emerging cardiovascular risk factor that contributes to the development of atherosclerosis and cardiac dysfunction and exacerbates cardiovascular diseases. CH is caused by somatic mutations in recurrent genes in hematopoietic stem cells, leading to the clonal expansion of mutated blood cell clones. Many of the mutated genes are known in the context of myeloid neoplasms. However, only some individuals carrying CH mutations develop hematologic abnormalities. CH is clearly age dependent and is not rare: at least 10%–20% of people >70 years old carry CH. The newly discovered association between myeloid leukemia-driver mutations and the progression of CVDs has raised medical interest. In this review, we summarize the current view on the contribution of CH in different cardiovascular diseases, CVD risk assessment, patient stratification, and the development of novel therapeutic strategies.
Despite advances in the medical and interventional clinical management of patients, cardiovascular diseases (CVDs) remain the leading cause of death worldwide. It is well appreciated that atherosclerosis represents the underlying cause of most CVDs [1]. Atherosclerosis is a chronic inflammatory disease that leads to the formation of atheromatous lesions in the vessel associated with increased recruitment, adhesion, and proliferation of different leukocyte subsets to the endothelium [1]. Several cardiovascular risk factors (CRFs) have been found to enhance the risk of CVD (Figure 1), including hypercholesterolemia (HC), diabetes mellitus (DM), hypertension, metabolic syndrome, obesity, and smoking [2]. Inflammation plays a crucial role in the development of CVDs and several studies have reported that CRFs enhance production of myeloid cells and multipotent hematopoietic progenitors in the bone marrow and in this way may promote atherosclerosis and disease development [3].
Vascular integrity is essential for organ homeostasis to prevent edema formation and infiltration of inflammatory cells. Long non-coding RNAs (lncRNAs) are important regulators of gene expression and often expressed in a cell type-specific manner. By screening for endothelial-enriched lncRNAs, we identified the undescribed lncRNA NTRAS to control endothelial cell functions. Silencing of NTRAS induces endothelial cell dysfunction in vitro and increases vascular permeability and lethality in mice. Biochemical analysis revealed that NTRAS, through its CA-dinucleotide repeat motif, sequesters the splicing regulator hnRNPL to control alternative splicing of tight junction protein 1 (TJP1; also named zona occludens 1, ZO-1) pre-mRNA. Deletion of the hnRNPL binding motif in mice (Ntras∆CA/∆CA) significantly repressed TJP1 exon 20 usage, favoring expression of the TJP1α- isoform, which augments permeability of the endothelial monolayer. Ntras∆CA/∆CA mice further showed reduced retinal vessel growth and increased vascular permeability and myocarditis. In summary, this study demonstrates that NTRAS is an essential gatekeeper of vascular integrity.
After myocardial infarction in the adult heart the remaining, non-infarcted tissue adapts to compensate the loss of functional tissue. This adaptation requires changes in gene expression networks, which are mostly controlled by transcription regulating proteins. Long non-coding transcripts (lncRNAs) are now recognized for taking part in fine-tuning such gene programs. We identified and characterized the cardiomyocyte specific lncRNA Sweetheart RNA (Swhtr), an approximately 10 kb long transcript divergently expressed from the cardiac core transcription factor coding gene Nkx2-5. We show that Swhtr is dispensable for normal heart development and function, but becomes essential for the tissue adaptation process after myocardial infarction. Re-expressing Swhtr from an exogenous locus rescues the Swhtr null phenotype. Genes depending on Swhtr after cardiac stress are significantly occupied, and therefore most likely regulated by NKX2-5. Our results indicate a synergistic role for Swhtr and the developmentally essential transcription factor NKX2-5 in tissue adaptation after myocardial injury.
Bone vasculature provides protection and signals necessary to control stem cell quiescence and renewal1. Specifically, type H capillaries, which highly express Endomucin, constitute the endothelial niche supporting a microenvironment of osteoprogenitors and long-term hematopoietic stem cells2–4. The age-dependent decline in type H endothelial cells was shown to be associated with bone dysregulation and accumulation of hematopoietic stem cells, which display cell-intrinsic alterations and reduced functionality3. The regulation of bone vasculature by chronic diseases, such as heart failure is unknown. Here, we describe the effects of myocardial infarction and post-infarction heart failure on the vascular bone cell composition. We demonstrate an age-independent loss of type H bone endothelium in heart failure after myocardial infarction in both mice and in humans. Using single-cell RNA sequencing, we delineate the transcriptional heterogeneity of human bone marrow endothelium showing increased expression of inflammatory genes, including IL1B and MYC, in ischemic heart failure. Inhibition of NLRP3-dependent IL-1β production partially prevents the post-myocardial infarction loss of type H vasculature in mice. These results provide a rationale for using anti-inflammatory therapies to prevent or reverse the deterioration of vascular bone function in ischemic heart disease.
Cathepsin D (CatD) is a lysosomal aspartic proteinase and plays an important role in the degradation of proteins and in apoptotic processes induced by oxidative stress, cytokines, and aging. All of these stimuli are potent inducers of endothelial cell apoptosis. Therefore, we investigated the role of CatD in endothelial cell apoptosis and determined the underlying mechanisms. Incubation with 100-500 microm H2O2 for 12 h induced apoptosis in endothelial cells. To determine a role for CatD, we co-incubated endothelial cells with the CatD inhibitor pepstatin A. Pepstatin A as well as genetic knock down of CatD abolished H2O2-induced apoptosis. In contrast, overexpression of CatD wild type but not a catalytically inactive mutant of CatD (CatDD295N) induced apoptosis under basal conditions. To gain insights into the underlying mechanisms, we investigated the effect of CatD on reactive oxygen species (ROS) formation. Indeed, knocking down CatD expression reduced H2O2-induced ROS formation and apoptosis. The major redox regulator in endothelial cells is thioredoxin-1 (Trx), which plays a crucial role in apoptosis inhibition. Thus, we hypothesized that CatD may alter Trx protein levels and thereby promote formation of ROS and apoptosis. Incubation with 100 microm H2O2 for 6 h decreased Trx protein levels, whereas Trx mRNA was not altered. H2O2-induced Trx degradation was inhibited by pepstatin A and genetic knock down of CatD but not by other protease inhibitors. Incubation of unstimulated cell lysates with recombinant CatD significantly reduced Trx protein levels in vitro, which was completely blocked by pepstatin A pre-incubation. Overexpression of CatD reduced Trx protein in cells. Moreover, H2O2 incubation led to a translocation of Trx to the lysosomes prior to the induction of apoptosis. Taken together, CatD induces apoptosis via degradation of Trx protein, which is an essential anti-apoptotic and reactive oxygen species scavenging protein in endothelial cells.
Hematopoietic mutations in epigenetic regulators like DNA methyltransferase 3 alpha (DNMT3A), play a pivotal role in driving clonal hematopoiesis of indeterminate potential (CHIP), and are associated with unfavorable outcomes in patients suffering from heart failure (HF). However, the precise interactions between CHIP-mutated cells and other cardiac cell types remain unknown. Here, we identify fibroblasts as potential partners in interactions with CHIP-mutated monocytes. We used combined transcriptomic data derived from peripheral blood mononuclear cells of HF patients, both with and without CHIP, and cardiac tissue. We demonstrate that inactivation of DNMT3A in macrophages intensifies interactions with cardiac fibroblasts and increases cardiac fibrosis. DNMT3A inactivation amplifies the release of heparin-binding epidermal growth factor-like growth factor, thereby facilitating activation of cardiac fibroblasts. These findings identify a potential pathway of DNMT3A CHIP-driver mutations to the initiation and progression of HF and may also provide a compelling basis for the development of innovative anti-fibrotic strategies.
After myocardial infarction in the adult heart the remaining, non-infarcted tissue adapts to compensate the loss of functional tissue. This adaptation requires changes in gene expression networks, which are mostly controlled by transcription regulating proteins. Long non-coding transcripts (lncRNAs) are taking part in fine-tuning such gene programs. We describe and characterize the cardiomyocyte specific lncRNA Sweetheart RNA (Swhtr), an approximately 10 kb long transcript divergently expressed from the cardiac core transcription factor coding gene Nkx2-5. We show that Swhtr is dispensable for normal heart development and function but becomes essential for the tissue adaptation process after myocardial infarction in murine males. Re-expressing Swhtr from an exogenous locus rescues the Swhtr null phenotype. Genes that depend on Swhtr after cardiac stress are significantly occupied and therefore most likely regulated by NKX2-5. The Swhtr transcript interacts with NKX2-5 and disperses upon hypoxic stress in cardiomyocytes, indicating an auxiliary role of Swhtr for NKX2-5 function in tissue adaptation after myocardial injury.