Abstract
Senescent vascular cells are detected in atherosclerotic lesion, and its involvement in the development of atherosclerosis has been revealed; however, whether and the mechanism by which ...endothelial cell (EC) senescence is causally implicated in atherosclerosis remains unclear. We here investigate a role of EC senescence in atherosclerosis by utilizing EC-specific progeroid mice that overexpress the dominant negative form of telomeric repeat-binding factor 2 under the control of the Tie2 or vascular endothelial cadherin promoter. EC-specific progeria accelerated atherosclerosis in mice with target deletion of ApoE. Mechanistically, senescent ECs were markedly sensitive for inflammation-mediated VCAM-1 induction, leading to enhanced monocyte adhesion. Inhibition of NF-κB signaling abolished the enhanced inflammatory responses in senescent ECs, while NF-κB nuclear translocation in response to TNF-α were similar between young and senescent ECs. We found a higher association of VCAM-1 gene with active histone H3 trimethylated on lysine 4, leading to increased NF-κB accessibility in senescent ECs. Our data revealed that EC cellular senescence causes endothelial hyper-inflammability through epigenetic alteration, which consequently accelerates atherosclerosis. Therefore, EC senescence is a promising therapeutic target for the prevention and/or treatment of atherosclerotic disease in elderly population.
Vascular senescence is thought to play a crucial role in an ageing-associated decline of organ functions; however, whether vascular senescence is causally implicated in age-related disease remains ...unclear. Here we show that endothelial cell (EC) senescence induces metabolic disorders through the senescence-associated secretory phenotype. Senescence-messaging secretomes from senescent ECs induced a senescence-like state and reduced insulin receptor substrate-1 in adipocytes, which thereby impaired insulin signaling. We generated EC-specific progeroid mice that overexpressed the dominant negative form of telomeric repeat-binding factor 2 under the control of the Tie2 promoter. EC-specific progeria impaired systemic metabolic health in mice in association with adipose tissue dysfunction even while consuming normal chow. Notably, shared circulation with EC-specific progeroid mice by parabiosis sufficiently transmitted the metabolic disorders into wild-type recipient mice. Our data provides direct evidence that EC senescence impairs systemic metabolic health, and thus establishes EC senescence as a bona fide risk for age-related metabolic disease.
Pulmonary arterial hypertension is a progressive fatal disease that is characterized by pathological pulmonary artery remodeling, in which endothelial cell dysfunction is critically involved. We ...herein describe a previously unknown role of endothelial angiocrine in pulmonary hypertension. By searching for genes highly expressed in lung microvascular endothelial cells, we identify inhibin-β-A as an angiocrine factor produced by pulmonary capillaries. We find that excess production of inhibin-β-A by endothelial cells impairs the endothelial function in an autocrine manner by functioning as activin-A. Mechanistically, activin-A induces bone morphogenetic protein receptor type 2 internalization and targeting to lysosomes for degradation, resulting in the signal deficiency in endothelial cells. Of note, endothelial cells isolated from the lung of patients with idiopathic pulmonary arterial hypertension show higher inhibin-β-A expression and produce more activin-A compared to endothelial cells isolated from the lung of normal control subjects. When endothelial activin-A-bone morphogenetic protein receptor type 2 link is overdriven in mice, hypoxia-induced pulmonary hypertension was exacerbated, whereas conditional knockout of inhibin-β-A in endothelial cells prevents the progression of pulmonary hypertension. These data collectively indicate a critical role for the dysregulated endothelial activin-A-bone morphogenetic protein receptor type 2 link in the progression of pulmonary hypertension, and thus endothelial inhibin-β-A/activin-A might be a potential pharmacotherapeutic target for the treatment of pulmonary arterial hypertension.
Advances in technology and biomedical knowledge have led to the effective diagnosis and treatment of an increasing number of rare diseases. Pulmonary arterial hypertension (PAH) is a rare disorder of ...the pulmonary vasculature that is associated with high mortality and morbidity rates. Although significant progress has been made in understanding PAH and its diagnosis and treatment, numerous unanswered questions remain regarding pulmonary vascular remodeling, a major factor contributing to the increase in pulmonary arterial pressure. Here, we discuss the role of activins and inhibins, both of which belong to the TGF-β superfamily, in PAH development. We examine how these relate to signaling pathways implicated in PAH pathogenesis. Furthermore, we discuss how activin/inhibin-targeting drugs, particularly sotatercep, affect pathophysiology, as these target the afore-mentioned specific pathway. We highlight activin/inhibin signaling as a critical mediator of PAH development that is to be targeted for therapeutic gain, potentially improving patient outcomes in the future.
Persistently high plasma endothelin-1 (ET-1) levels in diabetic patients have been associated with the development of cardiac fibrosis, which results from the deposition of extracellular matrix and ...fibroblast recruitment from an as-yet unknown source. The underlying mechanism, however, remains elusive. Here, we hypothesize that ET-1 might contribute to the accumulation of cardiac fibroblasts through an endothelial-to-mesenchymal transition in diabetic hearts.
We induced diabetes mellitus in vascular endothelial cell-specific ET-1 knockout ET-1(f/f);Tie2-Cre (+) mice and their wild-type littermates using the toxin streptozotocin. Gene expression and histological and functional parameters were examined at 8, 24, and 36 weeks after the induction of diabetes mellitus. Diabetes mellitus increased cardiac ET-1 expression in wild-type mice, leading to mitochondrial disruption and myofibril disarray through the generation of superoxide. Diabetic mice also showed impairment of cardiac microvascularization and a decrease in cardiac vascular endothelial growth factor expression. ET-1 further promotes cardiac fibrosis and heart failure through the accumulation of fibroblasts via endothelial-to-mesenchymal transition. All of these features were abolished in ET-1(f/f);Tie2-Cre (+) hearts. Targeted ET-1 gene silencing by small interfering RNA in cultured human endothelial cells ameliorated high glucose-induced phenotypic transition and acquisition of a fibroblast marker through the inhibition of transforming growth factor-beta signaling activation and preservation of the endothelial cell-to-cell contact regulator VE-cadherin.
These results provide new insights suggesting that diabetes mellitus-induced cardiac fibrosis is associated with the emergence of fibroblasts from endothelial cells and that this endothelial-to-mesenchymal transition process is stimulated by ET-1. Targeting endothelial cell-derived ET-1 might be beneficial in the prevention of diabetic cardiomyopathy.
Obesity is a global health problem that is often related to cardiovascular and metabolic diseases. Chronic low-grade inflammation in white adipose tissue (WAT) is a hallmark of obesity. Previously, ...during a search for differentially expressed genes in WAT of obese mice, we identified glycoprotein nonmetastatic melanoma protein B (GPNMB), of which expression was robustly induced in pathologically expanded WAT. Here, we investigated the role of GPNMB in obesity-related metabolic disorders utilizing GPNMB-deficient mice. When fed a high-fat diet (HFD), GPNMB-deficient mice showed body weight and adiposity similar to those of wild-type (WT) mice. Nonetheless, insulin and glucose tolerance tests revealed significant obesity-related metabolic disorders in GPNMB-KO mice compared with WT mice fed with HFD. Chronic WAT inflammation was remarkably worsened in HFD-fed GPNMB-KO mice, accompanied by a striking increase in crown-like structures, typical hallmarks for diseased WAT. Macrophages isolated from GPNMB-KO mice were observed to produce more inflammatory cytokines than those of WT mice, a difference abolished by supplementation with recombinant soluble GPNMB extracellular domain. We demonstrated that GPNMB reduced the inflammatory capacity of macrophages by inhibiting NF-κB signaling largely through binding to CD44. Finally, we showed that macrophage depletion by addition of clodronate liposomes abolished the worsened WAT inflammation and abrogated the exacerbation of metabolic disorders in GPNMB-deficient mice fed on HFD. Our data reveal that GPNMB negatively regulates macrophage inflammatory capacities and ameliorates the WAT inflammation in obesity; therefore we conclude that GPNMB is a promising therapeutic target for the treatment of metabolic disorders associated with obesity.
Background: The development of right ventricular (RV) dysfunction in pulmonary hypertension (PH) patients is associated with adverse outcome, so that the assessment of RV function has become ...increasingly important in the management of such patients. The present objective was to test the hypothesis that RV free-wall longitudinal speckle-tracking strain (RV-free), an independent echocardiographic predictor of hemodynamic RV performance, can predict long-term outcome. Methods and Results: Forty-two PH patients were studied. RV-free was calculated by averaging the 3 regional peak systolic strains for the RV free wall. For comparison, tricuspid annular plane systolic excursion (TAPSE), RV fractional area change, RV index of myocardial performance, and tissue Doppler-derived tricuspid lateral annular systolic velocity were also studied. Long-term follow-up was performed for 4 years after adding PH-specific drugs. Receiver operating characteristic curve analysis identified RV-free ≤19.4% as the best predictor of cardiovascular events with 90% sensitivity, 69% specificity, and area under the curve of 0.819 (P=0.0001). Furthermore, the Kaplan-Meier curve indicated that patients with RV-free >19.4% experienced fewer cardiovascular events than those with RV-free ≤19.4% (log-rank P=0.0008). Importantly, the co-occurrence of RV-free ≤19.4% and TAPSE <16mm was associated with the highest frequency of cardiovascular events. Conclusions: RV-free may serve as a non-invasive predictor of cardiovascular events for PH patients. Combining RV-free with TAPSE may be more effective for predicting long-term cardiovascular events. (Circ J 2013; 77: 756–763)
Endothelin was first discovered more than 30 years ago as a potent vasoconstrictor. In subsequent years, three isoforms, two canonical receptors, and two converting enzymes were identified, and their ...basic functions were elucidated by numerous preclinical and clinical studies. Over the years, the endothelin system has been found to be critical in the pathogenesis of several cardiovascular diseases, including hypertension, pulmonary arterial hypertension, heart failure, and coronary artery disease. In this review, we summarize the current knowledge on endothelin and its role in cardiovascular diseases. Furthermore, we discuss how endothelin-targeting therapies, such as endothelin receptor antagonists, have been employed to treat cardiovascular diseases with varying degrees of success. Lastly, we provide a glimpse of what could be in store for endothelin-targeting treatment options for cardiovascular diseases in the future.
Although dual endothelin receptor antagonists (ERAs) show great promise for treating various conditions, their propensity to induce liver injury limits their clinical usage. Inflammation and fibrosis ...are important processes in liver responses to injury and it has been suggested that they and dual ERA-induced liver injury are mediated by the proteoglycan component chondroitin sulfate (CS), which is synthesized by
and
. In this study, we investigated whether dual ER inhibition in the liver could alter
and
expression and thus CS production and whether liver CS content could prevent inflammatory and fibrosis responses after liver injury. We observed increased
and
expression after liver injury in bile duct ligated mice and histologically confirmed abundant CS deposition in the injured liver. Moreover, treating Hep3B cells with a dual ERA mimic significantly increased
and
expression, inflammatory cytokine levels, and glycosaminoglycan deposition. Furthermore, pro-inflammatory and pro-fibrotic markers were observed after dual ERA treatment, while treatment with CS-degrading chondroitinase ABC was able to successfully reverse these phenotypes. These observations suggest that
- and
-induced CS production can mediate liver injury responses caused by dual ER inhibition and thus could be an alternative pathway for treating ERA-induced liver injury.
Alveolar macrophages (AMs) are crucial for maintaining normal lung function. They are abundant in lung cancer tissues, but their pathophysiological significance remains unknown. Here we show, using ...an orthotopic murine lung cancer model and human carcinoma samples, that AMs support cancer cell proliferation and thus contribute to unfavourable outcome. Inhibin beta A (INHBA) expression is upregulated in AMs under tumor-bearing conditions, leading to the secretion of activin A, a homodimer of INHBA. Accordingly, follistatin, an antagonist of activin A is able to inhibit lung cancer cell proliferation. Single-cell RNA sequence analysis identifies a characteristic subset of AMs specifically induced in the tumor environment that are abundant in INHBA, and distinct from INHBA-expressing AMs in normal lungs. Moreover, postnatal deletion of INHBA/activin A could limit tumor growth in experimental models. Collectively, our findings demonstrate the critical pathological role of activin A-producing AMs in tumorigenesis, and provides means to clearly distinguish them from their healthy counterparts.
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