Role of long noncoding RNAs in diabetes-associated peripheral arterial disease.

Diabetes mellitus (DM) is a metabolic disease that heightens the risks of many vascular complications, including peripheral arterial disease (PAD). Various types of cells, including but not limited to endothelial cells (ECs), vascular smooth muscle cells (VSMCs), and macrophages (MΦs), play crucial roles in the pathogenesis of DM-PAD. Long non-coding RNAs (lncRNAs) are epigenetic regulators that play important roles in cellular function, and their dysregulation in DM can contribute to PAD.

Isolation of Mouse Pancreatic Endothelial Cells.

The pancreas is a vital organ for maintaining metabolic balance within the body, in part due to its production of metabolic hormones such as insulin and glucagon, as well as digestive enzymes. The pancreas is also a highly vascularized organ, a feature facilitated by the intricate network of pancreatic capillaries. This extensive capillary network is made up of highly fenestrated endothelial cells (ECs) important for pancreas development and function.

Institutional Support for the Career Advancement of Women Faculty in Science and Academic Medicine: Successes, Challenges, and Future Directions.

Institutional support is crucial for the successful career advancement of all faculty but in particular those who are women. Evolving from the past, in which gender disparities were prevalent in many institutions, recent decades have witnessed significant progress in supporting the career advancement of women faculty in science and academic medicine. However, continued advancement is necessary as previously unrecognized needs and new opportunities for improvement emerge.

Mapping Endothelial-Macrophage Interactions in Diabetic Vasculature: Role of TREM2 in Vascular Inflammation and Ischemic Response.

Vasculopathies occur 15 years earlier in individuals with diabetes mellitus (DM) as compared to those without, but the underlying mechanisms driving diabetic vasculopathy remain incompletely understood. Endothelial cells (ECs) and macrophages (MΦ) are critical players in vascular wall and their crosstalk is crucial in diabetic vasculopathy. In diabetes, EC activation enables monocyte recruitment, which transmigrate into the intima and differentiate into macrophages (MΦ).

Biomimetic nanodrug targets inflammation and suppresses YAP/TAZ to ameliorate atherosclerosis.

Atherosclerosis, a chronic inflammatory disease, is the primary cause of myocardial infarction and ischemic stroke. Recent studies have demonstrated that dysregulation of yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding domain (TAZ) contributes to plaque development, making YAP/TAZ potential therapeutic targets. However, systemic modulation of YAP/TAZ expression or activities risks serious off-target effects, limiting clinical applicability.

Regulation of nuclear transcription by mitochondrial RNA in endothelial cells.

Chromatin-associated RNAs (caRNAs) form a relatively poorly recognized layer of the epigenome. The caRNAs reported to date are transcribed from the nuclear genome. Here, leveraging a recently developed assay for detection of caRNAs and their genomic association, we report that mitochondrial RNAs (mtRNAs) are attached to the nuclear genome and constitute a subset of caRNA, thus termed mt-caRNA.

Inhibition of DNMT1 methyltransferase activity via glucose-regulated -GlcNAcylation alters the epigenome.

The DNA methyltransferase activity of DNMT1 is vital for genomic maintenance of DNA methylation. We report here that DNMT1 function is regulated by -GlcNAcylation, a protein modification that is sensitive to glucose levels, and that elevated -GlcNAcylation of DNMT1 from high glucose environment leads to alterations to the epigenome. Using mass spectrometry and complementary alanine mutation experiments, we identified S878 as the major residue that is -GlcNAcylated on human DNMT1.

Methods to Study RNA-Chromatin Interactions.

RNA plays a fundamental role in the organization of chromatin as well as the regulation of gene expression. Although the chromatin is pervasively attached by both coding and noncoding RNAs, the impact of these chromatin-associated RNAs (caRNAs) on gene expression and cellular functions and their underlying mechanisms have just begun to be unraveled. One approach to understand the potential mechanism of gene regulation by caRNAs is to identify the caRNA-associated genomic regions.

Lesion-specific suppression of YAP/TAZ by biomimetic nanodrug ameliorates atherosclerosis development.

Atherosclerosis, characterized by the buildup of lipid-rich plaque on the vessel wall, is the primary cause of myocardial infarction and ischemic stroke. Recent studies have demonstrated that dysregulation of yes-associated protein 1 (YAP) and transcriptional coactivator with PDZ-binding domain (TAZ) contributes to plaque development, making YAP/TAZ potential therapeutic targets. However, systemic modulation of YAP/TAZ expression or activities risks serious off-target effects, limiting clinical applicability.

How their environment influences endothelial cells.

Changes in gene expression in cultured endothelial cells can be partially reversed by simulating in vivo conditions.

Epitranscriptional Regulation: From the Perspectives of Cardiovascular Bioengineering.

The central dogma of gene expression involves DNA transcription to RNA and RNA translation into protein. As key intermediaries and modifiers, RNAs undergo various forms of modifications such as methylation, pseudouridylation, deamination, and hydroxylation. These modifications, termed epitranscriptional regulations, lead to functional changes in RNAs.

Mitochondrial Dysfunction in Cardiac Arrhythmias.

Electrophysiological and structural disruptions in cardiac arrhythmias are closely related to mitochondrial dysfunction. Mitochondria are an organelle generating ATP, thereby satisfying the energy demand of the incessant electrical activity in the heart. In arrhythmias, the homeostatic supply-demand relationship is impaired, which is often accompanied by progressive mitochondrial dysfunction leading to reduced ATP production and elevated reactive oxidative species generation.

Endotheliopathy in the metabolic syndrome: Mechanisms and clinical implications.

The increasing prevalence of the metabolic syndrome (MetS) is a threat to global public health due to its lethal complications. Nonalcoholic fatty liver disease (NAFLD) is the hepatic manifestation of the MetS characterized by hepatic steatosis, which is potentially progressive to the inflammatory and fibrotic nonalcoholic steatohepatitis (NASH). The adipose tissue (AT) is also a major metabolic organ responsible for the regulation of whole-body energy homeostasis, and thereby highly involved in the pathogenesis of the MetS.

Downregulation of hepatic lncRNA Gm19619 improves gluconeogenesis and lipogenesis following vertical sleeve gastrectomy in mice.

Long non-coding RNAs (lncRNAs) are emerging important epigenetic regulators in metabolic processes. Whether they contribute to the metabolic effects of vertical sleeve gastrectomy (VSG), one of the most effective treatments for sustainable weight loss and metabolic improvement, is unknown. Herein, we identify a hepatic lncRNA Gm19619, which is strongly repressed by VSG but highly up-regulated by diet-induced obesity and overnight-fasting in mice.

Long noncoding RNA LEENE promotes angiogenesis and ischemic recovery in diabetes models.

Impaired angiogenesis in diabetes is a key process contributing to ischemic diseases such as peripheral arterial disease. Epigenetic mechanisms, including those mediated by long noncoding RNAs (lncRNAs), are crucial links connecting diabetes and the related chronic tissue ischemia. Here we identify the lncRNA that enhances endothelial nitric oxide synthase (eNOS) expression (LEENE) as a regulator of angiogenesis and ischemic response.

Integration of single-cell transcriptomes and biological function reveals distinct behavioral patterns in bone marrow endothelium.

Heterogeneity of endothelial cell (EC) populations reflects their diverse functions in maintaining tissue's homeostasis. However, their phenotypic, molecular, and functional properties are not entirely mapped. We use the Tie2-CreERT2;Rosa26-tdTomato reporter mouse to trace, profile, and cultivate primary ECs from different organs.

Vascular Regulation by Super Enhancer-Derived LINC00607.

Vascular endothelial cells (ECs) play a pivotal role in whole body homeostasis. Recent advances have revealed enhancer-associated long non-coding RNAs (lncRNAs) as essential regulators in EC function. We investigated LINC00607, a super enhancer-derived lncRNA (SE-lncRNA) in human arteries with an emphasis on ECs.

The Dipeptidyl Peptidase-4 Inhibitor Linagliptin Ameliorates Endothelial Inflammation and Microvascular Thrombosis in a Sepsis Mouse Model.

The pathophysiology of sepsis involves inflammation and hypercoagulability, which lead to microvascular thrombosis and compromised organ perfusion. Dipeptidyl peptidase (DPP)-4 inhibitors, e.g.

Role of endothelial cells in pulmonary fibrosis via SREBP2 activation.

Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease with limited treatment options. Despite endothelial cells (ECs) comprising 30% of the lung cellular composition, the role of EC dysfunction in pulmonary fibrosis (PF) remains unclear. We hypothesize that sterol regulatory element-binding protein 2 (SREBP2) plays a critical role in the pathogenesis of PF via EC phenotypic modifications.

Chronic marijuana usage by human pancreas donors is associated with impaired islet function.

We investigated the effect of chronic marijuana use, defined as 4 times weekly for more than 3 years, on human pancreatic islets. Pancreata from deceased donors who chronically used marijuana were compared to those from age, sex and ethnicity matched non-users. The islets from marijuana-users displayed reduced insulin secretion as compared to islets from non-users upon stimulation with high glucose (AUC, 3.

"Enhancing" mechanosensing: Enhancers and enhancer-derived long non-coding RNAs in endothelial response to flow.

Endothelial cells (ECs), uniquely localized and strategically forming the inner lining of vascular wall, constitute the largest cell surface by area in the human body. The dynamic sensing and response of ECs to mechanical cues, especially shear stress, is crucial for maintenance of vascular homeostasis. It is well recognized that different flow patterns associated with atheroprotective vs atheroprone regions in the arterial tree, result in distinct EC functional phenotypes with differential transcriptome profiles.