Atherosclerosis and its attendant clinical complications, such as myocardial infarction, stroke, and peripheral artery disease, are the leading cause of morbidity and mortality in Western societies. ...In response to biochemical and biomechanical stimuli, atherosclerotic lesion formation occurs from the participation of a range of cell types, inflammatory mediators, and shear stress. Over the past decade, microRNAs (miRNAs) have emerged as evolutionarily conserved, noncoding small RNAs that serve as important regulators and fine-tuners of a range of pathophysiological cellular effects and molecular signaling pathways involved in atherosclerosis. Accumulating studies reveal the importance of miRNAs in regulating key signaling and lipid homeostasis pathways that alter the balance of atherosclerotic plaque progression and regression. In this review, we highlight current paradigms of miRNA-mediated effects in atherosclerosis progression and regression. We provide an update on the potential use of miRNAs diagnostically for detecting increasing severity of coronary disease and clinical events. Finally, we provide a perspective on therapeutic opportunities and challenges for miRNA delivery in the field.
Accumulating studies indicate that long non-coding RNAs (lncRNAs) play important roles in the regulation of diverse biological processes involved in homeostatic control of the vessel wall in health ...and disease. However, our knowledge of the mechanisms by which lncRNAs control gene expression and cell signaling pathways is still nascent. Furthermore, only a handful of lncRNAs has been functionally evaluated in response to pathophysiological stimuli or in vascular disease states. For example, lncRNAs may regulate endothelial dysfunction by modulating endothelial cell proliferation (e.g. MALAT1, H19) or angiogenesis (e.g. MEG3, MANTIS). LncRNAs have also been implicated in modulating vascular smooth muscle cell (VSMC) phenotypes or vascular remodeling (e.g. ANRIL, SMILR, SENCR, MYOSLID). Finally, emerging studies have implicated lncRNAs in leukocytes activation (e.g. lincRNA-Cox2, linc00305, THRIL), macrophage polarization (e.g. GAS5), and cholesterol metabolism (e.g. LeXis). This review summarizes recent findings on the expression, mechanism, and function of lncRNAs implicated in a range of vascular disease states from mice to human subjects. An improved understanding of lncRNAs in vascular disease may provide new pathophysiological insights and opportunities for the generation of a new class of RNA-based biomarkers and therapeutic targets.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Abstract
Chronic, low-grade systemic inflammation and impaired microvascular function are critical hallmarks in the development of insulin resistance. Accordingly, insulin resistance is a major risk ...factor for type 2 diabetes and cardiovascular disease. Accumulating studies demonstrate that restoration of impaired function of the diabetic macro- and microvasculature may ameliorate a range of cardiovascular disease states and diabetes-associated complications. In this review, we focus on the emerging role of microRNAs (miRNAs), noncoding RNAs that fine-tune target gene expression and signaling pathways, in insulin-responsive tissues and cell types important for maintaining optimal vascular homeostasis and preventing the sequelae of diabetes-induced end organ injury. We highlight current pathophysiological paradigms of miRNAs and their targets involved in regulating the diabetic microvasculature in a range of diabetes-associated complications such as retinopathy, nephropathy, wound healing, and myocardial injury. We provide an update of the potential use of circulating miRNAs diagnostically in type I or type II diabetes. Finally, we discuss emerging delivery platforms for manipulating miRNA expression or function as the next frontier in therapeutic intervention to improve diabetes-associated microvascular dysfunction and its attendant clinical consequences.
Cellular senescence is a stable form of cell cycle arrest in response to various stressors. While it serves as an endogenous pro-resolving mechanism, detrimental effects ensue when it is ...dysregulated. In this review, we introduce recent advances for cellular senescence and inflammaging, the underlying mechanisms for the reduction of nicotinamide adenine dinucleotide in tissues during aging, new knowledge learned from p16 reporter mice, and the development of machine learning algorithms in cellular senescence. We focus on pathobiological insights underlying cellular senescence of the vascular endothelium, a critical interface between blood and all tissues. Common causes and hallmarks of endothelial senescence are highlighted as well as recent advances in endothelial senescence. The regulation of cellular senescence involves multiple mechanistic layers involving chromatin, DNA, RNA, and protein levels. New targets are discussed including the roles of long noncoding RNAs in regulating endothelial cellular senescence. Emerging small molecules are highlighted that have anti-aging or anti-senescence effects in age-related diseases and impact homeostatic control of the vascular endothelium. Lastly, challenges and future directions are discussed including heterogeneity of endothelial cells and endothelial senescence, senescent markers and detection of senescent endothelial cells, evolutionary differences for immune surveillance in mice and humans, and long noncoding RNAs as therapeutic targets in attenuating cellular senescence. Accumulating studies indicate that cellular senescence is reversible. A better understanding of endothelial cellular senescence through lifestyle and pharmacological interventions holds promise to foster a new frontier in the management of cardiovascular disease risk.
Abstract The microRNA family, miR-181, plays diverse roles in regulating key aspects of cellular growth, development, and activation. Accumulating evidence supports a central role for the miR-181 ...family in vascular inflammation by controlling critical signaling pathways, such as downstream NF-κB signaling, and targets relevant to endothelial cell activation and immune cell homeostasis. This review examines the current knowledge of the miR-181 family's role in key cell types that critically control cardiovascular inflammation under pathological and physiological stimuli.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
To investigate whether high-sensitivity cardiac troponin T (hsTnT) correlates to markers of disease activity in inflammatory arthritis (IA), and whether antirheumatic treatment influences hsTnT ...levels.
We assessed 115 patients with active IA (64 rheumatoid arthritis (RA), 31 psoriatic arthritis and 20 ankylosing spondylitis) before and after using methotrexate (MTX) alone or tumor necrosis factor inhibitor (TNFi) with or without MTX co-medication (TNFi±MTX). All patients starting with TNFi had been previously unsuccessfully treated with MTX monotherapy. HsTnT (measured in serum by electro-chemiluminescence immunoassay (Roche Elecsys® Troponin T- high-sensitivity)), and other clinical and laboratory parameters were evaluated at baseline, and after 6 weeks and 6 months of treatment.
Of markers of disease activity, baseline levels of hsTnT positively correlated with Physicians' Global Assessment Score of disease activity in the total patient cohort (p = 0.039). In RA group, hsTnT positively correlated with swollen joints, Disease Activity Score for 28 joints with ESR and serum tumor necrosis factor levels (p = 0.025, p = 0.008, p = 0.01, respectively). Median hsTnT at baseline was 5.0 ng/L, and did not change significantly at 6-week visit (6.0 ng/L, p = 0.37) and 6-month visit (6.0 ng/L, p = 0.18) with either antirheumatic therapy.
HsTnT levels were associated with inflammatory markers for IA disease activity. However, while inflammatory markers significantly improved after antirheumatic treatment, hsTnT did not change during the 6-month follow-up period.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Diabetic wound healing is an incompletely understood pathophysiological state. It comprises a range of potentially devastating and common complications of diabetes mellitus (DM) leading to ...intractable infections, lower extremity amputations, and associated cardiovascular morbidity and mortality. MicroRNAs (miRNAs) have emerged as important regulators in various physiological processes in health and disease through their ability to fine-tune cellular responses. Herein, we summarize the versatile roles of miRNAs implicated in diabetic wound healing in key stages including inflammation, angiogenesis, re-epithelialization, and remodeling. Furthermore, we highlight current evidence through which miRNAs exert control of gene expression and signaling pathways in the reparative response that may provide opportunities for therapeutic intervention for this potentially devastating disease state.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Despite major advances in the primary and secondary prevention of atherosclerosis and its risk factors, atherosclerotic cardiovascular disease remains a major clinical and financial burden on ...individuals and health systems worldwide. In addition, neointima formation and proliferation due to mechanical trauma to the vessel wall during percutaneous coronary interventions can lead to vascular restenosis and limit the longevity and effectiveness of coronary revascularization. Long noncoding RNAs (lncRNAs) have emerged as a novel class of epigenetic regulators with critical roles in the pathogenesis of atherosclerosis and restenosis following vascular injury. Here, we provide an in-depth review of lncRNAs that regulate the development of atherosclerosis or contribute to the pathogenesis of restenosis following mechanical vascular injury. We describe the diverse array of intracellular mechanisms by which lncRNAs exert their regulatory effects. We highlight the utility and challenges of lncRNAs as biomarkers. Finally, we discuss the immense translational potential of lncRNAs and strategies for targeting them therapeutically using oligonucleotide-based therapeutics and novel gene therapy platforms.
Long non-coding RNAs (lncRNAs) are emerging regulators of pathophysiological processes including atherosclerosis. Using RNA-seq profiling of the intima of lesions, here we identify a ...macrophage-specific lncRNA MAARS (Macrophage-Associated Atherosclerosis lncRNA Sequence). Aortic intima expression of MAARS increases by 270-fold with atherosclerotic progression and decreases with regression by 60%. MAARS knockdown reduces atherosclerotic lesion formation by 52% in LDLR
mice, largely independent of effects on lipid profile and inflammation, but rather by decreasing macrophage apoptosis and increasing efferocytosis in the vessel wall. MAARS interacts with HuR/ELAVL1, an RNA-binding protein and important regulator of apoptosis. Overexpression and knockdown studies verified MAARS as a critical regulator of macrophage apoptosis and efferocytosis in vitro, in an HuR-dependent manner. Mechanistically, MAARS knockdown alters HuR cytosolic shuttling, regulating HuR targets such as p53, p27, Caspase-9, and BCL2. These findings establish a mechanism by which a macrophage-specific lncRNA interacting with HuR regulates apoptosis, with implications for a broad range of vascular disease states.
In this review, we focus on the emerging role of microRNAs, non-coding RNAs that regulate gene expression and signaling pathways, in dysfunctional adipose tissue. We highlight current paradigms of ...microRNAs involved in adipose differentiation and function in depots such as white, brown, and beige adipose tissues and potential implications of microRNA dysregulation in human disease such as obesity, inflammation, microvasculature dysfunction, and related cardiovascular diseases. We highlight accumulating studies indicating that adipocyte-derived microRNAs may not only serve as biomarkers of cardiometabolic disease, but also may directly regulate gene expression of other tissues. Finally, we discuss the future prospects, challenges, and emerging strategies for microRNA delivery and targeting for therapeutic applications in cardiovascular disease states associated with adipocyte dysfunction.
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