Long non-coding RNA in vascular disease and aging

Cardiovascular diseases are the most prominent cause of death in Western society, especially in the elderly. With the increasing life expectancy, the number of patients with cardiovascular diseases will rise in the near future, leading to an increased healthcare burden. There is a need for new therapies to treat this growing number of patients. The discovery of long non-coding RNAs has led to a novel group of molecules that could be considered for their potential as therapeutic targets. This review presents an overview of long non-coding RNAs that are regulated in vascular disease and aging and which might therefore give insight into new pathways that could be targeted to diagnose, prevent, and/or treat vascular diseases

Long Non-Coding RNA in Vascular Disease and Aging

Cardiovascular diseases are the most prominent cause of death in Western society, especially in the elderly. With the increasing life expectancy, the number of patients with cardiovascular diseases will rise in the near future, leading to an increased healthcare burden. There is a need for new therapies to treat this growing number of patients. The discovery of long non-coding RNAs has led to a novel group of molecules that could be considered for their potential as therapeutic targets. This review presents an overview of long non-coding RNAs that are regulated in vascular disease and aging and which might therefore give insight into new pathways that could be targeted to diagnose, prevent, and/or treat vascular diseases

Long noncoding RNA in cardiac aging and disease

Cardiovascular diseases (CVDs) are the main cause of morbidity and mortality in Western society and present an important age-related risk. With the constant rise in life expectancy, prevalence of CVD in the population will likely increase further. New therapies, especially in the elderly, are needed to combat CVD. This review is focused on the role of long noncoding RNA (lncRNA) in CVD. RNA sequencing experiments in the past decade showed that most RNA does not code for protein, but many RNAs function as ncRNA. Here, we summarize the recent findings of lncRNA regulation in the diseased heart. The potential use of these RNAs as biomarkers of cardiac disease prediction is also discussed

Endothelial microRNAs and long noncoding RNAs in cardiovascular ageing

Atherosclerosis and numerous other cardiovascular diseases develop in an age-dependent manner. The endothelial cells that line the vessel walls play an important role in the development of atherosclerosis. Non-coding RNA like microRNAs and long non-coding RNAs are known to play an important role in endothelial function and are implicated in the disease progression. Here, we summarize several microRNAs and long non-coding RNAs that are known to have an altered expression with endothelial aging and discuss their role in endothelial cell function and senescence. These processes contribute to aging-induced atherosclerosis development and by targeting the non-coding RNAs controlling endothelial cell function and senescence, atherosclerosis can potentially be attenuated

Mouse models to study the effect of cardiovascular risk factors on brain structure and cognition

Recent clinical data indicates that hemodynamic changes caused by cardiovascular diseases such as atherosclerosis, heart failure, and hypertension affect cognition. Yet, the underlying mechanisms of the resulting vascular cognitive impairment (VCI) are poorly understood. One reason for the lack of mechanistic insights in VCI is that research in dementia primarily focused on Alzheimer's disease models. To fill in this gap, we critically reviewed the published data and various models of VCI. Typical findings in VCI include reduced cerebral perfusion, blood-brain barrier alterations, white matter lesions, and cognitive deficits, which have also been reported in different cardiovascular mouse models. However, the tests performed are incomplete and differ between models, hampering a direct comparison between models and studies. Nevertheless, from the currently available data we conclude that a few existing surgical animal models show the key features of vascular cognitive decline, with the bilateral common carotid artery stenosis hypoperfusion mouse model as the most promising model. The transverse aortic constriction and myocardial infarction models may be good alternatives, but these models are as yet less characterized regarding the possible cerebral changes. Mixed models could be used to study the combined effects of different cardiovascular diseases on the deterioration of cognition during agin

The PNUTS-PP1 axis regulates endothelial aging and barrier function via SEMA3B suppression

Age-related diseases pose great challenges to health care systems worldwide. During aging, endothelial senescence increases the risk for cardiovascular disease. Recently, it was described that Phosphatase 1 Nuclear Targeting Subunit (PNUTS) has a central role in cardiomyocyte aging and homeostasis. Here, we determined the role of PNUTS in endothelial cell aging. We confirmed that PNUTS is repressed in senescent endothelial cells (ECs). Moreover, PNUTS silencing elicits several of the hallmarks of endothelial aging: senescence, reduced angiogenesis and loss of barrier function. To validate our findings in vivo, we generated an endothelial-specific inducible PNUTS-deficient mouse line (Cdh5-CreERT2;PNUTSfl/fl), termed PNUTSEC-KO. Two weeks after PNUTS deletion, PNUTSEC-KO mice presented severe multiorgan failure and vascular leakage. We showed that the PNUTS binding motif for protein phosphatase 1 (PP1) is essential to maintain endothelial barrier function. Transcriptomic analysis of PNUTS-silenced HUVECs and lungs of PNUTSEC-KO mice revealed that the PNUTS-PP1 axis tightly regulates the expression of semaphorin 3B (SEMA3B). Indeed, silencing of SEMA3B completely restored barrier function after PNUTS loss-of-function. These results reveal a pivotal role for PNUTS in endothelial homeostasis through a PP1-SEMA3B downstream pathway that provides a potential target against the effects of aging in ECs

Food restriction does not relieve PTSD-like anxiety

We used the inescapable foot shock paradigm (IFS) in rats as an animal model for post-traumatic stress disorder (PTSD). Previously we showed that exercise reversed the enhanced stress sensitivity induced by IFS. From literature it is known that food restriction has antidepressant and anxiolytic effects. Since both treatments influence energy expenditure, we questioned whether food restriction reduces anxiety in the IFS model via a comparable, NPY dependent mechanism as enrichment. Anxiety of IFS-exposed animals was measured as change in locomotion and freezing after sudden silence in an open field test, before and after two weeks of food restriction. In addition a forced swim test (FST) was performed. Next, using qPCR, the expression of neuropeptide Y (NPY) and the neuropeptide Y1 receptor (Y1 receptor) was measured in the amygdala. Food restriction increased locomotion and decreased freezing behavior both in control and IFS animals. These effects were small. IFS-induced anxiety was not abolished after two weeks of food restriction. IFS did not influence immobility or the duration of swimming in the FST of animals fed ad libitum. However, food restriction increased swimming and decreased the duration of immobility in IFS-exposed animals. Y1 receptor expression in the basolateral amygdala decreased after both IFS and food restriction. Although food restriction seems to induce a general anxiolytic effect, it does not operate via enhanced Y1 receptor expression and has no effect on the more pathogenic anxiety induced by IFS

MRI data part 2

Contains Bruker scan data (including localizer scans) as 2dseq files and can be easily read with Bruker ParaVision software. On request, data can be converted to Nifti/Dicom

MRI data part 1

Contains Bruker scan data (including localizer scans) as 2dseq files and can be easily read with Bruker ParaVision software. On request, data can be converted to Nifti/Dicom

Template and brain volumes

This zip file contains the following information: mouse brain template, brain ROIs, registration settings and the processed data. Each mouse brain was registered to a template mouse brain and volumes (whole brain + 22 structures) were extracted using the ROIs. Volumes are stored [per structure per mouse] and volumes are stored [per structure per strain]