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The role of lncRNAs in the CVS and the endothelium is highly diverse and has been subject to a substantial amount of research over the last decade. The identification of lncRNAs as clinically relevant biomarkers and as co-regulatory molecules let to the appreciation of the functional relevance of lncRNAs.
In the present study, LINC00607 was identified as an endothelial-enriched, human-specific lncRNA. With its distinct functions, LINC00607 maintains and supports the endothelial homeostasis especially in response to VEGF-A signalling.
In the first part of this study, LINC00607 was functionally characterized in human endothelial cells. LINC00607 is highly and specifically expressed in endothelial cells and is differentially regulated in CVDs. Depletion of LINC00607 resulted in decreased angiogenic sprouting, reduced integration of ECs in a newly formed vascular network in vivo, enhanced endothelial migration and differential expression of many important genes for endothelial cell homeostasis. Functionally, LINC00607 maintains ERG-driven endothelial gene expression programs through BRG1. BRG1 secures stably accessible enhancer regions as well as TSS of ERG target genes, thus enabling transcription of endothelial gene programs.
The second part of this study proposes an additional mode of action for LINC00607. The strongly impaired response to VEGF-A after LINC00607 KO can only be partially explained by its’ expression control of ERG target genes. It rather appears that LINC00607 is involved in the control of alternative splicing of VEGF receptor FLT1. The differential splicing of FLT1 produces the anti-angiogenic soluble isoform of FLT1. Even though further validation is needed to uncover the underlying mechanism, there is the potential of a more general role of LINC00607 in splicing control through BRG1. As AS of FLT1 is a clinical marker in preeclampsia, LINC00607 might qualify to be an additional marker for the onset and manifestation of the pregnancy disorder.
Taken together, LINC00607 is a target in future for molecular therapy in CVD to restore a healthy endothelial phenotype and has the potential to serve as a biomarker in preeclampsia.
Background & Aims: Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) are increasingly a cause of cirrhosis and hepatocellular carcinoma globally. This burden is expected to increase as epidemics of obesity, diabetes and metabolic syndrome continue to grow. The goal of this analysis was to use a Markov model to forecast NAFLD disease burden using currently available data.
Methods: A model was used to estimate NAFLD and NASH disease progression in eight countries based on data for adult prevalence of obesity and type 2 diabetes mellitus (DM). Published estimates and expert consensus were used to build and validate the model projections.
Results: If obesity and DM level off in the future, we project a modest growth in total NAFLD cases (0–30%), between 2016–2030, with the highest growth in China as a result of urbanization and the lowest growth in Japan as a result of a shrinking population. However, at the same time, NASH prevalence will increase 15–56%, while liver mortality and advanced liver disease will more than double as a result of an aging/increasing population.
Conclusions: NAFLD and NASH represent a large and growing public health problem and efforts to understand this epidemic and to mitigate the disease burden are needed. If obesity and DM continue to increase at current and historical rates, both NAFLD and NASH prevalence are expected to increase. Since both are reversible, public health campaigns to increase awareness and diagnosis, and to promote diet and exercise can help manage the growth in future disease burden.
Lay summary: Non-alcoholic fatty liver disease and non-alcoholic steatohepatitis can lead to advanced liver disease. Both conditions are becoming increasingly prevalent as the epidemics of obesity and diabetes continue to increase. A mathematical model was built to understand how the disease burden associated with non-alcoholic fatty liver disease and non-alcoholic steatohepatitis will change over time. Results suggest increasing cases of advanced liver disease and liver-related mortality in the coming years.
Recent advances in basic cardiovascular research as well as their translation into the clinical situation were the focus at the last "New Frontiers in Cardiovascular Research meeting". Major topics included the characterization of new targets and procedures in cardioprotection, deciphering new players and inflammatory mechanisms in ischemic heart disease as well as uncovering microRNAs and other biomarkers as versatile and possibly causal factors in cardiovascular pathogenesis. Although a number of pathological situations such as ischemia-reperfusion injury or atherosclerosis can be simulated and manipulated in diverse animal models, also to challenge new drugs for intervention, patient studies are the ultimate litmus test to obtain unequivocal information about the validity of biomedical concepts and their application in the clinics. Thus, the open and bidirectional exchange between bench and bedside is crucial to advance the field of ischemic heart disease with a particular emphasis of understanding long-lasting approaches in cardioprotection.
In this meeting report, particularly addressing the topic of protection of the cardiovascular system from ischemia/reperfusion injury, highlights are presented that relate to conditioning strategies of the heart with respect to molecular mechanisms and outcome in patients’ cohorts, the influence of co-morbidities and medications, as well as the contribution of innate immune reactions in cardioprotection. Moreover, developmental or systems biology approaches bear great potential in systematically uncovering unexpected components involved in ischemia–reperfusion injury or heart regeneration. Based on the characterization of particular platelet integrins, mitochondrial redox-linked proteins, or lipid-diol compounds in cardiovascular diseases, their targeting by newly developed theranostics and technologies opens new avenues for diagnosis and therapy of myocardial infarction to improve the patients’ outcome.