Enhancing Angiogenesis in Mice by VEGF-Targeting Small Activating RNAs
The prevalence of cardiovascular diseases is steadily increasing, and it is the leading cause of death worldwide. Therefore, new treatments, such as gene therapy are needed. During the last decade, the role of small noncoding RNAs (ncRNAs) in the regulati
- PDF / 329,033 Bytes
- 11 Pages / 439.37 x 666.142 pts Page_size
- 23 Downloads / 184 Views
Enhancing Angiogenesis in Mice by VEGFTargeting Small Activating RNAs Tiia A. Turunen, Seppo Yla¨-Herttuala, and Mikko P. Turunen
Abstract The prevalence of cardiovascular diseases is steadily increasing, and it is the leading cause of death worldwide. Therefore, new treatments, such as gene therapy are needed. During the last decade, the role of small noncoding RNAs (ncRNAs) in the regulation of gene expression at the transcriptional level has been shown. Promoter-targeted small RNAs recruit histone-modifying enzymes and can either repress or induce target gene expression. As an example, we have targeted mouse VEGF-A promoter with small hairpin RNAs (shRNAs) and identified two shRNAs which either repressed or induced VEGF-A expression on messenger RNA and protein level in vitro, depending on the targeted location. The changes in expression levels correlate with changes in the levels of epigenetic markers, such as histone modifications associated with repressed or active state of chromatin. In ischemic mouse hindlimbs, upregulation of VEGF-A expression increased vascularity and blood flow. When VEGF-A was upregulated in mouse myocardial infarction model, the blood vessel formation in the risk zone was observed and infarct size was significantly decreased already 2 weeks after treatment. We suggest that epigenetic upregulation of VEGF-A by ncRNAs can be transferred to clinical use for the treatment of ischemic diseases in the near future. Keywords VEGF-A • Angiogenesis • Lentiviral vectors • Gene therapy • Animal models
14.1
Introduction
14.1.1 Cardiovascular Disease Cardiovascular diseases (CVD) are the leading cause of death worldwide. An estimated 17.5 million people died from CVD in 2012, representing 31% of all global deaths according to the WHO. Clinically, the outcome of the disease is often
T.A. Turunen • S. Yla¨-Herttuala • M.P. Turunen (*) A.I.Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland e-mail: [email protected] © Springer Nature Singapore Pte Ltd. 2017 L.-C. Li (ed.), RNA Activation, Advances in Experimental Medicine and Biology 983, DOI 10.1007/978-981-10-4310-9_14
195
196
T.A. Turunen et al.
myocardial infarction, stroke, or peripheral vascular disease, all of which are influenced by atherosclerosis where arteries are narrowed by plaques and therefore the blood flow to the tissue is reduced [38]. This restricted blood flow results in problems in the transport of nutrients and oxygen to the tissue and ultimately leads to the formation of ischemic areas. Plaque formation is a slow process that develops throughout the lifespan. Plaque rupture leads to blood clots that block blood vessels either in the heart, initiating myocardial infarction, or elsewhere in the circulatory system, such as in the brain or in the legs. Currently, the most common operative treatments for CVD are bypass surgery that aims to replace the occluded blood vessels and thus restore the blood flow in the ischemic area, and the insertion of drug-eluting stents, that in the occl
Data Loading...
