RNA targets in cardiac disease

Abstract

The heart has one task: circulating blood throughout our bodies. An adequate circulation is essential for making sure all parts of our bodies receive enough oxygen and nutrients. This, in turn, is required for our health and feeling of well-being. Despite the importance of a healthy heart, the heart has no mechanism to repair itself after being damaged. Even worse, a damaged heart will slowly degrade further over time and cardiovascular disease is the leading cause of death worldwide. In this thesis, I describe the results of my PhD research. These results contribute to developing novel ways to treat heart patients. My first experimental chapter, chapter 2, describes our research on an experimental type of drug. This drug influences protein production by targetting the blueprints (RNAs) for the production of proteins. We show that the effects of such drugs are dependent on the type and severity of the heart disease. In the next study, described in chapter 3, we investigated how the type of drugs studied in chapter 2 can be delivered to the heart. Because of blood flow, injecting the drug into the heart directly will probably result in very quick washout of the drug. To prevent this, we injected the drug into the muscle tissue of the heart using a solution that forms a gel after injection. We show that this manner of injection is safe and results in a slightly stronger local effect of the drug. However, we cannot prove that delivering the drug in gel leads to improved cardiac repair in injured hearts. In order to develop novel drugs that are based on RNA-targeting, it is essential to know the RNA composition of cells within a diseased heart. In the fourth chapter, we studied the RNA composition of heart cells from patients with a hereditary cardiac disease. Our comprehensive dataset, linking cell size and gene expression, will enable future researchers to identify new RNAs that can be targeted to improve heart function.