Projects / Programmes
Role of cholesterol in cardiac development and function
| Code |
Science |
Field |
Subfield |
| 3.06.00 |
Medical sciences |
Cardiovascular system |
|
| Code |
Science |
Field |
| B007 |
Biomedical sciences |
Medicine (human and vertebrates) |
| Code |
Science |
Field |
| 3.02 |
Medical and Health Sciences |
Clinical medicine |
cholesterol, cardiovascular diseases, cardiomyocytes, genetic factors
Researchers (1)
| no. |
Code |
Name and surname |
Research area |
Role |
Period |
No. of publicationsNo. of publications |
| 1. |
22459 |
PhD Tadeja Režen |
Neurobiology |
Head |
2013 - 2015 |
235 |
Organisations (1)
Abstract
Cardiovascular diseases encompass diseases of vasculature, myocardium and also congenital heart diseases. They have been the number one cause of death for several decades and are the leading world health problem. Role of diet and life style in development of these diseases has been well accepted. However, role of the genetic background is gaining more and more acknowledgment. Studies predict that genetic factors could contribute from 40% up to 60% to the disease development. Genome-wide association studies have so far highlighted over 100 loci determining known risk factors like blood pressure, level of plasma lipids, etc. However, we are still far from understanding how these loci affect development of cardiovascular diseases. Analyses of functional consequences of these polymorphisms are therefore necessary.
Cholesterol is essential for normal development and function of cardiovascular system. Defects in cholesterol biosynthesis genes result in either embryonic lethality or in development of congenital heart malformations. Little is known about the role of cholesterol in cardiac development and function, therefore; some fundamental studies have to be first made in animal models in order to translate them to humans. The proposed postdoctoral project will use a unique mouse model of cholesterol biosynthesis defect. The question is: is one functional allele of cholesterol biosynthesis gene enough for normal embryonic development and later cardiac function. Or does it lead to development of a ‘silent’ phenotype which expresses later in life or under certain circumstances (diet, stress). Preliminary results in mice already show differences between genders in management of cholesterol and this will be in special focus of the project. Next we will perform experiments in isolated cardiomyocytes that will study the role of cholesterol in adaptation to stress and further elucidate the regulation and management of cholesterol in the heart.
Aim of the postdoctoral project is to evaluate the effects of cholesterol on cardiac development and function. Specific aims of the project are: (1) To define potential defects in cardiac function in Cyp51a1 heterozygous mouse under normal and stress conditions (diet); (2) In vitro studies of regulation of cholesterol homeostasis in myocardium and discovery of regulatory network and key proteins; (3) In vitro studies of role of cholesterol in adaptation to stress (hypoxia).
We expect to confirm that cardiomyocytes have low cholesterol biosynthesis and are solely dependent on outside source of cholesterol. We expect that the lack of liver cholesterol biosynthesis and no dietary cholesterol intake will have detrimental effect on the heart. We also expect to confirm that cardiomyocytes are more prone to hypoxia-induced damage in conditions of low cholesterol.
The experiments will enable us to select key genes in regulation and management of cholesterol homeostasis and tolerance to stress in the heart. These genes and their polymorphisms will be analysed using modern bioinformatical tools to evaluate their role in development of cardiovascular diseases. Moreover, elucidating the role of cholesterol in adaptation to stress will open new possibilities in drug discovery and methods developed within the project will be used for testing of novel cardioprotective molecules.
Significance for science
The main objective of the postdoctoral project was to understand how cholesterol is regulated in the heart and how changes in cholesterol level affect the development and function of cardiomyocytes. So far few studies have been done on effects of cholesterol and lipoproteins in the heart. Using a unique mouse model with a defect in the biosynthesis of cholesterol and isolated cardiomyocytes we studied how the heart adjusts to increased and decreased cholesterol and how it affects the development of cell damage induced by the endoplasmic reticulum stress. Using a mouse model we have studied if an impaired cholesterol biosynthesis during embryonic development resulted in congenital heart disease or in defects, which could be expressed later under stress, e.g. a diet rich in lipids and cholesterol. All results obtained during the project have enabled us to assess how much can genetic defects in studied genes add to development of cardiovascular diseases. A special discovery was a protective role of lipoprotein VLDL from starvation and endoplasmic reticulum stress, which has not yet been described in the literature, and throws new light on lipoprotein biology. Lipoproteins are attractive targets for the development of new drugs to prevent and treat cardiovascular disease. A number of drugs that affected the level of lipoproteins in the blood have been unsuccessful in preventing diseases and show that there are still significant gaps in the knowledge of lipoprotein biology.
Significance for the country
The project has made a significant contribution to the understanding of the mechanisms leading to the development of cardiovascular diseases. The project has enabled postdoctoral researcher to train in internationally acclaimed group in the field of cardiology, laboratory of dr. Mauro Giacca on the ICGEB in Italy. The project has further enhanced cooperation between a group of dr. Giacca at ICGEB and programme group P1-0390 (Functional Genomics and Biotechnology for Health), whose leader is Prof. Radovan Komel. An undergraduate thesis was completed within project. The project has enabled new insights into the biological role of lipoproteins, which are required for the development of new drugs for the treatment and prevention of cardiovascular diseases. Awareness of the role of genetic background in the development of cardiovascular diseases is growing in scientific and general public. Modern techniques using next-generation sequencing of human genomes and genome-wide association studies have already enabled a big step forward in the understanding the role of the genetic factors. However, scientists acknowledge that merely identifying polymorphisms that increase or decrease the risk of developing cardiovascular disease, is not enough (a review by Kathiresan S. and Srivastava D. in Cell, March 2012). Further steps, which will lead to an understanding of how mutations in genes affect the development of cardiovascular diseases, are necessary. The results of this project will contribute a piece of the puzzle to understand the role of genes involved in the maintenance of cholesterol level and in the development of heart diseases.
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