Cellular stress and cardiovascular diseases

The combined use of research tools of genetics, transcriptomics, epigenetics and metabolomics allowed Duke University scientists working under the guidance of Associate Professor Svati H. Shah to identify a new molecular signaling mechanism involved in the development of myocardial infarction and death from heart disease.

It turned out that the stress effect on the cellular structure, known as the endoplasmic reticulum, is associated with the risk of developing cardiovascular diseases in the future and can be identified by detecting particles of molecular detritus (decay products) circulating in the bloodstream. 

According to Dr. Shah, experts have long known about the existence of a relationship between endoplasmic reticulum stress and a number of diseases, including type 1 diabetes and Parkinson's disease. However, the data obtained indicate for the first time that this mechanism has a certain role in the development of myocardial infarction and death from heart disease. Moreover, the demonstrated ability to assess the stress level of the endoplasmic reticulum by analyzing one drop of blood looks very promising, which indicates the possibility of preventive intervention and reducing the risk of developing major diseases of the cardiovascular system.

Even after the mapping of the human genome was completed and the identification of genetic traits associated with cardiovascular diseases, the underlying mechanisms of inherited predisposition to these diseases were largely unclear. Using a set of methods to analyze more than a million measurement results in 3,700 patients allowed the authors to fill in some of the gaps in the cascade leading to the development of diseases of the cardiovascular system, often of a hereditary nature.

Dr. Shah explains that genetic analysis divides people into groups that have certain characteristics. However, it is obvious that if there are two people with the same sign, while one of them is overweight, smokes and leads an unhealthy lifestyle, cardiovascular disease in the latter will be the result of a completely different mechanism than in a person with a normal body weight, a non-smoker who adheres to a healthy diet and sports.

The researchers devoted their work to the search for intermediates connecting genes and mechanisms underlying the development of diseases. To do this, they used the method of metabolomics – the analysis of metabolites or trace amounts of byproducts of processes occurring in cells contained in the body.

To do this, they conducted a genome-wide analysis of the levels of a complex of specific metabolites in 3,700 patients targeted for cardiac catheterization. In their earlier work, scientists established that these metabolites are prognostic factors for diseases of the cardiovascular system, but they were unable to determine how they are synthesized and what biological mechanisms underlie this. The last work gave an answer to this question, as it turned out that the genes providing the synthesis of these metabolites are directly related to the stress of the endoplasmic reticulum, which develops in cases of excessive load on this organelle trying to cope with excess and damaged cellular proteins.

After that, the authors resorted to epigenetic and transcriptomic approaches to identify differences between patients with high and low levels of metabolites. In this case, the key component was again the mechanism triggered by the stress of the endoplasmic reticulum.

Thus, the use of a multi-platform "-ohm" approach made it possible to identify previously unknown genetic variants associated with the levels of metabolites and the development of diseases of the cardiovascular system. The authors note that they do not consider these metabolites to be the direct cause of myocardial infarction. Most likely, they are by-products of violations of some mechanism to which people have a genetic predisposition. However, this issue needs further study.

Article by William E. Kraus et al. Metabolic Quantitative Trait Loci (mQTL) Mapping Implies the Ubiquitin Proteasome System in Cardiovascular Disease Pathogenesis is published in the journal PLOS Genetics.

Evgeniya Ryabtseva

Portal "Eternal youth" http://vechnayamolodost.ru based on the materials of Duke University Medical Center: Cellular stress process identified in cardiovascular disease.