Human heart anatomy
Scientists have created a cellular and molecular map of the healthy human heart, to understand how this vital organ functions, and to shed light on what goes wrong in cardiovascular disease.
A study published in Nature today has mapped the structure and function of the heart, using a technique called cryo-electron microscopy (cryo-EM).
The researchers, led by researchers at the University of Edinburgh, found that the healthy heart consists of a dense network of myocardial capillaries that act as a ‘smart’ ‘internal transport system’ to distribute oxygen and nutrients around the heart.
In contrast, the damaged heart has more spindly myocardial capillaries that do not transport as much oxygen around the heart.
The team of scientists found that a new drug called plerixafor could reverse the progression of heart failure in mouse models of the disease by improving the flow of oxygen and nutrients around the heart.
This drug is already in clinical trials for other heart conditions and it has been tested in the laboratory for the first time.
Plerixafor, which is a drug for gout, has been found to increase the number of oxygen-carrying capillaries in the heart.
The drug is designed to activate an enzyme called HO-1, which is involved in regulating the blood flow around the heart.
However, until now, no one knew exactly how this enzyme works in the heart.
The researchers were able to identify the molecular mechanism by comparing the structure of the normal heart with the diseased heart.
They found that the structure of the diseased heart has more spindly capillaries, and the ratio of HO-1 to HO-3 is reduced.
The researchers also found that the expression of the HO-1 gene is increased in the diseased heart, and this gene regulates the movement of oxygen and nutrients in and out of the capillaries.
The study is part of the Scotland-France Health Programme and is funded by the French Ministry of Health.
Dr Javier Caceres, of the University of Edinburgh’s Medical Research Council Centre for Regenerative Medicine, said: “This is the first time that we have been able to use cryo-EM to visualise the heart in detail.
“The study shows that the diseased heart has a dense network of capillaries that carry oxygen and nutrients around the heart, but the normal heart has a sparser network.
“This means that the oxygen and nutrients are transported more efficiently in the normal heart.
“We also found that the enzyme HO-1, which is known to regulate blood flow, is upregulated in the diseased heart, and that this gene is upregulated in the blood vessels that supply the heart muscle.
“This suggests that the normal heart has a blood vessel system that works well, and that the diseased heart’s blood vessel system is poorly functioning.”
Dr Jeremy Pearson, Associate Medical Director at the British Heart Foundation, which part-funded the study, said: “This is an exciting advance in the field of heart disease.
“This technique is providing scientists with a more detailed understanding of how the heart works, and a way to potentially improve the function of the heart.
“It will be interesting to see if this drug is able to reverse the progress of heart failure in patients, as we know that there are currently no treatments available for this condition.”
To learn more about the role of a particular protein in the development of heart disease, scientists at University of Maryland School of Medicine (UMSOM) used a novel method of genetic engineering that enables the simultaneous study of a protein and its protein-coding gene in living cells.
The study, published in Nature Structural & Molecular Biology, provides a roadmap for the development of therapeutic strategies for heart disease and other major cardiovascular diseases.
“The key to our method is to genetically engineer the gene that encodes the heart protein beta-catenin and its protein-coding gene in a living cell,” says Jeffrey Cummings, MD, the Michelson Professor of Biochemistry and Molecular Genetics at UMSOM, and senior author of the study. “This allows us to monitor the activity of the gene, which tells us the level of expression of the protein. In this way, we can study the role of the protein in the heart and other organs.”
In the study, the scientists first used this genetic engineering technique to selectively inactivate the gene encoding beta-catenin in the heart of the zebrafish, a small, transparent fish. They then used other techniques to observe the effects of inactivation on the gene’s protein, which was originally encoded by the gene.
The scientists observed that the heart protein beta-catenin and its protein-coding gene were expressed at levels higher than those in the zebrafish’s muscle cells, and this protein had the ability to modify gene expression.
The heart protein beta-catenin has previously been linked to heart disease. To further understand the role of this protein in heart disease, the researchers examined gene expression in human heart cells. They found that a mutated form of beta-catenin had the ability to inhibit a gene that produces an enzyme called phospholipase C, which is necessary for heart muscle contraction. The heart muscle cells with this mutated form of beta-catenin also showed a greater number of tiny channels in their cell membranes, which allowed blood to flow into the heart.
“We now know that the heart protein beta-catenin can regulate the expression of other genes in the heart and other organs, and that it can inhibit certain enzymes,” says Dr. Cummings. “This is a significant finding because it means that we can potentially use drugs to block the activity of the heart protein beta-catenin and the phospholipase C enzyme to prevent heart disease and other diseases.”
This study is the first to show that the heart protein beta-catenin is a regulatory protein that modulates the expression of genes. It also provides a framework for future studies to investigate how this protein interacts with other genes and how these interactions may be disrupted to promote heart disease and other diseases.