Cardiovascular diseases represent the first cause of death in the world. Thus, research into this type of pathology is essential, not only because of the individual and family consequences that it entails, but also because of the economic burden that it places on the health system.
And among the numerous ailments associated with heart malfunction, one of the most frequent are electrical disorders or arrhythmias. Approximately 25% of the 17 million deaths each year from sudden cardiac death are attributed to arrhythmias.
Its origin is still unknown, but today we know that its severity varies depending on the involvement of the conduction system -the pacemaker of the heart – and the disorganization of the contractile fibers of cardiac cells. Because the rhythmic rhythm of our heartbeats depends on a sophisticated biological machinery that can easily go awry.
In mammalian embryos, as has been studied in mice, the heart begins to pump very early, since the simple physical diffusion of oxygen and metabolic energy to the tissues is not sufficient to nourish them. Therefore, this organ begins to form on the eighth day of gestation.
As embryonic development progresses, the heart increases in complexity. In fact, it is made up of numerous cell populations with different functions, which act simultaneously to maintain homeostasis or physiological balance.
Since the heart has to beat synchronously, any genetic or structural imbalance can trigger severe pathologies, leading to heart failure in the most extreme cases.
Don’t stop the rhythm
This constant rhythmic pumping movement is produced by highly specialized contractile cardiomyocytes or cardiac cells. The contraction is mainly due to the fact that they present a set of filamentous proteins, the myofilaments, organized into units called sarcomeres.
Cardiac sarcomeres are structurally identical to those of the other type of skeletal muscle, the skeletal muscle – which we simply call “muscle” – although the proteins that compose them are encoded by different genes.
These proteins interact with each other forming cross-bridges that allow cardiac cells to shorten and, as a consequence, propel blood from the atria to the ventricles and from these to the rest of the body.
To do this, the cardiomyocytes must receive an electrical stimulus (as happens in the neurons of the brain) that activates them in unison to achieve a complete contraction of each chamber of the heart. In skeletal fibers, by contrast, contraction through their myofilaments is voluntary. Due to these different functions of cardiac and skeletal muscles, the proteins expressed in one tissue or another are different.
This is of vital importance, since each myofilament has its own characteristics and response times to a stimulus, making cardiac and skeletal contraction extremely different. And the confusion between the two, as we will see, has fatal consequences.
The protein that maintains the double personality
A few years ago, we described that the chromatin remodeling protein Chd4 – a component of the NuRD multiprotein complex – plays a central role in maintaining the identity of both muscle tissues.
Thus, when Chd4 is knocked out in mouse hearts, aberrant expression of proteins from skeletal sarcomeres occurs, giving rise to a myocardium hybrid; while if it is removed in skeletal muscle, this tissue expresses cardiac proteins that prevent it from contracting properly.
This is disastrous for the animals, which suffer from malignant arrhythmias, dilated cardiomyopathies, fibrosis, and eventually heart failure and sudden death.
Since the Chd4 protein allows the heart and skeletal muscle to maintain the proper myofibrils and sarcomeres, some mutations in the gene that encodes it induce neurological and cardiac congenital malformations. This corroborates the importance of Chd4 in the regulation of cardiac cells to maintain the balance of the adult heart and during embryonic development.
A well matched couple
But Nhd4 had to have help in this complex task. To find out, we did a series of experiments looking at the hearts of wild mice. This led us to discover several proteins that physically interacted with Chd4 within cardiomyocytes; among them, Znf219, called “zinc fingers” due to its molecular structure.
To delve into the study of the Znf219-Chd4 molecular axis, we reduced the expression of the first to see what happened. in vitro, decreased Znf219 presence in cardiomyocytes cultured in a petri dish resulted in aberrant expression of skeletal muscle sarcomere genes and the proteins these genes encode. This is the same as what we had seen before in mice with Chd4-depleted hearts.
In addition, we corroborate these data by reducing Znf219 in the hearts of newborn mice and studying it at four weeks of life. The myocardia of these pups also abnormally expressed skeletal muscle sarcomeric genes, leading to cardiac arrhythmias, fibrosis, and cardiac hypertrophy.
From our work it can be concluded that the joint molecular and genetic action of Znf219 and Chd4 in cardiac muscle cells is very important for maintaining heart identity. And that any alteration in the expression of these proteins, or mutations in their genes, can lead to the development of cardiac arrhythmias.
This study opens up new expectations in the study of human cardiac arrhythmias at a basic level, but with possible implications in their diagnosis and in the study of new therapies for those conditions in which the described molecular pathways are involved.