Advance in preventing restenosis

José Pichel Andrés/DICYT One of the most popular cardiovascular problems is atherosclerosis, which consists in the obstruction of the passage of blood through arteries by the formation of an atheroma plaque because of cholesterol excess and other substances, which may cause cardiac arrests and cerebrovascular problems. A common solution is to place a stent, a tube that presses the atheroma plaque against the blood vessel and doing so restores the blood flow. Though, after this operation usually occurs a restenosis, a new obstruction in the same place due to the proliferation of cells in the smooth musculature of blood vessels’ inner layers.

An article published by German scientists in the electronic issue of Nature, April 20th, suggests a new way of addressing this problem, since it proposes a mechanism which could prevent the proliferation of the aforementioned cells. The researchers have counted on Juan Pedro Bolaños, researcher of the Functional and Genomics Biology Institute (IBFG, a mix of CSIC and the University of Salamanca). “The restenosis is an immune response as a consequence of surgical manipulation or because of the presence of the stent and we are facing a big challenge for the research, because it is the first cause of death in the United States”, declares the IBFG scientist in interview to DiCYT.

Until now, the only solution has been to add to the stent a medicine which inhibits the proliferation of cells, in a way that it reduces partially the effect of this hyperplasia, but it does not solve the problem entirely. That is why the German surgeon Tobias Deuse, who leads the research along with Sonja Schrepfer, both of University Heart Center Hamburg, have begun to study the mechanisms by which the cells proliferate quickly until it blocks the artery again from one to four weeks after the stent has been placed.

Using experimental animals in which they have implanted sections of human arteries, the German researchers have discovered two important phenomena in the smooth musculature cells, which are injured because of the placement of the stent: the mitochondrial hyperpolarization and the resistance to apoptosis (the suicide of cells which have some abnormality), two characteristic phenomena of tumor cells which proliferate uncontrolled.

In this stage of research, they have turned to dichloroacetic acid (DCA), a synthetic molecule which prevents the increase of cell proliferation and it is used in some trials against cancer, although it is not used in clinical practice because it generates certain secondary problems in high doses and chronic treatments.

However, in this case, there is an important difference related to cancer, since the smooth musculature’s proliferation of cells only occurs until the fourth week, in a way that the treatment is transitory, reducing no wanted effects.

In this moment, the coordinators of the study have made contact with Juan Pedro Bolaños, expert in mitochondrial function, with the objective of trying to understand the molecular mechanisms of the problem as well as the mechanisms of a possible solution in the treatment with DCA.

The molecular mechanism

This way, the study has revealed that the DCA inhibits an enzyme called piruvato deshidrogenasa quinasa 2 (PDK2), which inhibits another enzyme, piruvato deshidrogenasa (PDH), which benefits the apoptosis or programmed death of cells. “If you inhibit an enzyme which is inhibiting another one, the effect obtained is a stimulation of the last one”, explains Bolaños, an essential aspect of this researcher. Therefore, using DCA allows the restoration of apoptosis and, consequently, avoiding the proliferation of vascular cells which would block the artery again.

A very important aspect is that this DCA action does not prevent the natural proliferation of cells. “This medicine would only affect the cells which proliferate in excess because of a PDK2 increase, so it would allow the recovery of normal cells, which is necessary and physiological”, comments the IBFG researcher.

Bibliography

Tobias Deuse, Xiaoqin Hua, Dong Wang, Lars Maegdefessel, Joerg Heeren, Ludger Scheja, Juan P. Bolaños, Aleksandar Rakovic, Joshua M. Spin, Mandy Stubbendorff, Fumiaki Ikeno, Florian Länger, Tanja Zeller, Leonie Schulte-Uentrop, Andrea Stoehr, Ryo Itagaki, Francois Haddad, Thomas Eschenhagen, Stefan Blankenberg, Rainer Kiefmann,Hermann Reichenspurner, Joachim Velden, Christine Klein, Alan Yeung, Robert C. Robbins & Sonja Schrepfer. Dichloroacetate prevents restenosis in preclinical animal models of vessel injury. Nature, 2014. doi: 10.1038/nature13232