Discovery of a new gene that stimulates the growth of natural bypasses

World Congress of Cardiology Report - Researchers from the Max-Planck-Institute for Heart and Lung Research (MPI) in Bad Nauheim, Germany, have identified a gene, whose therapeutic use may be beneficial for patients suffering from obstructive arterial diseases.

The work was done in cooperation with scientists from the Academisch Medisch Centrum (AMC) in Amsterdam, The Netherlands, and from the Johann-Wolfgang-Goethe-University in Frankfurt, Germany.

Obstructive arterial diseases are the leading cause of death in industrialized societies. Patients typically suffer from coronary artery diseases leading to myocardial infarctions or peripheral ischemia, which often leads to the loss of limbs. "It is known for centuries that the body tries to compensate for blood flow deficits by the growth of bridging arteries," said Professor Wolfgang Schaper, senior scientist at the MPI and expert in the field. "Because it is somewhat similar to bypass operations, we call them 'natural bypasses'." He added that all previous attempts to stimulate the growth of these collateral arteries were inconclusive: "Clinical studies on the use of growth factors have failed because they did not take account the complexity of the growth process."

Kerstin Troidl, head of this project, who presented the results of the study at the World Congress of Cardiology, organized by the European Society of Cardiology (ESC) in Barcelona, said the breakthrough became possible after they had decided to look closely for the mechanisms. "We knew that specific physical forces represent the initial triggers for this kind of vessel growth. Therefore Professor Thomas Schmitz-Rixen (M.D., Head of the Dept. of endovascular surgery, University of Frankfurt) helped us to adapt our animal model in a way that these forces were chronically and markedly increased."

Using this technique, MPI-scientists found a dramatic enhancement in the growth of collateral vessels. These vessels were then isolated to hunt for genes, which are switched on only under the conditions present in this particular model. "We identified several candidates and overexpressed them locally inside the growing collaterals," Troidl said. "One of them, called ABRA, seems to be the interface between the physical force and the induction of collateral growth."

Data presented during the "science hotline session" in Barcelona, suggests that ABRA can be used to compensate for insufficient physical triggers, which probably limits spontaneous collateral growth in patients. In their experiments in rats and rabbits, she and her colleagues could dramatically enhance the growth of the natural bypasses using a gene therapeutic approach. The researchers at the MPI are convinced that ABRA has a strong potential for an upcoming clinical use. For example, patients may benefit because a novel ABRA-based therapy could significantly improve surgical interventions. Investigators are currently fundraising for advanced studies. Different application routes of the substance will be tested in collaboration with Matthias Heil, MPI. The particular important clinical implication will be promoted in a study in association with the Kerckhoff Heart Center, Bad Nauheim.

Troidl's research of ABRA-based therapy of collateral growth is funded by the DGK (German Society of Cardiology). The co-workers include Inka Eitenmueller, M.D., veterinarian (funded by the "Deutsche Herzstiftung"), Christian Troidl, PhD, post-doctoral fellow at the Max-Planck-Institute in Bad Nauheim, and Anton Hoerevoets, PhD, AMC Amsterdam, the Netherlands.