The Heart Attack Research Team

  The HeART-Team

Cardiovascular diseases are the leading cause of death worldwide. Despite undeniable achievements of modern medicine, many millions people are chronically ill and one of two dies due to a disease of the cardiovascular system. Therefore, the study of the underlying mechanisms of these diseases and finding new therapeutic methods for treating them is of great importance for the scientific community.

Due to the modern predominance of sedentary, yet stressful lifestyles, atherosclerosis, the deterioration of arterial walls as a result of the accumulation of cholesterol, is the most common disease afflicting humans worldwide. This accumulation of cholesterol is followed by a severe thickening and other changes in vessel morphology, including narrowing of the vessel lumen. In this context, the high shear stress that develops in the narrowing arteries can cause the luminal endothelium to rupture and release its lipid content into the vessels, which in turn determines the local accumulation of thrombotic material and obstruction of blood flow. In the case of coronary arteries, which do not develop collaterals, the acute reduction in blood flow cannot be properly compensated. Given the greater oxygen demands of the myocardium, this means that even a short interruption to blood flow here can have serious consequences. Damaged cardiac tissue is replaced by granulation tissue that later matures into a scar, which in turn induces global changes in heart architecture with progressive dilatation and, ultimately, development of heart failure. Therefore, beyond acute mortality, myocardial infarction results in subsequent complications that reduce patients’ quality of life.

  The HeART-Team The HeART-Team

Because the molecular mechanisms are poorly understood, it is difficult to develop new therapeutic strategies. However, it seems that the chemokines play an important role in initiating and controlling events at the molecular level during pathologic processes. Therefore our group has a special focus on studying their role in cardiovascular diseases, in order to sustain the development of novel therapeutical strategies to treat atherosclerosis and myocardial infarction.

Although there are reports on the negative effects of ERL motif contained CXC chemokines on the neointima formation, our work demonstrates the protective role of CXC chemokines CXCL1 (KC mouse or human Growth-Related Oncogene GRO) by accelerating re-endothelialization after vessel injury. Yet, after myocardial infarction, it failed to be involved in the neutrophil recruitment or angiogenesis. Also CCL5 or RANTES and its receptors CCR1 and CCR5 showed different functions in the induction and progression of atherosclerotic plaques and the healing after myocardial infarction. While CCR1 supports inflammation and neointima formation, CCR5 has a protective effect through IL-10 upregulation. A preservation of cardiac function after myocardial infarction and accelerated wound healing was not mediated by CCR5, but by CCR1 blocking. Therefore, the use of RANTES antagonists in clinical practice should be critically analyzing. Since the oligomerization of the RANTES plays a significant role, blocking it on the endothelial surface by an antagonist CKEY2 could represent a viable therapeutical strategy, which need to be considered. CXC chemokine SDF-1a proved also to have a very high therapeutic potential, by its crucial role in the recruitment of adult stem cells, such as endothelial progenitor cells (EPCs) and smooth muscle progenitor cells (SPCs) in the context of repair processes following ischemia. Furthermore, CCL2 or MCP-1 (monocyte chemoattractant protein-1) and its receptor CCR2 is responsible for monocyte recruitment in both atherosclerotic plaques and in regenerating myocardium and could therefore represent another therapeutic target with significant implications for clinical application.

On the other side, cell-based therapy is a novel strategy considered to have a great potential in regenerative medicine. The ultimate goal of stem cell-based cardiac repair is the regeneration of healthy, functionally integrated myocardial tissue. However, in spite of encouraging results from experimental studies, cell-therapy has not yielded satisfying results in clinical implementation, probably due to the difficulties of translating knowledge from animal to human systems. Therefore, in order to create efficient therapies, we urgently need to understand how each of these processes is modulated and controlled.

In this regard, we have performed extensive experimental research on rats and mice, demonstrating some important insight mechanisms, which lead to an improvement of the global cardiac function. We demonstrated that inflammation after cell therapy plays a critical role, independent of the transplanted cell-type. This could partly explain the heterogeneous and conflicting results from the clinical trials in recent years. On the other side, cell therapy after atherosclerosis seems to be more appropriate and of a real benefit for the patients. Selective coating of the stents to induce re-endothelialization, without influencing the smooth muscle cell proliferation or thrombus formation seems to be realistic and of great clinical significance.

Although little studied, chemokines may play a key role in modulation, control, improving survival and integration of transplanted cells at the site of myocardial infarction. Extensive research is still necessary to establish the exact role of each chemokine and any ways one or more of them may be used to improve the cell-based therapy.