Periodic Reporting for period 1 - MATRICARD (The extracellular matrix as a mediator of cell-cell communication in cardiovascular inflammation)
Reporting period: 2023-01-01 to 2025-06-30
Cardiovascular diseases, in particular coronary artery disease, myocardial infarction and ischemic heart failure, represent the leading cause of death worldwide. Atherosclerosis and myocardial infarction are characterized by a inflammatory processes. Several cell types, as leukocytes, endothelial cells, vascular smooth muscle cells, platelets, fibroblasts, and cardiomyocytes, are invovled in the initiation, propagation, and termination of the processes. Recent research projects revealed that genetic variation influencing extracellular matrix proteins is associated with cardiovascular diseases. We found that such proteins which are secreted by one cell type influence phenotypes of other cell types via, e.g. silencing of inflammatory functions or modulation of extracellular matrix composition. The extracellular matrix hence not only represents a meshwork in which cells are organized but also a communication hub to transduce mechanical stimuli and heterocellular interaction signals. In MATRICARD, we will explore the extracellular matrix proteome composition in atherosclerosis and myocardial infarction. We aim to identify novel regulators which give insights into the underlying processes and we will study the molecular and cellular mechanisms modifying the course of the disease. Ultimately, we hope to identy novel therapeutic targets. MATRICARD will go beyond technical boundaries and lead to a deep knowledge of ECM-mediated heterocellular communication and reveal its translational potential.
We were able to establish the animal models for both conditions which are investigated in MATRICARD, i.e. atherosclerosis and myocardial infarction, and established the workflow to analyse tissue proteome and the proteome of the extracellular matrix (ECM), the matrisome, in unprecedented depth. Using our so far generated data, we explored the role of the ECM protease ADAMTS-7 in atherosclerotic plaque formation and found that ADAMTS-7 also modulates plaque stability via differential degradation of collagens. As an example for heterocellular communication via ECM proteins, we identified TIMP-1, an endogenous inhibitor of metalloproteinases such as matrix metalloproteinase (MMP) 9, as a novel target of ADAMTS-7 and dissected the downstream mechanism influencing atherosclerotic plaque formation and stability. The goal of MATRICARD is furthermore to develop modulators of the identified and explored mechanisms. Here, we developed an assay which is able to quantify the interaction between ADAMTS-7 and its downstream targets and identified modulators of this interaction which are currently explored regarding safety and efficacy.
Will be updated during the course of the project due to confidentiality.