The extracellular matrix as a mediator of cell-cell communication in cardiovascular inflammation

Project Information

MATRICARD

Grant agreement ID: 101077205

DOI

10.3030/101077205

EC signature date 1 December 2022

Start date 1 January 2023

End date 31 December 2027

Funded under

• European Research Council (ERC)

Total cost

€ 1 495 750,00

EU contribution

€ 1 495 750,00

Coordinated by

UNIVERSITAT DES SAARLANDES
Germany

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

Summary of the context and overall objectives of the project

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.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

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.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

Will be updated during the course of the project due to confidentiality.