Atherosclerosis is a systemic disease affecting the large arteries caused by the accumulation of lipids in the vessel wall. Cardiovascular disease due to atherosclerosis is today the most common cause of death globally through its end consequences: myocardial infarctions and stroke.
The extracellular matrix (ECM) is a network of structural fibrous proteins, proteoglycans and glycoproteins. ECM proteins are involved in all steps of the disease progression from the initial lipoprotein accumulation to the failure of the fibrous cap causing clinical symptoms. It is therefore attractive to focus on these proteins to find novel ways of treating atherosclerosis. The basement membrane is a sheet like structure composed of ECM proteins underlying the endothelial cells and surrounding smooth muscle cells. The two major proteins in the basement membrane are the network forming collagen type IV and laminin. In the clinical context there is a great need of finding the patients that are at high risk of suffering from impending cardiovascular events, thereby qualifiying them for a more intensive treatement. The ECM is continuously being degraded by matrix metalloproteinases (MMPs) and synthesized mostly by smooth muscle cells. The balance between these two processes are important for tissue homeostasis and stability in the atherosclerotic plaque.
The purpose of this thesis was to explore the role of different parts of the ECM and their association to plaque vulnerability. We measured the the small leucin rich proteogylcans (SLRPs), neoepitopes of degraded ECM proteins and the three isoforms of transforming growth factor-β in human atherosclerotic plaque tissue. Plaque sections, homogenate and blood samples were obtained from the Carotid Plaque Imaging Project (CPIP).
In this thesis three different SLRPs, fibromodulin lumican and mimecan were examined by immunohistochemistry and their association to plaque components, vulnerable plaque features and their association with future cardiovascular events were explored. We also explored the association of serum levels of the degraded basement membrane proteins collagen typ IV (C4M), laminin (LG1M) and collagen typ I (C1M) and the risk of suffering from future cardiovascular events and death. Finally, we assessed the three isoforms of TGF-β (TGF-β1, TGF-β2 and TGF-β3) in 223 plaques, to investigate if they were associated to a specific plaque phenotype and future cardiovascular events.
Fibromodulin, lumican and mimecan were all expressed in the atherosclerotic plaque tissue and fibromodulin plaque area was greated in symptomatic and diabetic plaques and correlated to plaque levels of lipids and proinflammatory cytokines. Mimecan plaque area was associated with a vulnerable plaque phenotype, the proinflammatory cytokine MCP-1 and matrix degrading proteinase MMP-9. Larger plaques areas of mimecan were also associated with an increased risk for cardiovascular death. All three isoforms of TGF-β were detected in the human plaque tissue although TGF-β2 was present in much higher levels. TGF-β2 was also found to correlate to features of plaque stability and tissue remodelling. C4M, LG1M and C1M were in varying degrees independently associated with all-cause mortality, cardiovascular death and cardiovascular events.
The regulation of ECM synthesis and degradation harbour the potential of novel and beneficial reparatory mechanisms that awaits to be discovered. The findings in this thesis may lead to the discovery of new mechanisms involved in vascular repair.
- Department of Clinical Sciences, Malmö
- Gonçalves, Isabel, Supervisor
- Edsfeldt, Andreas, Assistant supervisor
- Hultgårdh, Anna, Assistant supervisor
|Award date||2020 Dec 17|
|Place of Publication||Lund|
|Publication status||Published - 2020|
Place: Agardh föreläsningssal, CRC, Jan Waldenströms gata 35, Skånes Universitetssjukhus i Malmö
Name: Gigante, Bruna
Title: Associate Professor
Affiliation: Karolinska Institute, Sweden
- Cardiac and Cardiovascular Systems
- Extracellular matrix
- Carotid plaque