Final Report Summary - IN-SMC (SMOOTH MUSCLE CELL TRANSCRIPTOMICS AND INFECTIOUS AGENTS)
An executive summary
The pathology of coronary heart disease (CHD) includes a complex series of events, the key steps being the loss of normal endothelial function, lipid levels favouring lipid entry into endothelial intima, leukocyte (monocyte and lymphocyte) recruitment to artery walls, smooth muscle cell (SMC) proliferation and inflammation. The key events leading to the transformation of a silent atheroma into a life-threatening ruptured and thrombosed coronary plaque are still uncovered. One of the most important hypotheses is that this is due to the development of inflammation within the plaque. The molecular mechanisms through which SMC can modulate the inflammatory response in atherosclerosis are currently unknown. Apoptotic death of SMC may cause thinning of the fibrous cap, leading to a rupture-prone plaque. Erosion or rupture of the fibrous cap exposes the pro-thrombotic lipid core to the blood flow causing thrombus formation, which can occlude the artery and lead to acute cardiovascular events. SMC are highly plastic, and can alter their state of differentiation in response to environmental cues. Recently it was shown that a periodontal pathogen P. gingivalis is able to promote transformation of a contractile SMC to proliferative phenotype and induce SMC proliferation.
We aimed to identify molecular basis of the pro-inflammatory phenotype of atherosclerotic plaque-derived SMCs. We wanted to study the initiation of the inflammatory process within the artery, specifically focusing on studying the role of oral bacteria. The overall goals of the present project were: a) to identify the molecular basis of the pro-inflammatory phenotype of atherosclerotic plaque-derived SMC via transcriptome analysis; and b) to investigate the contribution of oral bacteria and their components to induce inflammatory gene expression in SMC.
Our results show that the transcriptome of atherosclerotic SMC clearly differs from that of healthy SMC. In plaque-derived SMC pathways relating to protein metabolism (e.g. translation, protein folding) are up-regulated whereas pathways related to lipid metabolism are down-regulated. We also identified bacterial species and their relative amounts present in dental abscesses from patients. Bacterial preparates originating from these dental abscesses were used to stimulate SMC in vitro and cytokine production was measured from the cell culture supernatants, and patient samples with high amounts of certain bacteria were found to be more potent in inducing cytokine production in SMCs.
In summary, our studies demonstrate that SMC resident in human plaques acquire a distinct gene expression compared to control cells. Plaque-derived SMC seem to be translationally more active whereas pathways related to lipid metabolism are down-regulated. Moreover, bacteria have the ability, once deposited in plaques to activate SMC directly and promote their cytokine production thus possibly having an effect on plaque stability.
The pathology of coronary heart disease (CHD) includes a complex series of events, the key steps being the loss of normal endothelial function, lipid levels favouring lipid entry into endothelial intima, leukocyte (monocyte and lymphocyte) recruitment to artery walls, smooth muscle cell (SMC) proliferation and inflammation. The key events leading to the transformation of a silent atheroma into a life-threatening ruptured and thrombosed coronary plaque are still uncovered. One of the most important hypotheses is that this is due to the development of inflammation within the plaque. The molecular mechanisms through which SMC can modulate the inflammatory response in atherosclerosis are currently unknown. Apoptotic death of SMC may cause thinning of the fibrous cap, leading to a rupture-prone plaque. Erosion or rupture of the fibrous cap exposes the pro-thrombotic lipid core to the blood flow causing thrombus formation, which can occlude the artery and lead to acute cardiovascular events. SMC are highly plastic, and can alter their state of differentiation in response to environmental cues. Recently it was shown that a periodontal pathogen P. gingivalis is able to promote transformation of a contractile SMC to proliferative phenotype and induce SMC proliferation.
We aimed to identify molecular basis of the pro-inflammatory phenotype of atherosclerotic plaque-derived SMCs. We wanted to study the initiation of the inflammatory process within the artery, specifically focusing on studying the role of oral bacteria. The overall goals of the present project were: a) to identify the molecular basis of the pro-inflammatory phenotype of atherosclerotic plaque-derived SMC via transcriptome analysis; and b) to investigate the contribution of oral bacteria and their components to induce inflammatory gene expression in SMC.
Our results show that the transcriptome of atherosclerotic SMC clearly differs from that of healthy SMC. In plaque-derived SMC pathways relating to protein metabolism (e.g. translation, protein folding) are up-regulated whereas pathways related to lipid metabolism are down-regulated. We also identified bacterial species and their relative amounts present in dental abscesses from patients. Bacterial preparates originating from these dental abscesses were used to stimulate SMC in vitro and cytokine production was measured from the cell culture supernatants, and patient samples with high amounts of certain bacteria were found to be more potent in inducing cytokine production in SMCs.
In summary, our studies demonstrate that SMC resident in human plaques acquire a distinct gene expression compared to control cells. Plaque-derived SMC seem to be translationally more active whereas pathways related to lipid metabolism are down-regulated. Moreover, bacteria have the ability, once deposited in plaques to activate SMC directly and promote their cytokine production thus possibly having an effect on plaque stability.