Cellular stress reactions in atherogenesis

Atherosclerosis is initiated and propagated by pathogenic factors inducing damage and inflammation of arterial wall. Unfolded protein response (UPR) and electrophilic stress response (ESR) are transcriptional programs induced by a variety of environmental and endogenous insults. In addition to their major role in orchestrating cellular stress adaptation, ESR and UPR also induce danger alerts such as production of inflammatory cytokines. Furthermore, it is well documented that UPR initiates cell apoptosis. Thus, UPR and ESR are potentially relevant for initiation and progression of inflammatory disease such as atherosclerosis. Indeed, several atherogenic factors such as cholesterol, homocysteine and oxidized phospholipids (OxPLs) have been shown to initiate UPR and/or ESR in vitro. Furthermore, upregulation of a few ESR- and UPR-dependent genes has been found in human and animal atherosclerotic lesions. However, the mechanisms of induction and relevance of UPR and ESR for atherogenesis are poorly understood. A hypothesis put forward in this project states that UPR and ESR are important signaling mechanisms at different stages of atherogenesis, and in particular mediate atherogenic effects of OxPLs, which accumulate in lesions and are increasingly recognized as culprits in atherosclerosis. The major aim of the study is to characterize the mechanisms and consequences of OxPL-induced activation of UPR and ESR in the context of atherosclerosis. To this end, activation of UPR- and ESR-responsive genes by OxPLs in cultured vascular wall cells and atherosclerotic lesions will be studied using microarrays and quantitative RT-PCR. Specific goal of these experiments is to identify genes, which 1) are induced by OxPLs via the UPR and ESR signaling pathways, 2) are upregulated in atherosclerotic lesions in vivo and 3) are likely to be mechanistically involved in initiation and progression of atherogenesis as judged by their known functions as chemokines, cell adhesion molecules, metalloproteinases, etc. Special emphasis in the project will be put on investigating the mechanisms of OxPL- induced activation of UPR and ESR. In particular, lipid structure/activity relationship, the importance of scavenger receptor-mediated endocytosis, and the interplay between UPR and ESR will be studied. Furthermore, inhibition of UPR by low molecular weight compounds or recombinant DNA techniques will be tested as approaches for inhibiting atherogenic effects of stress reactions. Results of the study will provide further insights into the role of cellular stress reactions in atherogenesis, and will clarify transcriptional mechanisms of atherogenic action of OxPLs. In addition, novel targets and tools for prevention of atherosclerosis are likely to be identified.

Atherosclerosis is initiated and propagated by pathogenic factors inducing damage and inflammation of arterial wall. Unfolded protein response (UPR) and electrophilic stress response (ESR) are transcriptional programs induced by a variety of environmental and endogenous insults. In addition to their major role in orchestrating cellular stress adaptation, ESR and UPR also induce danger alerts such as production of inflammatory cytokines. Furthermore, it is well documented that UPR initiates cell apoptosis. Thus, UPR and ESR are potentially relevant for initiation and progression of inflammatory disease such as atherosclerosis. Indeed, several atherogenic factors such as cholesterol, homocysteine and oxidized phospholipids (OxPLs) have been shown to initiate UPR and/or ESR in vitro. Furthermore, upregulation of a few ESR- and UPR-dependent genes has been found in human and animal atherosclerotic lesions. However, the mechanisms of induction and relevance of UPR and ESR for atherogenesis are poorly understood. A hypothesis put forward in this project states that UPR and ESR are important signaling mechanisms at different stages of atherogenesis, and in particular mediate atherogenic effects of OxPLs, which accumulate in lesions and are increasingly recognized as culprits in atherosclerosis. The major aim of the study is to characterize the mechanisms and consequences of OxPL-induced activation of UPR and ESR in the context of atherosclerosis. To this end, activation of UPR- and ESR-responsive genes by OxPLs in cultured vascular wall cells and atherosclerotic lesions will be studied using microarrays and quantitative RT-PCR. Specific goal of these experiments is to identify genes, which 1) are induced by OxPLs via the UPR and ESR signaling pathways, 2) are upregulated in atherosclerotic lesions in vivo and 3) are likely to be mechanistically involved in initiation and progression of atherogenesis as judged by their known functions as chemokines, cell adhesion molecules, metalloproteinases, etc. Special emphasis in the project will be put on investigating the mechanisms of OxPL- induced activation of UPR and ESR. In particular, lipid structure/activity relationship, the importance of scavenger receptor-mediated endocytosis, and the interplay between UPR and ESR will be studied. Furthermore, inhibition of UPR by low molecular weight compounds or recombinant DNA techniques will be tested as approaches for inhibiting atherogenic effects of stress reactions. Results of the study will provide further insights into the role of cellular stress reactions in atherogenesis, and will clarify transcriptional mechanisms of atherogenic action of OxPLs. In addition, novel targets and tools for prevention of atherosclerosis are likely to be identified.