Oncostatin M reduces atherosclerosis development in APOE*3Leiden.CETP mice and is associated with increased survival probability in humans

Abstract

Objective Previous studies indicate a role for Oncostatin M (OSM) in atherosclerosis and other chronic inflammatory diseases for which inhibitory antibodies are in development. However, to date no intervention studies with OSM have been performed, and its relation to coronary heart disease (CHD) has not been studied. Approach and results Gene expression analysis on human normal arteries (n = 10) and late stage/advanced carotid atherosclerotic arteries (n = 127) and in situ hybridization on early human plaques (n = 9) showed that OSM , and its receptors, OSM receptor ( OSMR ) and Leukemia Inhibitory Factor Receptor ( LIFR ) are expressed in normal arteries and atherosclerotic plaques. Chronic OSM administration in APOE*3Leiden.CETP mice (n = 15/group) increased plasma E-selectin levels and monocyte adhesion to the activated endothelium independently of cholesterol but reduced the amount of inflammatory Ly-6C High monocytes and atherosclerotic lesion size and severity. Using aptamer-based proteomics profiling assays high circulating OSM levels were shown to correlate with post incident CHD survival probability in the AGES‐Reykjavik study (n = 5457). Conclusions Chronic OSM administration in APOE*3Leiden.CETP mice reduced atherosclerosis development. In line, higher serum OSM levels were correlated with improved post incident CHD survival probability in patients, suggesting a protective cardiovascular effect.

Common Variants Associated With OSMR Expression Contribute to Carotid Plaque Vulnerability, but Not to Cardiovascular Disease in Humans

“…Another possibility is that there is not only a decrease of OSMR expression on the arterial wall, but also a decrease in circulating OSMR levels, which can also bind to OSM and acts as a neutralizer (54), also resulting in no net difference in OSM signaling. Moreover, this study cannot make a distinction between the timing and the duration of OSM signaling, which may differentially affect atherosclerosis development as previous studies have shown that OSM, like IL-6, can act differently in the acute phase than in the chronic phase (8,9,55,56). Finally, we focused on only three genes (OSM, OSMR and LIFR), while atherosclerosis is a multifactorial disease.…”

“…These observations are in line with our previous work, in which we showed that simultaneous signaling of OSM through OSMR and leukemia inhibitory factor receptor (LIFR), induces activation in human endothelial cells, suggestive of a role in atherosclerosis development (8). In contrast, chronic OSM administration to APOE * 3Leiden.CETP mice reduces the atherosclerotic lesion size and severity, and high circulating OSM levels correlate with increased post-incident coronary heart disease survival probability in humans (9).…”

The Role of Oncostatin M and Its Receptor Complexes in Cardiomyocyte Protection, Regeneration, and Failure

“…Moreover, OSM has also been detected in atherosclerotic lesions of the human aorta and ApoE-deficient mice [92]. However, a recent study showed that the development of atherosclerosis was reduced on chronic administration of OSM, and high OSM levels coincided with an increased post-incident coronary heart disease survival probability in the AGES-Reykjavik study [93], indicating the complexity of correlation studies.…”

Common variants associated withOSMRexpression contribute to carotid plaque vulnerability, but not to cardiovascular disease in humans

“…Another possibility is that there is not only a decrease of OSMR expression on the arterial wall, but also a decrease in circulating OSMR levels, which can also bind to OSM and acts as a neutralizer(54), also resulting in no net difference in OSM signaling. Moreover, this study cannot make a distinction between the timing and the duration of OSM signaling, which may differentially affect atherosclerosis development as previous studies have shown that OSM, like IL-6, can act differently in the acute phase than in the chronic phase(8,9,55,56). Finally, we focused on only three genes ( OSM, OSMR and LIFR ), while atherosclerosis is a multifactorial disease.…”

“…These observations are in line with our previous work, in which we showed that simultaneous signaling of OSM through OSMR and leukemia inhibitory factor receptor (LIFR), induces activation in human endothelial cells, suggestive of a role in atherosclerosis development(8). In contrast, chronic OSM administration to APOE*3Leiden.CETP mice reduces the atherosclerotic lesion size and severity, and high circulating OSM levels correlate with increased post-incident coronary heart disease survival probability in humans(9).…”