Diabetes mellitus, which is largely driven by nutritional and behavioral factors, is characterized
by accelerated atherosclerosis with impaired plaque stability. Atherosclerosis and associated
complications are the major cause of mortality in diabetic patients. Efficient therapeutic concepts for
diabetes-associated atherosclerosis are lacking. Atherosclerosis among diabetic patients is associated
with reduced endothelial thrombomodulin (TM) expression and impaired activated protein C (aPC)
generation. Here, we demonstrate that atherosclerotic plaque stability is reduced in hyperglycemic
mice expressing dysfunctional TM (TMPro/Pro mice), which have a pro-coagulant phenotype due to
impaired thrombin inhibition and markedly reduced aPC generation. The vessel lumen and plaque
size of atherosclerotic lesions in the truncus brachiocephalic were decreased in diabetic TMPro/Pro
ApoE-/- mice compared to diabetic ApoE-/- mice. While lipid accumulation in lesions of diabetic
TMPro/Pro ApoE-/- mice was lower than that in diabetic ApoE-/- mice, morphometric analyses revealed
more prominent signs of instable plaques, such as a larger necrotic core area and decreased
fibrous cap thickness in diabetic TMPro/Pro ApoE-/- mice. Congruently, more macrophages and fewer
smooth muscle cells were observed within lesions of diabetic TMPro/Pro ApoE-/- mice. Thus, impaired
TM function reduces plaque stability, a characteristic of hyperglycemia-associated plaques, thus suggesting
the crucial role of impaired TM function in mediating diabetes-associated atherosclerosis.
| Identifer | oai:union.ndltd.org:DRESDEN/oai:qucosa:de:qucosa:87168 |
| Date | 22 September 2023 |
| Creators | Ambreen, Saira, Fatima, Sameen, Elwakiel, Ahmed, Rana, Rajiv, Singh, Kunal, Gupta, Anubhuti, Gupta, Dheerendra, Khawaja, Hamzah, Manoharan, Jayakumar, Besler, Christian, Laufs, Ulrich, Kohli, Shrey, Isermann, Berend, Shahzad, Khurrum |
| Publisher | MDPI |
| Source Sets | Hochschulschriftenserver (HSSS) der SLUB Dresden |
| Language | English |
| Detected Language | English |
| Type | info:eu-repo/semantics/publishedVersion, doc-type:article, info:eu-repo/semantics/article, doc-type:Text |
| Rights | info:eu-repo/semantics/openAccess |
| Relation | 1991, 10.3390/nu14101991 |
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