Trigger mechanisms and micro-RNA-related regulation of inflammasomes in abdominal aortic aneurysm
Final Report Abstract
The role of miR-223, the miR-30-family, miR-143, and the miR-23a/b-family in regulating inflammasomes NLRP3 and AIM2 at a transcriptional level was studied. Results indicated that only miR-223 functions as an important rheostat controlling NLRP3. However, the role of miR-223 seem ambivalent, as while suppressing NLRP3 expression it simultaneously up-regulates IL-1b in inflammatory M1-macrophages, which is the major indirect mediator of NLRP3 activation. Moreover, when using a smallmolecule inhibitor of NLRP3 (MCC950), aneurysm diameter did not differ compared to control animals over a 28-day time course. In conclusion, results suggest that NLRP3 activation in the aneurysm post-surgery may rather be an inflammatory side-effect than a key regulator of inflammatory signaling. Due to these adverse results an alternative project studying the role of platelet activation and its contribution to segmental aortic stiffness was initiated. Segmental aortic stiffness contributes to aneurysm growth over time as a high stiffness gradient between the aneurysm and the proximal adjacent segment increases wall shear stress. Platelets migrate into the aneurysm wall, and their activation contributes to stiffness regulation in the aneurysmal segment (by ultrasound in an animal model). Platelets are capable of regulating stiffness-related gene expression in the aneurysm wall. Given these findings, platelets appear to contribute to aneurysm progression over a 10-day post-surgery time course. Among inflammatory cytokines, platelets seem to regulate Osteopontin (OPN) gene expression in the aneurysm and other organs such as the heart, lung and spleen. Accordingly, OPN plasma levels differ significantly between platelet depleted (PDM) and control (CTRL) mice, suggesting that OPN may be a key regulator for differences in aneurysm progression and aneurysm stiffness between the study groups. When platelets are activated in vitro, aortic fibroblast (hAF) and M0-macrophages displayed an activator-dependent up-regulation of OPN gene expression. As Thrombin activity may be suppressed in PDM, the role of thrombin-cleaved (tr-OPN) seems particularly important. Future experiments will study the role of tr-OPN in AAA disease and whether or not direct inhibition of thrombin may be beneficial for aneurysm progression. This approach may have a major translational impact for the treatment of small-size aneurysm patients, with minor bleeding risks. Another side-project proved that nicotine primarily increases artic stiffness in the abdominal rather than the thoracic segment using a variety of approaches. These findings might be due to an up-regulation of MMP2 along with elevated activity levels. Results were presented at the ATVB 2017 in Minneapolis and awarded with an Exchange Idea Award from the Cardiovascular Institute, Stanford University.
Publications
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(2018) MicroRNA-Mediated Therapy Modulating Blood-Brain Barrier Disruption Improves Vascular Cognitive Impairment. Arteriosclerosis, thrombosis, and vascular biology 38 (6) 1392–1406
Toyama, Kensuke; Spin, Joshua M.; Deng, Alicia C.; Huang, Ting-Ting; Wei, Ke; Wagenhäuser, Markus U.; Yoshino, Takuya; Nguyen, Huy; Mulorz, Joscha; Kundu, Soumajit; Raaz, Uwe; Adam, Matti; Schellinger, Isabel N.; Jagger, Ann; Tsao, Philip S.
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Nicotine Differentially Influences Segmental Aortic Stiffening. Arteriosclerosis, Thrombosis, and Vascular Biology 37 (Suppl 1), A465-A465
Wagenhaeuser MU, Schellinger IN, Guenther SP, Yoshino T, Toyama K, Kayama Y, Deng AC, Zoellner AM, Raaz U, Spin JM, Tsao PS
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Oxidized (non)-regenerated cellulose affects fundamental cellular processes of wound healing. Sci Rep. 2016 Aug 25;6:32238
Wagenhäuser MU, Mulorz J, Ibing W, Simon F, Spin JM, Schelzig H, Oberhuber A
