Gender-dependent impact on epigenetic modifications caused by nicotine in abdominal aortic aneurysm
Final Report Abstract
Gender-dependent differences in experimental abdominal aortic aneurysm (AAA) development were studied in the context nicotine exposure. Using a novel in-vivo inhalation system, mice of both genders were exposed to e-cigarette (e-cig) vapor containing nicotine for 6 weeks on a daily basis. After AAA induction using the porcine pancreatic elastase (PPE) model, mice exposed to e-cig vapor containing nicotine developed significantly larger and faster growing AAA when compared to room airexposed control animals. This was accompanied with significant upregulation of central pro-inflammatory and vascular remodeling genes. Opposing the initially proposed hypothesis, female mice were not protected from the augmenting effects of nicotine inhalation. Results indicated that inhaled nicotine through e-cigs leads to downregulation of miR-24 and subsequent upregulation of one of it’s targets, the vascular-injury-protein CHI3L1/Chil1. Here, nicotine induced reactive oxygen species (ROS) production, which in turn regulated miR-24 and subsequent Chil1. Finally, Chil1 knockout in mice exposed to e-cig protected from the aforementioned augmenting effects, marking its central role in nicotine-augmented AAA formation in both genders. Additionally, exposure to e-cig vapor containing nicotine led to increased aortic stiffening assessed with pulse-wave velocity and ex-vivo pressure myography. Effects were pronounced in young mice, suggesting e-cig usage as a cardiovascular risk factor especially for younger populations where e-cigs a particular popular. Further, the effects of hyperlipidemia on the PPE model were studied using rAAV8- D377Y-mPcsk9 viral genomes in C57/BL6J mice and additional dietary manipulation. In difference to the Angiotensin-II model for AAA, where hyperlipidemia is essential for the model to work, increased plasma lipids did not lead to augmented AAA formation in the PPE model. This was verified in independent experiments using ApoE-knockout mice versus wildtype. Histological evaluation of AAA lesions revealed accumulated lipid in the medial layer, which correlated with plasma cholesterol. Analysis of human AAA-lesions showed similar medial lipid deposition. Despite this observation, the data suggested that elevated plasma lipids do not contribute significantly to AAA progression in the mouse PPE model.
Publications
- Chronic Nicotine Exposure Induces Murine Aortic Remodeling and Stiffness Segmentation-Implications for Abdominal Aortic Aneurysm Susceptibility. Front Physiol. 2018 Oct 31;9:1459
Wagenhäuser MU, Schellinger IN, Yoshino T, Toyama K, Kayama Y, Deng A, Guenther SP, Petzold A, Mulorz J, Mulorz P, Hasenfuß G, Ibing W, Elvers M, Schuster A, Ramasubramanian AK, Adam M, Schelzig H, Spin JM, Raaz U, Tsao PS
(See online at https://doi.org/10.3389/fphys.2018.01459) - MicroRNA-Mediated Therapy Modulating Blood-Brain Barrier Disruption Improves Vascular Cognitive Impairment. Arterioscler Thromb Vasc Biol. 2018 Jun;38(6):1392-1406
Toyama K, Spin JM, Deng AC, Huang TT, Wei K, Wagenhäuser MU, Yoshino T, Nguyen H, Mulorz J, Kundu S, Raaz U, Adam M, Schellinger IN, Jagger A, Tsao PS
(See online at https://doi.org/10.1161/ATVBAHA.118.310822) - Clinical outcomes after direct and indirect surgical venous thrombectomy for inferior vena cava thrombosis. J Vasc Surg Venous Lymphat Disord. 2019 May;7(3):333-343.e2
Wagenhäuser MU, Dimopoulos C, Antakyali K, Meyer-Janiszewski YK, Mulorz J, Ibing W, Ertas N, Spin JM, Schelzig H, Duran M
(See online at https://doi.org/10.1016/j.jvsv.2018.11.005) - Controlled isoflurane anesthesia exposure is required for reliable behavioral testing in murine surgical models. J Pharmacol Sci. 2019 May;140(1):106-108
Toyama K, Spin JM, Abe Y, Suzuki Y, Deng AC, Wagenhäuser MU, Yoshino T, Mulorz J, Liu S, Tsao PS, Mogi M
(See online at https://doi.org/10.1016/j.jphs.2019.03.007) - Endovascular Occlusion of a Renal Arteriovenous Fistula with Renal Vein Aneurysm Formation for Rupture Prevention. Vasc Med. 2019 Oct 31;2019:8530641
Rhee YH, Busch L, Sansone R, Ertas N, Floros N, Schelzig H, Mulorz J, Wagenhäuser MU
(See online at https://doi.org/10.1155/2019/8530641)
