Chronic Nicotine Exposure Induces Murine Aortic Remodeling and Stiffness Segmentation-Implications for Abdominal Aortic Aneurysm Susceptibility.

Markus U Wagenhäuser,Pireyatharsheny Mulorz,Alicia Deng,Uwe Raaz,Joshua M Spin,Margitta Elvers,Matti Adam,Gerd Hasenfuß,Anand K Ramasubramanian,Philip S Tsao,Andreas Schuster,Kensuke Toyama,Isabel N Schellinger,Yosuke Kayama,Wiebke Ibing,Hubert Schelzig,Anne Petzold,Joscha Mulorz,S Guenther ,Tatsuhiko Yoshino

doi:10.3389/fphys.2018.01459

Abstract

Aim: Arterial stiffness is a significant risk factor for many cardiovascular diseases, including abdominal aortic aneurysms (AAA). Nicotine, the major active ingredient of e-cigarettes and tobacco smoke, induces acute vasomotor effects that may temporarily increase arterial stiffness. Here, we investigated the effects of long-term nicotine exposure on structural aortic stiffness.Methods: Mice (C57BL/6) were infused with nicotine for 40 days (20 mg/kg/day). Arterial stiffness of the thoracic (TS) and abdominal (AS) aortic segments was analyzed using ultrasound (PWV, pulse wave velocity) and ex vivo pressure myograph measurements. For mechanistic studies, aortic matrix-metalloproteinase (MMP) expression and activity as well as medial elastin architecture were analyzed.Results: Global aortic stiffness increased with nicotine. In particular, local stiffening of the abdominal segment occurred after 10 days, while thoracic aortic stiffness was only increased after 40 days, resulting in aortic stiffness segmentation. Mechanistically, nicotine exposure enhanced expression of MMP-2/-9 and elastolytic activity in both aortic segments. Elastin degradation occurred in both segments; however, basal elastin levels were higher in the thoracic aorta. Finally, MMP-inhibition significantly reduced nicotine-induced MMP activity, elastin destruction, and aortic stiffening.Conclusion: Chronic nicotine exposure induces aortic MMP expression and structural aortic damage (elastin fragmentation), irreversibly increasing aortic stiffness. This process predominantly affects the abdominal aortic segment, presumably due in part to a lower basal elastin content. This novel phenomenon may help to explain the role of nicotine as a major risk factor for AAA formation and has health implications for ECIGs and other modes of nicotine delivery.

Highlights

In United States and globally, the use of ECIGs has increased annually across all age groups, and recently ECIGs have become more commonly used among 12th graders than tobacco cigarettes (Arrazola et al, 2015; Bunnell et al, 2015; Gravely et al, 2015; McMillen et al, 2015)
We found significantly elevated serum cotinine levels in nicotineinfused mice after 10 and 40 days when compared to phosphate buffered saline (PBS)-infused controls, indicating effective nicotine delivery (Supplementary Figure 1B)
Mice that received nicotine infusion showed significantly elevated overall aortic stiffness both 10 and 40 days after osmotic pump implantation compared to mice that received PBS infusion (Figure 1A)

Summary

Introduction

In United States and globally, the use of ECIGs has increased annually across all age groups, and recently ECIGs have become more commonly used among 12th graders than tobacco cigarettes (Arrazola et al, 2015; Bunnell et al, 2015; Gravely et al, 2015; McMillen et al, 2015). ECIGs are promoted as a “healthy” smoking cessation aid among nicotine-dependent young adult conventional smokers, recent research suggests a potential to damage DNA at a chromosomal and a gene level in urine (Canistro et al, 2017). In this context, a more complete understanding of the risks of nicotine is mandatory, given that ECIGs can exceed the nicotine delivery profile of tobacco cigarettes (Talih et al, 2015; Dawkins et al, 2016). Arterial stiffness has been identified as a strong independent risk factor for many cardiovascular conditions, e.g., heart failure, myocardial infarction, stroke, and AAA formation (Lyle and Raaz, 2017)

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