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Abdominal aortic aneurysm (AAA) is a common cardiovascular disease with a strong correlation to smoking, although underlying mechanisms have been minimally explored. Electronic cigarettes (e-cigs) have gained recent broad popularity and can deliver nicotine at comparable levels to tobacco cigarettes, but effects on AAA development are unknown.We evaluated the impact of daily e-cig vaping with nicotine on AAA using two complementary murine models and found that exposure enhanced aneurysm development in both models and genders. E-cigs induced changes in key mediators of AAA development including cytokine chitinase-3-like protein 1 (CHI3L1/Chil1) and its targeting microRNA-24 (miR-24). We show that nicotine triggers inflammatory signaling and reactive oxygen species while modulating miR-24 and CHI3L1/Chil1 in vitro, and that Chil1 is crucial to e-cig-augmented aneurysm formation using a knockout model.In conclusion our work shows increased aneurysm formation along with augmented vascular inflammation in response to e-cig exposure with nicotine. Further we identify Chil1 as a key mediator in this context. Our data raise concerns regarding the potentially harmful long-term effects of e-cig nicotine vaping.Smoking is one of the most hazardous modifiable risk factors, with clear links to abdominal aortic aneurysm. E-cig vaping has displayed explosive growth in popularity. Intended for smoking cessation, it has been taken up by millions with no such clinical need, delivering nicotine addiction to new generations. The presumption that vaping is safer than tobacco overlooks the potential cardiovascular risks of nicotine. This study shows for the first time that inhaled e-cig nicotine vapor augments experimental AAA and aortic inflammation, suggests a mechanistic role for the cytokine Chil1/CHI3L1 and its regulator microRNA-24, and raises red flags regarding longitudinal e-cig safety.

Patients with type 2 diabetes (T2D) are threatened by excessive cardiovascular morbidity and mortality. While accelerated arterial stiffening may represent a critical mechanistic factor driving cardiovascular risk in T2D, specific therapies to contain the underlying diabetic arterial remodeling have been elusive. The present translational study investigates the role of microRNA-29b (miR-29b) as a driver and therapeutic target of diabetic aortic remodeling and stiffening. Using a murine model (db/db mice), as well as human aortic tissue samples, we find that diabetic aortic remodeling and stiffening is associated with medial fibrosis, as well as fragmentation of aortic elastic layers. miR-29b is significantly downregulated in T2D and miR-29b repression is sufficient to induce both aortic medial fibrosis and elastin breakdown through upregulation of its direct target genes COL1A1 and MMP2 thereby increasing aortic stiffness. Moreover, antioxidant treatment restores aortic miR-29b levels and counteracts diabetic aortic remodeling. Concluding, we identify miR-29b as a comprehensive—and therefore powerful—regulator of aortic remodeling and stiffening in T2D that moreover qualifies as a (redox-sensitive) target for therapeutic intervention., Graphical Abstract, Stiffening of large arteries represents a significant complication in patients with diabetes mellitus resulting in high blood pressure levels and widespread organ damage (in particular in heart, brain, and kidneys). In this study we identify microRNA-29b as a comprehensive regulator and potential therapeutical target of diabetic arterial remodeling and stiffening.

Aging has a significant impact not only on every single individual but on society as a whole. Today, people throughout the world exhibit an extended lifespan. Therefore, it becomes increasingly important to develop novel concepts that encourage a modern understanding of the aging process. The concept of healthy aging shifts the perception of aging as a burden towards aging as an opportunity for an extended healthy phase in later life. Morbidity and mortality in the elderly population are greatly defined by a raise in the incidence and prevalence of cardiovascular diseases. Consequently, it is critical to identify risk factors and underlying mechanisms that render the aging (cardio)vascular system prone to disease. In this review, we focus on structural mechanisms of arterial stiffening as a major manifestation of vascular aging and its functional implications for the concept of healthy aging.

Aging has a significant impact not only on every single individual but on society as a whole. Today, people throughout the world exhibit an extended lifespan. Therefore, it becomes increasingly important to develop novel concepts that encourage a modern understanding of the aging process. The concept of healthy aging shifts the perception of aging as a burden towards aging as an opportunity for an extended healthy phase in later life. Morbidity and mortality in the elderly population are greatly defined by a raise in the incidence and prevalence of cardiovascular diseases. Consequently, it is critical to identify risk factors and underlying mechanisms that render the aging (cardio)vascular system prone to disease. In this review, we focus on structural mechanisms of arterial stiffening as a major manifestation of vascular aging and its functional implications for the concept of healthy aging.

Background: Arterial stiffness is part of arterial aging and strongly associated with increased risk for cardiovascular events. Unfortunately, until today there is no treatment available effectively counteracting arterial stiffening. One key feature of arterial stiffening is elastin fragmentation. Breakdown of elastin is mediated by matrix metalloproteinases (MMPs), in particular MMP-2 and MMP-9 play a pivotal role in this process. Non-coding micro RNAs (miRs) were found to effectively regulate gene expression, consequentially representing potential therapeutic targets. We hypothesize that miR146a inhibits MMP-2 and MMP-9, thus leading to decreased elastin fragmentation in the vascular extracellular matrix. Methods and Results: RNA Sequencing found miR146a to be upregulated in a stiffness-dependent manner in vitro and in an age dependent manner in vivo . Since both MMP-2 and MMP-9 are predicted targets of miR146a, we transfected aortic smooth muscle cells with constructs either increasing (mimicking construct) or decreasing (inhibitory anti-sense construct) effective miR146a levels and evaluated the effect on MMP-2 and MMP-9 expression and activity in vitro . qRT-PCR analysis demonstrated significantly de-repressed MMP-2 and MMP-9 levels upon transfection with inhibitor constructs, while mimic constructs further repressed the expression of MMP-2 and MMP-9. Overall MMP activity was significantly altered accordingly after transfection with the respective constructs as determined by a fluorimetric MMP Activity Assay. MMP-2 activity could be specifically assessed using Zymography. After transfection with miR146a inhibitor, both active MMP-2 as well as pro-MMP-2 activity were found to be significantly increased. Conclusion: Our study provides first evidence that miR146a reduces the levels and activity of MMP-2 and MMP-9 in vascular smooth muscle cells. We conclude that miR146a might have protective function on the integrity of the elastin network in the arterial media. We therefore consider miR146a a potential drug target in the context of elastin fragmentation and arterial stiffness, thus potentially alleviating the development of aortic aneurysm.

Background: Arterial stiffness, which may develop due to vascular calcification, is a significant pathophysiological factor associated with arterial aging or diseases such as type-2 diabetes or end stage renal disease. With no effective therapy clinically available to date, molecular and epigenetic mechanisms of ectopic calcification in conduit arteries are receiving increasing attention to identify targets for therapeutical interference. Here we show that miR-146a may serve as a therapeutic candidate to counteract vascular calcification. Methods: Ectopic calcification was assessed in human aortic smooth muscle cells (AoSMCs) using Alizarin red and Von kossa stainings. The total calcium content in hydroxyapatite crystals was assessed using QuantiChrom TM calcium assay kit. The mRNA expression levels of BMP2, MSX2 and SORT1 were assessed by TaqMan real-time PCR. Results: The endogenous expression of miR-146a was significantly decreased and simultaneously ectopic calcium deposition was significantly increased in AoSMCs exposed to osteogenic stimulation. However, overexpression of miR-146a in AoSMCs cultured in vitro reduced the ectopic calcium deposits. Simultaneously, mRNA expression levels of osteogenic markers and drivers of calcification, such as BMP2, MSX2 and SORT1 - all predicted miR-146a target genes - were significantly reduced. Conversely, significantly increased calcium deposits were observed when miR-146a was inhibited in these cells in similar culture conditions with upregulated BMP2, MSX2 and SORT1 mRNA expression levels. Conclusion: The results suggest that miR-146a may serve as a modulator of AoSMC calcification and miR-146a supplementation may qualify as a therapeutic intervention to counteract vascular calcification due to aging, type-2 diabetes or end stage renal disease.

We recently developed a class of novel antitumor agents that elicit a potent growth-inhibitory response in many tumor cells cultured in vitro. WK175, a member of this class, was chosen as a model compound that showed strong in vitro efficacy. WK175 interferes with the intracellular steady-state level of NAD(+), resulting in a decreased cellular NAD(+) concentration. We found that WK175 induces apoptotic cell death without any DNA-damaging effect. The apoptotic death signaling pathway initiated by WK175 was examined in detail: mitochondrial membrane potential, cytochrome c release, caspase 3 activation, caspase 3 and poly(ADP-ribose) polymerase cleavage, and the appearance of a sub-G(1) cell cycle population were determined in time course studies in THP-1 (a human monocytic leukemia cell line) cells. We found activation of this cascade after 24 h of treatment with 10 nM WK175. Induction of apoptosis was prevented by bongkrekic acid, Z-Asp-Glu-Val-Asp-fluoromethylketone, and Z-Leu-Glu-His-Asp-fluoromethylketone, inhibitors of the mitochondrial permeability transition and of caspase 3 and 9, respectively, but not by Ac-Tyr-Val-Ala-Asp-CHO, a specific caspase 1 inhibitor, suggesting the involvement of the permeability transition pore, caspase 3, and caspase 9 in the WK175-induced apoptotic cascade. These results imply that decreased NAD(+) concentration initiates the apoptotic cascade, resulting in the antitumor effect of WK175.