Cardiovascular dysfunction induced by combined exposure to nicotine inhalation and high-fat diet.

Smoking and high-fat diet (HFD) consumption are two modifiable risk factors for cardiovascular (CV) diseases, and individuals who are overweight or obese due to unhealthy diet are more likely to use tobacco products. In this study, we aim to investigate the combined effects of nicotine (the addictive component of all tobacco products) and HFD on CV health, which are poorly understood. C57BL/6N male mice were placed on either HFD (60 kcal% fat) or regular diet (22 kcal% fat) and exposed to air or nicotine vapor for 10-12 wk. CV function was monitored by echocardiography and radiotelemetry, with left ventricular (LV) catheterization and aortic ring vasoreactivity assays performed at end point. Mice on HFD exhibited increased heart rate and impaired parasympathetic tone, whereas nicotine exposure increased sympathetic vascular tone as evidenced by increased blood pressure (BP) response to ganglionic blockade. Although neither nicotine nor HFD alone or in combination significantly altered BP, nicotine exposure disrupted circadian BP regulation with reduced BP dipping. LV catheterization revealed that combined exposure to nicotine and HFD led to LV diastolic dysfunction with increased LV end-diastolic pressure (LVEDP). Moreover, combined exposure resulted in increased inhibitory phosphorylation of endothelial nitric oxide synthase and greater impairment of endothelium-dependent vasodilation. Finally, a small cohort of C57BL/6N females with combined exposure exhibited similar increases in LVEDP, indicating that both sexes are susceptible to the combined effect of nicotine and HFD. In summary, combined exposure to nicotine and HFD leads to greater CV harm, including both additive and new-onset CV dysfunction.NEW & NOTEWORTHY Nicotine product usage and high-fat diet consumption are two modifiable risk factors for cardiovascular diseases. Here, we demonstrate that in mice, combined exposure to inhaled nicotine and high-fat diet results in unique cardiovascular consequences compared with either treatment alone, including left ventricular diastolic dysfunction, dysregulation of blood pressure, autonomic dysfunction, and greater impairment of endothelium-dependent vasorelaxation. These findings indicate that individuals who consume both nicotine products and high-fat diet have distinctive cardiovascular risks.

Nicotine and novel tobacco products drive adverse cardiac remodeling and dysfunction in preclinical studies.

Background: The heart undergoes structural and functional changes in response to injury and hemodynamic stress known as cardiac remodeling. Cardiac remodeling often decompensates causing dysfunction and heart failure (HF). Cardiac remodeling and dysfunction are significantly associated with cigarette smoking. Although cigarette smoking has declined, the roles of nicotine and novel tobacco products (including electronic cigarettes and heat-not-burn tobacco) in cardiac remodeling are unclear. In this perspective, we present evidence demonstrating maladaptive cardiac remodeling in nicotine-exposed mice undergoing hemodynamic stress with angiotensin (Ang)-II infusion and review preclinical literature linking nicotine and novel tobacco products with cardiac remodeling and dysfunction. Methods: Adult, male C57BL/6J mice were exposed to room air or chronic, inhaled nicotine for 8 weeks. A subset of mice was infused with Ang-II via subcutaneous osmotic mini-pumps during the final 4 weeks of exposure. Left ventricular structure and function were assessed with echocardiography. Results: Chronic, inhaled nicotine abrogated Ang-II-induced thickening of the left ventricular posterior wall, leading to reduced relative wall thickness. Ang-II infusion was associated with increased left ventricular mass index in both air- and nicotine-exposed mice. Conclusions: These changes suggest a phenotypic shift from concentric hypertrophy to eccentric hypertrophy in nicotine-exposed, hemodynamically-stressed mice which could drive HF pathogenesis. These findings join a growing body of animal studies demonstrating cardiac remodeling and dysfunction following nicotine and electronic cigarette exposure. Further exploration is necessary; however, clinicians and researchers should not overlook these emerging products as potential risk factors in the pathogenesis of cardiac remodeling and associated diseases including HF.

Alpha7 nicotinic acetylcholine receptor mediates chronic nicotine inhalation-induced cardiopulmonary dysfunction.

Cigarette smoking remains the leading modifiable risk factor for cardiopulmonary diseases; however, the effects of nicotine alone on cardiopulmonary function remain largely unknown. Previously, we have shown that chronic nicotine vapor inhalation in mice leads to the development of pulmonary hypertension (PH) with right ventricular (RV) remodeling. The present study aims to further examine the cardiopulmonary effects of nicotine and the role of the α7 nicotinic acetylcholine receptor (α7-nAChR), which is widely expressed in the cardiovascular system. Wild-type (WT) and α7-nAChR knockout (α7-nAChR-/-) mice were exposed to room air (control) or nicotine vapor daily for 12 weeks. Consistent with our previous study, echocardiography and RV catheterization reveal that male WT mice developed increased RV systolic pressure with RV hypertrophy and dilatation following 12-week nicotine vapor exposure; in contrast, these changes were not observed in male α7-nAChR-/- mice. In addition, chronic nicotine inhalation failed to induce PH and RV remodeling in female mice regardless of genotype. The effects of nicotine on the vasculature were further examined in male mice. Our results show that chronic nicotine inhalation led to impaired acetylcholine-mediated vasodilatory response in both thoracic aortas and pulmonary arteries, and these effects were accompanied by altered endothelial nitric oxide synthase phosphorylation (enhanced inhibitory phosphorylation at threonine 495) and reduced plasma nitrite levels in WT but not α7-nAChR-/- mice. Finally, RNA sequencing revealed up-regulation of multiple inflammatory pathways in thoracic aortas from WT but not α7-nAChR-/- mice. We conclude that the α7-nAChR mediates chronic nicotine inhalation-induced PH, RV remodeling and vascular dysfunction.

Sex-Dependent Effects of Inhaled Nicotine on the Gut Microbiome.

INTRODUCTION: The impact of nicotine, the addictive component of both traditional cigarettes and e-cigarettes, on many physiological processes remains poorly understood. To date, there have been few investigations into the impact of nicotine on the gut microbiome, and these studies utilized oral administration rather than inhalation. This study aimed to establish if inhaled nicotine alters the gut microbiome and the effect of sex as a biological variable. METHODS: Female (n = 8 air; n = 10 nicotine) and male (n = 10 air; n = 10 nicotine) C57BL6/J mice were exposed to air (control) or nicotine vapor (12 hour/day) for 13 weeks. A fecal sample was collected from each mouse at the time of sacrifice, and the gut microbiome was analyzed by 16S rRNA gene sequencing. QIIME2, PICRUSt, and STAMP were used to detect gut bacterial differences and functional metabolic pathways. RESULTS: Sex-specific differences were observed in both alpha and beta diversities in the absence of nicotine. While nicotine alters microbial community structure in both male and female mice as revealed by the beta diversity metric, nicotine significantly reduced alpha diversity only in female mice. A total of 42 bacterial taxa from phylum to species were found to be significantly different among the treatment groups. Finally, analysis for functional genes revealed significant differences in twelve metabolic pathways in female mice and ten in male mice exposed to nicotine compared to air controls. CONCLUSIONS: Nicotine inhalation alters the gut microbiome and reduces bacterial diversity in a sex-specific manner, which may contribute to the overall adverse health impact of nicotine. IMPLICATIONS: The gut microbiota plays a fundamental role in the well-being of the host, and traditional cigarette smoking has been shown to affect the gut microbiome. The effects of nicotine alone, however, remain largely uncharacterized. Our study demonstrates that nicotine inhalation alters the gut microbiome in a sex-specific manner, which may contribute to the adverse health consequences of inhaled nicotine. This study points to the importance of more detailed investigations into the influence of inhaled nicotine on the gut microbiota.

Nicotine and vascular dysfunction.

Cigarette smoking is the single most important risk factor for the development of cardiovascular diseases (CVDs). However, the role of nicotine, the addictive component of all tobacco products, in the development of CVD is incompletely understood. Although increased public awareness of the harms of cigarette smoking has successfully led to a decline in its prevalence, the use of electronic cigarettes (e-cig) or electronic nicotine delivery system has increased dramatically in recent years because of the perception that these products are safe. This review summarizes our current knowledge of the expression and function of the nicotinic acetylcholine receptors in the cardiovascular system and the impact of nicotine exposure on cardiovascular health, with a focus on nicotine-induced vascular dysfunction. Nicotine alters vasoreactivity through endothelium-dependent and/or endothelium-independent mechanisms, leading to clinical manifestations in both cigarette smokers and e-cig users. In addition, nicotine induces vascular remodelling through its effects on proliferation, migration and matrix production of both vascular endothelial and vascular smooth muscle cells. The purpose of this review is to identify critical knowledge gaps regarding the effects of nicotine on the vasculature and to stimulate continued nicotine research.

Poly (ethylene glycol) hydrogel elasticity influences human mesenchymal stem cell behavior.

Coordinated investigations into the interactions between biologically mimicking (biomimetic) material constructs and stem cells advance the potential for the regeneration and possible direct replacement of diseased cells and tissues. Any clinically relevant therapies will require the development and optimization of methods that mass produce fully functional cells and tissues. Despite advances in the design and synthesis of biomaterial scaffolds, one of the biggest obstacles facing tissue engineering is understanding how specific extracellular cues produced by biomaterial scaffolds influence the proliferation and differentiation of various cell sources. Matrix elasticity is one such tailorable property of synthetic scaffolds that is known to differ between tissues. Here, we investigate the interactions between an elastically tailorable polyethylene glycol (PEG)-based hydrogel platform and human bone marrow-derived mesenchymal stem cells (hMSCs). For these studies, two different hydrogel compositions with elastic moduli in the ranges of 50-60 kPa and 8-10 kPa were implemented. Our findings demonstrate that the different elasticities in this platform can produce changes in hMSC morphology and proliferation, indicating that the platform can be implemented to produce changes in hMSC behavior and cell state for a broad range of tissue engineering and regenerative applications. Furthermore, we show that the platform's different elasticities influence stem cell differentiation potential, particularly when promoting stem cell differentiation toward cell types from tissues with stiffer elasticity. These findings add to the evolving and expanding library of information on stem cell-biomaterial interactions and opens the door for continued exploration into PEG-based hydrogel scaffolds for tissue engineering and regenerative medicine applications.

Poly(ethylene glycol) Hydrogels with Tailorable Surface and Mechanical Properties for Tissue Engineering Applications.

Advanced cellular biomanufacturing requires the large-scale production of biocompatible materials that can be utilized in the study of cell-matrix interactions and directed stem cell differentiation as well as the generation of physiologically relevant tissues for therapeutic applications. Herein we describe the development of a hydrogel based platform with tailorable mechanical properties that supports the attachment and proliferation of both pluripotent and multipotent stem cells. The biomimetic hydrogel scaffold generated provides biocompatible compositions for generating various tissue-like elasticities for regenerative medicine applications and advanced biomanufacturing.