Abstract
Endothelial dysfunction represents the initial stage in atherosclerotic lesion development which occurs physiologically during aging, but external factors like diet, sedentary lifestyle, smoking accelerate it. Since cigarette smoking promotes oxidative stress and cell damage, we developed an in vitro model of endothelial dysfunction using vascular cells exposed to chemicals present in cigarette smoke, to help elucidate the protective effects of anti-inflammatory and antioxidant agents, such as ubiquinol and vitamin K, that play a fundamental role in vascular health. Treatment of both young and senescent Human Umbilical Vein Endothelial Cells (HUVECs) for 24 h with cigarette smoke extract (CSE) decreased cellular viability, induced apoptosis via reactive oxygen species (ROS) imbalance and mitochondrial dysfunction and promoted an inflammatory response. Moreover, the senescence marker SA-β-galactosidase was observed in both young CSE-exposed and in senescent HUVECs suggesting that CSE exposure accelerates aging in endothelial cells. Supplementation with 10 µM ubiquinol and menaquinone-7 (MK7) counteracted oxidative stress and inflammation, resulting in improved viability, decreased apoptosis and reduced SA-β-galactosidase, but were ineffective against CSE-induced mitochondrial permeability transition pore opening. Other K vitamins tested like menaquinone-4 (MK4) and menaquinone-1 (K1) were less protective. In conclusion, CSE exposure was able to promote a stress-induced senescent phenotype in young endothelial cells likely contributing to endothelial dysfunction in vivo. Furthermore, the molecular changes encountered could be offset by ubiquinol and menaquinone-7 supplementation, the latter resulting the most bioactive K vitamin in counteracting CSE-induced damage.
Highlights
Over the past half century, a steady decline in deaths from cardiovascular diseases (CVDs) has been observed in highly developed countries, atherosclerosis-associated vascular diseases remain the leading cause of morbidity and mortality worldwide [1,2]
Young Human Umbilical Vein Endothelial Cells (HUVECs) were first exposed to a range of cigarette smoke extract (CSE) (0.106 puffs/mL–1.7 puffs/mL) for 24 h in order to develop a model of CSE-induced cellular stress and premature aging
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Summary
Over the past half century, a steady decline in deaths from cardiovascular diseases (CVDs) has been observed in highly developed countries, atherosclerosis-associated vascular diseases remain the leading cause of morbidity and mortality worldwide [1,2]. The major modifiable risk factors for CVDs are diet, sedentary lifestyle, excessive alcohol consumption and tobacco smoke. The latter is a highly complex aerosol of >5000 compounds, including reactive oxygen species (ROS), reactive nitrogen species, carbon monoxide, nitric oxides, nicotine, polycyclic hydrocarbons, cadmium, as well as other metals and oxidants [3]. Cigarette smoke-derived ROS trigger the activation of nuclear factor-κB (NF-κB) resulting in the expression of pro-inflammatory cytokines, such as interleukin-6 and interleukin-8, adhesion molecules, such as intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1) on the surface of endothelial cells [7]. Therapeutic strategies to slow down this senescence-induced process is an attractive approach for improving vascular function and reducing the risk of developing vascular dysfunction
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