The Protective Role of Bioactive Quinones in Stress-induced Senescence Phenotype of Endothelial Cells Exposed to Cigarette Smoke Extract

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.

Exogenous Vitamins K Exert Anti-Inflammatory Effects Dissociated from Their Role as Substrates for Synthesis of Endogenous MK-4 in Murine Macrophages Cell Line

“…Specifically, there were stronger anti-inflammatory effects of K 3 and forms of vitamins K with shorter isoprenoid chains (K 1 , MK-4 and MK-5) than among MK-6 and MK-7, which contain longer isoprenoid chains. This pattern diverged, for example, from endothelial cells, where MK-7 displayed more potent effects than MK-4 [ 26 ], as well as in the case of in vivo model, where MK-7 was shown to be more efficient to achieve carboxylation of extrahepatic (e.g., osteocalcin) and hepatic (e.g., prothrombin) proteins [ 27 ]. The latter could be due to the advantageous pharmacokinetic profile of MK-7, but the order of potency of binding of K 1 , MK-4, MK-7 and K 3 to VCORC1 and the efficacy of various forms of vitamins K to serve as substrates for post-translational γ-carboxylation pointed to the weakest effects for K 3 [ 28 ]; in contrast, in our experiments, K 3 was among the more potent forms of vitamins K in inducing anti-inflammatory effects in RAW 264.7 cells.…”

Role of Coenzyme Q10 in Health and Disease: An Update on the Last 10 Years (2010–2020)

“…Precisely, these studies show that CoQ deficiency in such conditions promotes increased ROS generation, and depletion of intracellular antioxidant defense systems, such as uncoupling protein 2 (UCP2), and superoxide dismutase 2 (SOD2), leading to cellular damage. Apparently, in HUVECs subjected to conditions of oxidative stress and inflammation, using stressors such as oxidized low-density lipoprotein (oxLDL) or lipopolysaccharide (LPS), CoQ treatment proves to be effective in suppressing endothelial oxidative injuries [ 22 , 23 , 24 , 25 ]. Here, prime mechanisms of protection against oxidative stress include blocking the activities of protein kinase C (PKC)/NADPH oxidase, as well as improving mitochondrial function.…”

Vitamin K Epoxide Reductase Complex Subunit 1-Like 1 (VKORC1L1) Inhibition Induces a Proliferative and Pro-inflammatory Vascular Smooth Muscle Cell Phenotype

“…Finally, after describing putative mechanisms for VKA-induced vascular dysfunction, we found also that MK7 treatment can dose-dependently reduce vascular remodeling, inflammation and ER stress in vitro . K2 vitamins have previously been attributed anti-inflammatory effects ( 40 , 41 ). However, we show here for the first time that vitamin K can alleviate inflammation in vascular cells.…”