This randomized crossover trial was carried out in healthy young adults who lived in campus, we aimed to examine the potential cardiovascular impact of vitamin C supplementation against air pollution exposure, and potential molecular mechanism were explored. The crossover design with repeated measures is conducive to evaluate the effect of the intervention, and we took advantage of the fact that the participants lived and studied in the same building and had similar time-activity patterns. A series of markers of cardiovascular health in response to short-term air pollution exposure were assessed, and found that VC supplementation had beneficial effects on BP, oxidative stress biomarkers and inflammation biomarkers.
Epidemiological studies have established that increasing mortality of CVDs was associated with exposure to air pollution, and the most intuitive indicator of response is blood pressure(Brook et al. 2010). A recent study showed that very short-term exposure to PM has positive relationship with higher BP, and this effect occurred on the same hour of BP measurement(Hu et al. 2021). Although many methods (e.g. indoor air filtration, wearing respirators) have been conducted to avoid this adverse effect of PM(Shi et al. 2017), those are still unconvincing. In a study of 35 healthy college volunteers in Shanghai, China, SBP was decreased by 2.7% and DBP was decreased by 4.8% when the students lived in dormitories with air purification(Chen et al. 2015). However, another air purification-related intervention study indicated that air purification had no significant effect on BP(Dong et al. 2019). Therefore, there is an urgent need for a more effective therapy to decrease the adverse effects of PM exposure on BP. In our study, we found that vitamin C supplementation lead a notable decrease in SBP and PP comparing with placebo group. This discovery is consistent with previously published studies. A meta-analysis, enrolled in 29 studies, conducted from 1982 to 2010, included 1407 participants reported that the dose of vitamin C supplementation ranged from 60 to 4000mg per day could significantly reduce SBP and DBP(Juraschek et al. 2012). Vitamin C has potential hypotensive effect may relate to its antioxidant activity through increasing nitric oxide (NO) synthesis and bioavailability. Vitamin C is thought to scavenge superoxide, and it can reduce the reactivity of NO with superoxide and inhibit the formation of peroxynitrite(Mason et al. 2021). It has also been shown that Vitamin C can preserve concentrations of the endothelial NO synthase cofactor tetrahydrobiopterin, in turn, the production of NO is maintained by the NO synthase of endothelial cells(Huang et al. 2000).
Inflammation is thought to an important pathological mechanism of adverse cardiovascular effects caused by air pollution. Vitamin C is a water-soluble vitamin and its anti-inflammatory activity has been widely proved(Akolkar et al. 2017; Ang et al. 2018). Ellulu et al found(Ellulu et al. 2015) dietary vitamin C supplement had potential effects in reducing the inflammatory state, mediated through hs-CRP, IL-6, in hypertensive and/or diabetic obese patients. Also, He et al(He et al. 2021) proved that the animals were fed vitamin C could reduce the levels of inflammatory factors, such as IL -1β, IL-6 and TNF-α. However, no such treatment-related benefits were found in a previous study among healthy adults when the patient is exposed to high level of PM2.5. In our study, multiple biomarkers relevant to inflammation, such as IL-6, TNF-a, CRP and IL-8, were detected. Our results showed vitamin C supplementation lead a notable decrease in IL-6, TNF-a and CRP compared with the placebo group. Such potential anti-inflammatory effect of vitamin C against air pollution exposure is consistent with in vitro and in vivo experimental studies(Su et al. 2013; Zhang et al. 2018).
Oxidative stress represents another important pathophysiological mechanism of how air pollutants jeopardize cardiovascular health. Our study suggests that vitamin C supplementation was association with a significant increase in GSH-Px in response to air pollution exposure, probably by reducing the occurrence of oxidative stress and increasing antioxidant enzyme activity. Our results are consistent with the previously published studies(Eatemadyboroujeni et al. 2021). Previous experiments in animal model and cultured cells showed that vitamin C led to a notable increase in GSH-Px and SOD activities in response to PM exposure, accompanied by reduced levels of MDA(Liu et al. 2019a; Frikke-Schmidt et al. 2011). Similarly, Previous studies have shown that individuals with high vitamin C concentrations have stronger antioxidant capacity than individuals with low vitamin C concentrations(Paschalis et al. 2016). The protective effect of vitamin C observed in those study is biologically plausible. Vitamin C, act as an electron donor for the enzymes present in the human body and free-radical scavenger(Wilson 2005), can replace glucose in many chemical reactions and prevent the non-enzymatic glycosylation of proteins(Afkhami-Ardekani M 2003). It has been reported that oxidative stress could lead to the release of inflammatory cytokines, such as IL-8 and NO(Qiu et al. 2015). The beneficial effects of vitamin C may relate to its effect on the release of NO to protect the human body from oxidative stress damage, and then play an important role in disease prevention. Our findings yielded consistent results that VC supplementation alleviated oxidative stress caused by exposure to PM air pollution, which may decrease incidence of adverse cardiovascular events.
Accumulating evidence indicated that the effect of PM on circulating biomarkers were generally stronger among male participants than female participants(Wang et al. 2015). Previous two studies have shown that the inflammation caused by short-term and long-term exposure to PM are more pronounced in men(Allen et al. 2011; Hoffmann B 2009). In this study, limited evidence on the effectiveness of vitamin C interventions for individuals of different genders are inconsistent. Stratification analyzes indicated that vitamin C supplementation resulted in a significant reduction in APOB and GSH-Px in females but not in males. On the contrary, vitamin C supplementation resulted in a significant reduction in TNF-α in males but not in females. The results described above suggest that dietary vitamin C supplementation may have more obvious benefits on inflammation in male and have more obvious benefits on blood lipid and oxidative stress in female, while there was no statistically significant effect modification by gender. Similarly, Allen et al. (Allen et al. 2011) observed that healthy male living in woodsmoke-impacted community affected the community’s vascular endothelial function and systemic inflammation were more pronounced than healthy female. It has been reported that female and male individuals have different microvasculature and dynamics in balancing vasoconstriction and vasodilation(Joyner et al. 2016; Cui X 2018). additionally, different hormone levels may also account for the effects of the intervention differ between men and women.
Our study has certain advantages. First, this study is, to our knowledge, first evidence of vitamin C supplementation on cardiovascular health among free-living population over a reasonably long follow-up period. Compared with exposure to a control environment, our findings may be more applicable to real-world situations. Second, we obtain personal exposure data of PM in all public places on the campus, thus our environmental pollution data can more accurately reflect the individual PM exposure level. Finally, the biomarkers we evaluated were chosen that have been implicated as markers of possible mechanism that reflect cardiovascular risk induced by air pollution exposure. This allows us to have a better understanding of the potential cardiovascular benefits of VC supplementation linked with PM exposure.
There are also several limitations to this study. First, our study only recruited healthy young adults rather than those are more sensitive to ambient air pollution (e. g. patients with CVD), which may be better to balance various factors. However, healthy young adults may be less susceptible to air pollution-linked adverse health effects and underestimate the treatment benefits of vitamin C supplementation. Our results should be extrapolated to other populations carefully. Therefore, future research should be verified in populations who are more sensitive to adverse effects in order to fully reveal the protective effect of vitamin C. Second, although we use a three-day diet record method to calculate dietary Vitamin C intake, we cannot rule out the possible role of assimilate ingested other nutrients to the results. However, because of randomly grouped volunteers have a regular diet at university canteens, this potential confounding might not be substantial. Third, since the sample size of our study is small, this limitation affects the precision and statistical power. Finally, the short-term nature of our study might lead us to underestimate or miss some potential lagged health benefits attributable to vitamin C supplementation.