Oxidative stress is an important risk factor contributing to the pathogenesis of cardiovascular diseases. Oxidative stress that results from excessive reactive oxygen species (ROS) production accounts for impaired endothelial function, a process which promotes atherosclerotic lesion or fatty streaks formation (foam cells). Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor involved in cellular redox homeostasis. Upon exposure to oxidative stress, Nrf2 is dissociated from its inhibitor Keap-1 and translocated into the nucleus, where it results in the transcriptional activation of cell defense genes. Nrf2 has been demonstrated to be involved in the protection against foam cells formation by regulating the expression of antioxidant proteins (HO-1, Prxs, and GPx1), ATP-binding cassette (ABC) efflux transporters (ABCA1 and ABCG1) and scavenger receptors (scavenger receptor class B (CD36), scavenger receptor class A (SR-A) and lectin-type oxidized LDL receptor (LOX-1)). However, Nrf2 has also been reported to exhibit pro-atherogenic effects. A better understanding on the mechanism of Nrf2 in oxidative stress-induced cardiac injury, as well as the regulation of cholesterol uptake and efflux, are required before it can serve as a novel therapeutic target for cardiovascular diseases prevention and treatment.

Cardiovascular diseases (CVDs) are closely linked to cellular oxidative stress and inflammation. This may be resulted from the imbalance generation of reactive oxygen species and its role in promoting inflammation, thereby contributing to endothelial dysfunction and cardiovascular complications. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor that plays a significant role in regulating expression of antioxidant and cytoprotective enzymes in response to oxidative stress. Natural products have emerged as a potential source of bioactive compounds which have shown to protect against atherogenesis development by activating Nrf2 signaling. This review aims to provide a comprehensive summary of the published data on the function, regulation and activation of Nrf2 as well as the molecular mechanisms of natural products in regulating Nrf2 signaling. The beneficial effects of using natural bioactive compounds as a promising therapeutic approach for the prevention and treatment of CVDs are reviewed.

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Secretory phospholipase A2-IIA (sPLA2-IIA) is one of the key enzymes causing lipoprotein modification and vascular inflammation. Maslinic acid is a pentacyclic triterpene which has potential cardioprotective and anti-inflammatory properties. Recent research showed that maslinic acid interacts with sPLA2-IIA and inhibits sPLA2-IIA-mediated monocyte differentiation and migration. This study elucidates the potential of maslinic acid in modulating sPLA2-IIA-mediated inflammatory effects in THP-1 macrophages. We showed that maslinic acid inhibits sPLA2-IIA-mediated LDL modification and suppressed foam cell formation. Further analysis revealed that sPLA2-IIA only induced modest LDL oxidation and that inhibitory effect of maslinic acid on sPLA2-IIA-mediated foam cells formation occurred independently of its anti-oxidative properties. Interestingly, maslinic acid was also found to significantly reduce lipid accumulation observed in macrophages treated with sPLA2-IIA only. Flow cytometry analysis demonstrated that the effect observed in maslinic acid might be contributed in part by suppressing sPLA2-IIA-induced endocytic activity, thereby inhibiting LDL uptake. The study further showed that maslinic acid suppresses sPLA2-IIA-induced up-regulation of PGE2 levels while having no effects on COX-2 activity. Other pro-inflammatory mediators TNF-a and IL-6 were not induced in sPLA2-IIA-treated THP-1 macrophages. The findings of this study showed that maslinic acid inhibit inflammatory effects induced by sPLA2-IIA, including foam cells formation and PGE2 production.

Macrophage foam cell formation represents a key feature that contributes to the development of atherosclerotic lesions. Assessment of cardioprotective natural compounds targeting macrophage foam cell formation processes including lipid uptake and cholesterol efflux could lead to the identification of potential lead compounds for development into novel anti-atherosclerotic drugs. In this case study, maslinic acid, a natural product was used to study the effect on lipid uptake and cholesterol efflux in THP-1-derived macrophages.  Oil red O (ORO) staining and 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate-labeled oxidized low-density lipoprotein (Dil-labeled oxLDL) uptake assays were performed to determine lipid uptake by macrophages while cholesterol efflux was assessed using 3-hexanoyl-NBD labeled cholesterol. ORO-stained images were further analyzed using ImageJ analysis software to determine intracellular lipid droplets accumulation and flow cytometric analysis of mean fluorescence intensity were obtained to quantify Dil-labeled oxLDL uptake by macrophages. Meanwhile, 3-hexanoyl-NBD labeled cholesterol uptake and efflux from THP-1-derived macrophages were characterized. The fluorescence intensity values obtained from the medium and cell lysates were then converted into percentage of cholesterol efflux. The results have shown that incubation with maslinic acid suppressed oxLDL-induced macrophage foam cell formation which may be contributed from its effect in reducing lipid uptake and enhancing cholesterol efflux. In conclusion, the optimized ORO staining, Dil-labeled oxLDL uptake, and fluorescent-labeled cholesterol efflux assays provide reproducible and reliable results for assessment of foam cells formation.

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