Ancient Greece was the cradle of the Mediterranean food tradition, characterized by the Mediterranean"eternal trinity"wheat - olive oil - wine, the very essence of the country's traditional agricultural and dietary regime, enriched by a culture of sharing and commensality. This food model, subsequently adopted and spread by the Romans, was rediscovered at the end of the Second World War by two American researchers, Leland Allbaugh and Ancel Keys. With the famous Seven Countries Study, Keys demonstrated for the first time that populations practicing a Mediterranean diet - such as the Greeks and southern Italians - showed low mortality rates from ischemic heart disease compared to the peoples of Northern Europe and North America. Since then, numerous subsequent epidemiological studies and randomized clinical trials have confirmed the beneficial effects of the Mediterranean diet both in primary and secondary prevention of cardiovascular diseases. This review will focus on the origins of the Mediterranean diet from its roots and its relationship to cardiovascular disease, with a brief overview of the nutritional mechanisms that influence atherosclerosis.

Based on the findings presented in this study, we propose the hypothesis that calcium could be a mediator for the development of atherosclerosis. Figure 8 shows a schematic illustration of the hypothesis. The presence of risk factors such as hypertension, hyperlipidemia, and smoking may increase the influx of calcium into vascular ECs. We have shown that reactive oxygen species, which are considered to be a risk factor for the development of atherosclerosis, actually increase [Ca++]i in vascular ECs. Increased intracellular calcium may damage the function of ECs, resulting in platelet aggregation at the damaged site. Increased intracellular calcium may also increase uptake of macromolecules in plasma such as fibrinogen and LDL, eventually forming atherosclerotic plaque. We have also shown that the influx of calcium into vascular ECs is associated with LDL transport across vascular ECs. The pretreatment by nifedipine inhibited both the increase in [Ca++]i and the increase in LDL transport, suggesting that intracellular calcium modulates LDL transport across ECs. Growth factors released from platelets may provoke migration and proliferation of medial SMCs in the aterial intima. It has been reported that migration of SMCs from arterial media to intima is enhanced by the presence of calcium, and can be inhibited by the pretreatment of calcium antagonist. As demonstrated in this study, calcium also plays an important role in the proliferation of SMCs provoked by some kinds of growth factors such as EGF. On the other hand, we found that an increased amount of dietary Mg suppressed the development of atherosclerotic lesions in the aorta of cholesterol-fed rabbits without affecting plasma total cholesterol and HDL-cholesterol concentrations. The mechanism of action might also be related to the calcium entry blocking action. The clinical and nutritional implications of these phenomena should be investigated further. The evidences presented in this study, however, would not be sufficient to fully explain the etiological role of calcium in atherogenesis. Further studies are required to elucidate the mechanism of the contribution of calcium to atherogenesis. The efficacy of calcium antagonist for the prevention of atherosclerosis in humans should also be investigated further.

Although many cardiovascular (CVD) medications, such as antithrombotics, statins, and antihypertensives, have been identified to treat atherosclerosis, at most, many of these therapeutic agents only delay its progression. A growing body of evidence suggests physical exercise could be implemented as a non-pharmacologic treatment due to its pro-metabolic, multisystemic, and anti-inflammatory benefits. Specifically, it has been discovered that certain anti-inflammatory peptides, metabolites, and RNA species (collectively termed"exerkines") are released in response to exercise that could facilitate these benefits and could serve as potential therapeutic targets for atherosclerosis. However, much of the relationship between exercise and these exerkines remains unanswered, and there are several challenges in the discovery and validation of these exerkines. This review primarily highlights major anti-inflammatory exerkines that could serve as potential therapeutic targets for atherosclerosis. To provide some context and comparison for the therapeutic potential of exerkines, the anti-inflammatory, multisystemic benefits of exercise, the basic mechanisms of atherosclerosis, and the limited efficacies of current anti-inflammatory therapeutics for atherosclerosis are briefly summarized. Finally, key challenges and future directions for exploiting these exerkines in the treatment of atherosclerosis are discussed.

OBJECTIVE:UVB irradiation is an established treatment for immunoinflammatory cutaneous disorders and has been shown to suppress cutaneous and systemic inflammatory diseases through modulation of the adaptive immune response. However, it remains unknown whether UVB irradiation prevents an immunoinflammatory disease of arteries such as atherosclerosis.

APPROACH AND RESULTS:Here, we show that UVB exposure inhibits the development and progression of atherosclerosis in atherosclerosis-prone mice by expanding and enhancing the functional capacity of CD4forkhead box P3regulatory T cells and regulating proatherogenic T-cell responses. Experimental studies in Langerhans cell-depleted mice revealed that epidermal Langerhans cells play a critical role in UVB-dependent induction of CD4forkhead box P3regulatory T cells, suppression of proatherogenic T-cell responses, and prevention of atherosclerotic plaque development.

CONCLUSIONS:Our findings suggest the skin immune system as a novel therapeutic target for atherosclerosis and provide a novel strategy for the treatment and prevention of atherosclerosis.

Cardiovascular (CV) disease (CVD) is the leading global cause of mortality, being responsible for 46% of non-communicable disease deaths. It has been estimated that about 85.6 million Americans are living with some form of CVD, which continues to rise. Healthy lifestyle choices may reduce the risk of myocardial infarction by>80%, with nutrition playing a key role. Vegetarian dietary patterns reduce CVD mortality and the risk of coronary heart disease (CHD) by 40%. Plant-based diets are the only dietary pattern to have shown reversal of CHD. Additionally, evidence suggests benefits of vegetarian dietary patterns in both the prevention and the treatment of heart failure and cerebrovascular disease. Plant-based diets are associated with lower blood pressure, lower blood lipids, and reduced platelet aggregation than non-vegetarian diets and are beneficial in weight management, reduce the risk of developing metabolic syndrome, and type 2 diabetes. They have also been shown an effective treatment method in diabetes management. Well planned vegetarian diets provide benefits in preventing and reversing atherosclerosis and in decreasing CVD risk factors and should be promoted through dietary guidelines and recommendations.

Whole body vibration (WBV) has a marked impact on lipid metabolism and the endocrine system, which is related to the progression of atherosclerosis (AS). To investigate the effects of WBV, we measured the atherosclerotic plaque area of apolipoprotein E-knockout (ApoE) AS mice, which were trained by WBV (15 Hz, 30 min) for 12 weeks. Simultaneously, serum levels of lipids, insulin-like growth factor 1 (IGF-1), insulin-like growth factor 1 receptor (IGF-1R), interleukin 6 (IL-6), and the mRNA and protein levels of the same in the aorta were compared between the control and WBV groups. The results indicated that WBV significantly reduced the atherosclerotic plaque area with lower very low-density lipoprotein (VLDL) and oxidized low-density lipoprotein (ox-LDL) in the blood. Moreover, the levels of IGF-1 in serum and expression of IL-6, IGF-1R, and p-IGF-1R protein in the mice aorta decreased significantly in the WBV group. In addition, we found that serum IGF-1 in mice increased to the highest concentration in 30 min after WBV for 10, 30, 60, and 120 minutes. These results suggested that appropriate WBV may delay the progression of AS, which was associated with acutely elevated serum IGF-1 and lower levels of IGF-1 and IL-6 in the aorta for long-term treatment.