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Gut microbiome alterations have recently been linked to many chronic conditions including cardiovascular disease (CVD). There is an interplay between diet and the resident gut microbiome, where the food eaten affects populations of certain microbes. This is important, as different microbes are associated with various pathologies, as they can produce compounds that are disease-promoting or disease-protecting. The Western diet negatively affects the host gut microbiome, ultimately resulting in heightened arterial inflammation and cell phenotype changes as well as plaque accumulation in the arteries. Nutritional interventions including whole foods rich in fiber and phytochemicals as well as isolated compounds including polyphenols and traditional medicinal plants show promise in positively influencing the host gut microbiome to alleviate atherosclerosis. This review investigates the efficacy of a vast array of foods and phytochemicals on host gut microbes and atherosclerotic burden in mice. Reduction in plaque by interventions was associated with increases in bacterial diversity, reduction in the Firmicutes/Bacteroidetes (F/B) ratio, and upregulation of Akkermansia. Upregulation in CYP7 isoform in the liver, ABC transporters, bile acid excretion, and the level of acetic acid, propionic acid, and butyric acid were also noted in several studies reducing plaque. These changes were also associated with attenuated inflammation and oxidative stress. In conclusion, an increase in the abundance of Akkermansia with diets rich in polyphenols, fiber, and grains is likely to reduce plaque burden in patients suffering from CVD.

Smoking is the foremost modifiable risk factor for cardiovascular disease, the leading cause of death in the U.S., yet almost 14% of American adults continue to smoke. Cigarettes contain nicotine, a highly addictive stimulant which prevents users from quitting smoking without withdrawal. Nicotine and other chemicals in cigarette smoke damage the endothelium, a process that in turn influences smooth muscle cells and contributes to atherosclerosis or plaque build‐up in the arteries causing cardiovascular diseases. Gender differences have emerged between risk for both cardiovascular disease and the effect of smoking on cardiovascular disease. While risk of developing cardiovascular disease is highest in men, women's risk increases post‐menopause, which may be partly explained by a decrease in protective estrogen levels. In addition, while slightly more men smoke than women (15% vs 13%), smoking is more harmful to women's cardiovascular system, resulting in an increased risk for heart attacks compared to men with a similar background. Despite understanding the role of smoking on the cardiovascular system and apparent human sex differences the specific processes accounting for female and male differences and whether nicotine alone is sufficient for these mechanisms is not fully understood. Therefore, we exposed female and male ApoE‐/‐ (8 mice per group) to either nicotine in drinking water (0.2 mg/ml) or cigarette smoke for 4 months. Exposure was matched to a comparable nicotine ingestion by a moderate smoker. Males exposed to nicotine or smoke accrued significantly more plaque in the aortic arch (22.4 ± 7.2 and 21.7 ± 5%, respectively), but not descending aorta, compared to controls (12.4 ± 4.7%). In contrast, females exposed to nicotine and cigarette smoke accumulated significantly more plaque in the arch (30.3 ± 8.5% and 38.8 ± 4.3%, respectively) and descending aorta (3.4 ± 0.9% and 5.8 ± 2.7%, respectively), compared with controls (arch: 18.7 ± 5% and descending aorta: 1.5 ± 0.5%). These sex differences were independent of changes in cholesterol, triglycerides and LDL, but correlated with changes in the blood levels of IL‐17. Altogether these data suggest that females are at higher risk of developing atherosclerosis than males exposed to nicotine and cigarette smoke which could be mediated by an inflammatory response induced by IL‐17.

Adiponectin, a hormone highly abundant in circulation, has many beneficial effects in atherosclerosis; however, gene deficiency of this hormone or its receptor have shown detrimental effects on plaque burden in mice. Our objective was to understand the role of sex and aging in the effects of adiponectin deficiency on plaque content, inflammation, and the mechanisms regulating the phenotype of adipoq-/- vascular smooth muscle cells (VSMCs). Even a 50% reduction in the expression of adiponectin led to a plaque reduction in males and an increase in females, compared with apoe-/- controls. Plaque reduction may be attributable to chemokines upregulated in males and downregulated in females. Changes in plaque were not attributed to changes in cholesterol or cardiovascular disease (CVD) markers. In old mice, both genotypes and sexes accumulated more plaque than apoe-/-. RNA sequencing of VSMCs from male mice in vitro uncovered a critical role for adiponectin in AKT signaling, regulation of the extracellular matrix, and TGF-b signaling. Upregulation of AKT activity mediated proliferation and migration of adipoq-/- cells. Activation of AMPK with metformin or AdipoRon reduced AKT-dependent proliferation and migration of adipoq-/- cells but did not improve the expression of contractile genes. Anti-atherogenic mechanisms targeted the ECM in adipoq-/- cells, downregulating MMP2 and 9 and upregulating decorin. Our study uncovered sex and age-dependent effects of adiponectin deficiency in atherosclerosis.