Defective macroautophagy/autophagy and mitochondrial dysfunction are known to stimulate senescence. The mitochondrial regulator PPARGC1A (peroxisome proliferator activated receptor gamma, coactivator 1 alpha) regulates mitochondrial biogenesis, reducing senescence of vascular smooth muscle cells (VSMCs); however, it is unknown whether autophagy mediates PPARGC1A-protective effects on senescence. Using ppargc1a −/-VSMCs, we identified the autophagy receptor SQSTM1/p62 (sequestosome 1) as a major regulator of autophagy and senescence of VSMCs. Abnormal autophagosomes were observed in VSMCs in aortas of ppargc1a −/mice. ppargc1a −/-VSMCs in culture presented reductions in LC3-II levels; in autophagosome number; and in the expression of SQSTM1 (protein and mRNA), LAMP2 (lysosomalassociated membrane protein 2), CTSD (cathepsin D), and TFRC (transferrin receptor). Reduced SQSTM1 protein expression was also observed in aortas of ppargc1a −/mice and was upregulated by PPARGC1A overexpression, suggesting that SQSTM1 is a direct target of PPARGC1A. Inhibition of autophagy by 3-MA (3 methyladenine), spautin-1 or Atg5 (autophagy related 5) siRNA stimulated senescence. Rapamycin rescued the effect of Atg5 siRNA in Ppargc1a +/+ , but not in ppargc1a −/-VSMCs, suggesting that other targets of MTOR (mechanistic target of rapamycin kinase), in addition to autophagy, also contribute to senescence. Sqstm1 siRNA increased senescence basally and in response to AGT II (angiotensin II) and zinc overload, two known inducers of senescence. Furthermore, Sqstm1 gene deficiency mimicked the phenotype of Ppargc1a depletion by presenting reduced autophagy and increased senescence in vitro and in vivo. Thus, PPARGC1A upregulates autophagy reducing senescence by a SQSTM1-dependent mechanism. We propose SQSTM1 as a novel target in therapeutic interventions reducing senescence.

The purpose of this review is to highlight current research on the benefits of supplementation with foods with a diverse polyphenol composition, including fruits, vegetables, nuts, grains, oils, spices, and teas in blunting atherosclerosis. We searched PubMed for publications utilizing whole food or polyphenols prepared from whole foods in Apolipoprotein E (ApoE) or Low-Density Lipoprotein Receptor (LDLR) knockout mice, and identified 73 studies in which plaque was measured. The majority of the studies reported a reduction in plaque. Nine interventions showed no effect, while three using Agaricus blazei mushroom, HYJA-ri-4 rice variety, and safrole-2’, 3’-oxide (SFO) increased plaque. The mechanisms by which atherosclerosis was reduced include improved lipid profile, antioxidant status, and cholesterol clearance, and reduced inflammation. Importantly, not all dietary interventions that reduce plaque showed an improvement in lipid profile. Additionally, we found that, out of 73 studies, only 9 used female mice and only 6 compared both sexes. Only one study compared the two models (LDLR vs. ApoE), showing that the treatment worked in one but not the other. Not all supplementations work in both male and female animals, suggesting that increasing the variety of foods with different polyphenol compositions may be more effective in mitigating atherosclerosis.

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With the increasing appreciation for sex as a biological variable and the inclusion of female mice in research, it is important to understand the influence of the estrous cycle on physiological function. Sex hormones are known to modulate vascular function, but the effects of the mouse estrous cycle phase on arterial stiffness, endothelial function, and arterial estrogen receptor expression remain unknown. In 23 female C57BL/6 mice (6 months of age), we determined the estrous cycle stage via vaginal cytology and plasma hormone concentrations. Aortic stiffness, assessed by pulse wave velocity, was lower during the estrous phase compared with diestrus. In ex vivo assessment of isolated pressurized mesenteric and posterior cerebral arteries, the responses to acetylcholine, insulin, and sodium nitroprusside, as well as nitric oxide-mediated dilation, were not different between estrous cycle phases. In the aorta, expression of phosphorylated estrogen receptor α was higher for mice in estrus compared with mice in proestrus. In the cerebral arteries, gene expression for estrogen receptor β (Esr2) was lowest for mice in estrus compared with diestrus and proestrus. These results demonstrate that the estrous phase is associated with lower in vivo large artery stiffness in mice. In contrast, ex vivo resistance artery endothelial function is not different between estrous cycle phases. Estrogen receptor expression is modulated by the estrous cycle in an artery-dependent manner. These results suggest that estrous cycle phase should be considered when measuring in vivo arterial stiffness in young female mice.

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.