Dichotomous mechanisms of aortic stiffening in high-fat diet fed young and old B6D2F1 mice

Abstract

Advancing age is associated with increased stiffness of large elastic arteries as assessed by aortic pulse wave velocity (PWV). Greater PWV, associated with increased risk of cardiovascular diseases, may result from altered expression of the extracellular matrix proteins, collagen and elastin, as well as cross‐linking of proteins by advanced glycation end products (AGEs). Indeed, aortic PWV is greater in old (28–31 months) normal chow (NC, 16% fat by kcal)‐fed male B6D2F1 mice compared with young (Y: 5–7 months) NC‐fed mice (397 ± 8 vs. 324 ± 14 cm/s, P <0.05). Aging also induces a ~120% increase in total aortic collagen content assessed by picosirius red stain, a ~40% reduction in medial elastin assessed by Verhoeff's Van Geison stain, as well as a 90% greater abundance of AGEs in the aorta (P <0.05). The typical American diet contains high dietary fat and may contribute to the etiology of arterial stiffening. To that end, we hypothesized that the age‐associated detriments in arterial stiffening are exacerbated in the face of high dietary fat. In young animals, high‐fat (40% fat by kcal) diet increases aortic stiffness by 120 ± 18 cm/s relative to age‐matched NC‐fed mice (P <0.001). High‐fat was without effect on aortic collagen or AGEs content in young animals; however, elastin was greatly reduced (~30%) after high‐fat in young mice. In old animals, high‐fat increased aortic stiffness by 108 ± 47 cm/s but was without effect on total collagen content, medial elastin, or AGEs. These data demonstrate that both aging and high‐fat diet increase aortic stiffness, and although a reduction in medial elastin may underlie increased stiffness in young mice, stiffening of the aorta in old mice after high‐fat diet does not appear to result from a similar structural modification.

Experimental reduction of miR-92a mimics arterial aging

“…Similar to what we have observed with aging in this mouse model, 14 Our group has previously shown that PWV of old mice is 22% higher compared to young mice, 15 and here, we demonstrate a 37% increase in PWV in mice treated with anti-miR-92a compared to scr-miR treated mice. Scr-miR treatment also appears to be without effect on PWV in young mice (untreated: 324±14cm/s 15 vs. scr-miR: 309±12cm/s). Although IMT has been demonstrated to increase with advancing age, IMT was unaltered by anti-miR-92a treatment (date not shown).…”

“…Compared to our previously published studies, body mass was similar in untreated young mice and young mice treated with scrambled miR (young: 32.7±1.34 15 vs. scr-miR: 30±0.3, g). In addition, mean arterial pressure (young: 130±1 16 vs. scr-miR: 131±7, mm Hg) and pulse wave velocity (young: 324 ± 14 15 vs. scr-miR: 309±12, cm/s) were also similar between young untreated and scr-miR treated mice.…”

“…In addition, mean arterial pressure (young: 130±1 16 vs. scr-miR: 131±7, mm Hg) and pulse wave velocity (young: 324 ± 14 15 vs. scr-miR: 309±12, cm/s) were also similar between young untreated and scr-miR treated mice. Carotid artery maximal dilation to ACh was 95% in untreated mice 16 and 92% in scr-miR treated mice.…”

Hypertension and decreased aortic compliance due to reduced elastin amounts do not increase atherosclerotic plaque accumulation in Ldlr−/− mice

“…Diet and Ldlr genotype have no significant effects on aortic compliance. In B6D2F1 mice, WD decreases aortic compliance as measured by pulse wave velocity 46 and in vitro mechanical tests 47 . Previous studies have found reduced aortic compliance in Ldlr −/− mice 48 .…”

Nutrition and other lifestyle influences on arterial aging

“…However, preclinical (mouse model) evidence demonstrates that “Western” diet (high fat/sugar) increases arterial stiffness (DeMarco et al, 2015; Henson et al, 2014) and reduces endothelial function (Lesniewski et al, 2013) with age. Direct evidence for this in humans is limited and less consistent.…”