Aortic perivascular adipose-derived interleukin-6 contributes to arterial stiffness in low-density lipoprotein receptor deficient mice

Abstract

Du B, Ouyang A, Eng JS, Fleenor BS. Aortic perivascular adipose-derived interleukin-6 contributes to arterial stiffness in lowdensity lipoprotein receptor deficient mice. Am J Physiol Heart Circ Physiol 308: H1382-H1390, 2015. First published April 3, 2015 doi:10.1152/ajpheart.00712.2014.-We tested the hypothesis that aortic perivascular adipose tissue (PVAT) from young low-density lipoprotein receptor-deficient (LDLr Ϫ/Ϫ ) mice promotes aortic stiffness and remodeling, which would be mediated by greater PVAT-derived IL-6 secretion. Arterial stiffness was assessed by aortic pulse wave velocity and with ex vivo intrinsic mechanical properties testing in young (4 -6 mo old) wild-type (WT) and LDLr Ϫ/Ϫ chow-fed mice. Compared with WT mice, LDLr Ϫ/Ϫ mice had increased aortic pulse wave velocity (407 Ϯ 18 vs. 353 Ϯ 13 cm/s) and intrinsic mechanical stiffness (5,308 Ϯ 623 vs. 3,355 Ϯ 330 kPa) that was associated with greater aortic protein expression of collagen type I and advanced glycation end products (all P Ͻ 0.05 vs. WT mice). Aortic segments from LDLr Ϫ/Ϫ compared with WT mice cultured in the presence of PVAT had greater intrinsic mechanical stiffness (6,092 Ϯ 480 vs. 3,710 Ϯ 316 kPa), and this was reversed in LDLr Ϫ/Ϫ mouse arteries cultured without PVAT (3,473 Ϯ 577 kPa, both P Ͻ 0.05). Collagen type I and advanced glycation end products were increased in LDLr Ϫ/Ϫ mouse arteries cultured with PVAT (P Ͻ 0.05 vs. WT mouse arteries), which was attenuated when arteries were cultured in the absence of PVAT (P Ͻ 0.05). PVAT from LDLr Ϫ/Ϫ mice secreted larger amounts of IL-6 (3.4 Ϯ 0.1 vs. 2.3 Ϯ 0.7 ng/ml, P Ͻ 0.05), and IL-6 neutralizing antibody decreased intrinsic mechanical stiffness in LDLr Ϫ/Ϫ aortic segments cultured with PVAT (P Ͻ 0.05). Collectively, these data provide evidence for a role of PVAT-derived IL-6 in the pathogenesis of aortic stiffness and remodeling in chow-fed LDLr Ϫ/Ϫ mice. periaortic fat; aorta; cholesterol; inflammation; triglycerides DEATHS DUE TO CARDIOVASCULAR DISEASES (CVD) are the leading cause of mortality in the United States and in other modern societies worldwide (21). Recent meta-analysis data have indicated that the increased risk for CVD and related events are, in part, attributable to stiffening of the aorta as assessed by aortic pulse wave velocity (aPWV) (3). Importantly, nearly 50% of Americans have total cholesterol values above the desirable level (21), which, in turn, promotes aortic stiffening (13,23,42). Thus, gaining insights for the mechanisms by which traditional risk factors, such as hypercholesterolemia, promote aortic stiffening is of clinical importance. Aortic stiffness is, in part, due to changes in the expression of extracellular matrix proteins within the arterial wall and increased cross-linking of these proteins (15, 44). Collagen type I is a key load-bearing collagen isoform with increased expression in arteries with greater aortic stiffness (18). In contrast, elastin, a protein that provides elasticity to arteries, has an attenuated expression that also ...

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

“…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 . Differences in the effects of diet and Ldlr genotype on aortic compliance may be due to differences in mouse strain, diet protocol, and measurement methods.…”

Suppression of gut dysbiosis reverses Western diet-induced vascular dysfunction

“…Chronic low-grade inflammation is a major factor contributing to the development of obesity-related vascular dysfunction (24). Increased circulating and adipose tissue cytokines, such as interleukin-6 (IL-6), can induce vascular inflammatory signaling and oxidative stress, two key processes involved in the development of vascular dysfunction (3,15). An emerging hypothesis for the origin of obesity-related inflammation is an elevation in circulating bacterial lipopolysaccharide (LPS or endotoxin).…”

Tauroursodeoxycholic Acid Reduces Arterial Stiffness and Improves Endothelial Dysfunction in Type 2 Diabetic Mice

“…The reasons for this differential susceptibility along the vascular tree are unclear, although one notable difference between mesenteric and carotid arteries is the lack of PVAT that accumulates along the carotid bodies, even in models of extreme obesity such as DB mice. This difference is particularly relevant, given the increasing evidence that PVAT contributes to endothelial dysfunction and arterial stiffness in models of chronic disease [25,26]. Our data are the first to demonstrate that PVAT is a source of ER stress in DB mice, and the reduced ER stress markers in PVAT following TUDCA treatment suggest that PVAT-ER stress may play a role in diabetes-related vascular dysfunction, although future studies are necessary to determine the causality of this relation.…”