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 ...

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Increased peripheral conduit artery stiffness has been shown in patients with heart failure (HF) with preserved ejection fraction. However, it is unknown whether this phenomenon extends to the coronary vasculature. HF with preserved ejection fraction may be driven, in part, by coronary inflammation, and inhibition of the enzyme DPP-4 (dipeptidyl-peptidase 4) reduces inflammation and oxidative stress. The purpose of this study was to determine the effect of saxagliptin-a DPP-4 inhibitor-on coronary stiffness in aortic-banded mini swine. We hypothesized saxagliptin would prevent increased coronary artery stiffness in a translational swine model with cardiac features of HF with preserved ejection fraction by inhibiting perivascular adipose tissue inflammation. Yucatan mini swine were divided into 3 groups: control, aortic-banded untreated HF, and aortic-banded saxagliptin-treated HF. Ex vivo mechanical testing was performed on the left circumflex and right coronary arteries, and advanced glycation end product, NF-κB (nuclear factor-κB), and nitrotyrosine levels were measured. An increase in the coronary elastic modulus of HF animals was associated with increased vascular advanced glycation end products, NF-κB, and nitrotyrosine levels compared with control and prevented by saxagliptin treatment. Aortas from healthy mice were treated with media from swine perivascular adipose tissue culture to assess its role on vascular stiffening. Conditioned media from HF and saxagliptin-treated HF animals increased mouse aortic stiffness; however, only perivascular adipose tissue from the HF group showed increased advanced glycation end products and NF-κB levels. In conclusion, our data show increased coronary conduit vascular stiffness was prevented by saxagliptin and associated with decreased advanced glycation end products, NF-κB, and nitrotyrosine levels in a swine model with potential relevance to HF with preserved ejection fraction.

Previous findings from our laboratory have shown increased coronary artery stiffness is associated with increased vascular advanced glycation end product (AGE) levels from aortic‐banded (AB) mini‐swine. Perivascular adipose tissue (PVAT) promotes arterial stiffness, yet the mechanisms underlying PVAT‐related arterial stiffening and whether exercise is therapeutically efficacious in preventing this phenomenon are unknown. We hypothesized that both chronic low‐intensity continuous and interval exercise training (LICT and LIIT, respectively) would prevent PVAT‐related AGE secretion and coronary arterial stiffening in AB mini‐swine. Male Yucatan mini‐swine (8 mo. old) were divided into 4 groups (n=7/group): sedentary control (CON), sedentary AB heart failure (HF), AB plus LICT (HF+LICT), and AB plus LIIT (HF+LIIT). Significance was set at P < 0.05 using one way ANOVA. Following the development of left ventricular (LV) hypertrophy (2 mo. post‐AB), animals began LICT or LIIT consisting of treadmill running 3 days/wk, 55 min/day, for 15 weeks. Only animals in the HF group showed both increased lung weight and LV brain natriuretic peptide mRNA levels, suggestive of heart failure. Coronary artery mechanical stiffness was assessed via a DMT Myograph system, and protein levels in arterial and PVAT samples was examined by immunohistochemistry. HF compared to CON had a significantly lower coronary elastin elastic modulus (EEM) (284.3±27.58 vs. 444.35±37.55 kPa) associated with reduced elastin content. Both LICT and LIIT prevented the decreases in the EEM (474.2±37.83 and 510.6±55.98 kPa, respectively) and coronary elastin content observed in the HF group. Compared to CON, HF animals had significantly increased AGE levels in both the coronary artery and PVAT, along with increased AGE secretion from isolated PVAT samples conditioned in media. Increased PVAT secretion and coronary AGE accumulation were prevented by both LICT and LIIT. To determine if PVAT contributes to arterial stiffness, aortas from young healthy mice exposed to PVAT‐conditioned media were mechanically tested. Aortas exposed to HF‐conditioned media had a significant decrease in the EEM (368.47±20.34 vs. 582.41±28.99 kPa) and decreased elastin content compared to CON, which was prevented when treated with PVAT‐conditioned media from LICT and LIIT animals (542.84±58.09 and 517.8±22.03 kPa, respectively). The AGE inhibitor, aminogunadine (AMG), prevented decreases in the EEM (368.47±20.34 vs. 642.58±35.32 kPa), arterial elastin content, and increases in arterial AGE accumulation observed after exposure to PVAT‐conditioned media from the HF group. In summary, both LICT and LIIT prevent coronary artery stiffness and preserve normal elastin levels via inhibition of PVAT‐derived AGE in a pre‐clinical model of pressure overload‐induced heart failure. Support or Funding Information R01 HL112998 (Emter, PI) This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

We tested the hypothesis that hesperidin would reverse age-related aortic stiffness, perivascular adipose (PVAT) mediated-arterial stiffening and PVAT advanced glycation end-products (AGE) accumulation. Aortic pulse wave velocity (aPWV) and intrinsic mechanical stiffness, two measures of arterial stiffness, were assessed in C57BL/6 mice that were young (6months), old (27-29months), or old treated with hesperidin for 4weeks. Old compared with young mice had increased aPWV (444±10 vs. 358±8cm/s, P<0.05) and mechanical stiffness (6506±369 vs. 3664±414kPa, P<0.05). In old mice hesperidin reduced both aPWV (331±38cm/s) and mechanical stiffness (4445±667kPa) to levels not different from young. Aortic segments from old animals cultured with (+) PVAT had greater mechanical stiffness compared to young (+) PVAT (6454±323 vs. 3575±440kPa, P<0.05) that was ameliorated in arteries from old hesperidin treated cultured (+) PVAT (2639±258kPa). Hesperidin also reversed the aging-related PVAT AGE accumulation (all, P<0.05). A 4-week treatment with the AGE inhibitor aminoguanidine reversed both the age-related increase in aPWV (390±7cm/s) and mechanical stiffness (3396±1072kPa), as well as mechanical stiffness in arteries cultured (+) PVAT (3292±716kPa) (all, P<0.05) to values not different from young. In conclusion, hesperidin ameliorates the age-related increase in aortic stiffness and the PVAT-mediated effects on arterial stiffening. Hesperidin also reversed PVAT AGE accumulation, where PVAT AGE were shown to promote aortic stiffness with aging.

Background: Coronary artery disease (CAD) is one of the main fatal diseases all over the world. CAD is a complex disease, which has multiple risk factors mechanisms. In recent years, genome-wide association study (GWAS) had revealed single nucleotide polymorphism genes (SNPs) which were closely related with CAD risks. The relationship between long non-coding RNA (lncRNA) MALAT1 (metastasis-associated lung adenocarcinoma transcript 1) and CAD risk is largely unknown. To our knowledge, this is the first study which demonstrated the interaction effects of SNP–SNP and SNP–environment with CAD risk. In general, our case–control study is to detect the association between MALAT1 (rs619586, rs4102217) SNPs and CAD risk. Methods: Three hundred and sixty-five CAD patients and three hundred and eighty-four matched control participants blood samples were collected in Liaoning province, China. Two polymorphisms (rs619586, rs4102217) in lncRNA MALAT1 were genotyped by KASP platform. Results: In a stratified analysis, we found that non-drinkers with GC genotype and the recessive model of rs4102217 had higher CAD risk (P=0.010, odds ratio (OR): 1.96, 95% confidence interval (CI) = 1.17–3.28; P=0.026, OR: 1.73, 95% CI = 1.07–2.79) and diabetes mellitus (DM) history group (P=0.010, OR: 4.07, 95% CI = 1.41–11.81; P=0.019, OR: 3.29, 95% CI = 1.22–8.88). In SNP–SNP interactions analysis between MALAT1 and CAD risk, we found rs4102217 had an increase in smokers (GG: OR: 2.04, 95% CI = 1.42–2.92; CC+GC: OR: 2.64, 95% CI = 1.64–4.26) and a decrease in drinkers (CC+GC: OR: 0.33, 95% CI = 0.20–0.55). Smokers with MALAT1 rs619586 AA genotype (OR: 2.20, 95% CI = 1.57–3.07) and GG+AG genotype (OR: 2.11, 95% CI = 1.17–3.81) had a higher risk of CAD. Moreover, drinkers with AA genotype (OR: 0.22, 95% CI = 0.10–0.48) and GG+AG genotype (OR: 0.38, 95% CI = 0.22–0.65) had a lower risk of CAD. According to the MDR software, MALAT1 rs4102217 polymorphism-smoking-drinking was the best interaction model, which has higher risk of CAD (Testing Bal.ACC. = 0.6979). Conclusion: Our study demonstrated that the GC genotype and the recessive model of rs4102217 potentially increased CAD risk in some specific group.

We hypothesized a sweet potato intervention would prevent high-fat (HF) diet-induced aortic stiffness, which would be associated with decreased arterial oxidative stress and increased mitochondrial uncoupling. Young (8-week old) C57BL/6J mice were randomly divided into 4 groups: low fat (LF; 10% fat), HF (60% fat), low-fat sweet potato (LFSP; 10% fat containing 260.3 μg/kcal sweet potato), or high-fat sweet potato diet (HFSP; 60% fat containing 260.3 μg/kcal sweet potato) for 16 weeks. Compared with LF and LFSP, HF- and HFSP-fed mice had increased body mass and percent fat mass with lower percent lean mass (all, P < 0.05). Sweet potato intervention did not influence body composition (all, P > 0.05). Arterial stiffness, assessed by aortic pulse wave velocity and ex vivo mechanical testing of the elastin region elastic modulus (EEM) was greater in HF compared with LF and HFSP animals (all, P < 0.05). Advanced glycation end products and nitrotyrosine abundance were greater in aortic segments from HF mice compared with LF and HFSP animals (all, P < 0.05). Aortic elastin and uncoupling protein 2 expressions, however, were reduced in HF compared with LF and HFSP mice (all, P < 0.05). Aortic segments cultured with 2,4-dinitrophenol (DNP), a mitochondrial uncoupler, for 72 h reduced the EEM of HF arteries compared with nontreated HF segments (P < 0.05). DNP had no effect on the EEM of aortic segments from HFSP mice. In conclusion, sweet potato attenuates diet-induced aortic stiffness independent of body mass and composition, which is associated with a normalization of arterial oxidative stress possibly due to mitochondrial uncoupling.

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