Objective: To determine if myostatin deficiency attenuates body fat gain with increased dietary fat intake. Methods: Normal and myostatin-deficient mice were fed control (8-10 kcal %fat) and high-fat (HF) (45 kcal %fat) diets for a period of 8 weeks, starting at 2 months of age. Body composition, including percent body fat, lean mass, and fat mass, were measured using DXA. Serum adipokines were measured using a Beadlyte assay. Results: Two-factor ANOVA revealed significant treatment  genotype interactions for body fat (g), percent body fat, and serum leptin. The HF diet significantly increased body fat, percent body fat, and serum leptin in normal mice but not in myostatindeficient mice. Conclusion: Loss of myostatin function not only increases muscle mass in animal models but also attenuates the body fat accumulation that usually accompanies an HF diet.

Objective: We aimed to characterize circulating HMGB1 (high-mobility group box-1) levels, one of the better-characterized damage-associated molecular patterns, with respect to age, sex, and race in the general population, and investigate the longitudinal associations of HMGB1 with inflammatory markers, obesity, and preclinical markers of cardiovascular disease. Approach and Results: The analyses included 489 participants (50% Blacks, aged 24.6±3.3 years at the first visit) with up to 4 follow-up visits (1149 samples) over a maximum of 8.5 years. Systolic blood pressure, diastolic blood pressure, carotid-femoral pulse wave velocity, and carotid intima-media thickness together with plasma HMGB1, hs-CRP (high-sensitivity C-reactive protein), IFN-γ (interferon-γ), IL-6 (interleukin-6), IL-10 (interleukin-10), and TNF-α (tumor necrosis factor-α) were measured at each visit. At baseline, plasma HMGB1 concentrations were higher in Blacks compared with Whites (3.86 versus 3.20 ng/mL, P <0.001), and in females compared with males (3.75 versus 3.30 ng/mL, P =0.005). HMGB1 concentrations increased with age ( P =0.007), and higher levels of obesity measures ( P <0.001). Without adjustment for age, sex, race, and body mass index, HMGB1 concentrations were positively associated with hs-CRP, IL-6, TNF-α, systolic blood pressure, diastolic blood pressure, and carotid-femoral pulse wave velocity ( P <0.05) but not IL-10, IFN-γ or carotid intima-media thickness. After covariate adjustments, the associations of HMGB1 with hs-CRP, and carotid-femoral pulse wave velocity remained statistically significant ( P <0.05). Conclusions: This is the first study to demonstrate the age, sex, and race differences in circulating HMGB1. The increasing circulating concentrations of HMGB1 with age suggest a potential role of HMGB1 in the pathogenesis of chronic low-grade inflammation, obesity, and subclinical cardiovascular disease risk.

Background Aging is a major non‐modifiable risk factor for hypertension. Structural, functional and mechanical changes occur with aging. These changes are similar to those seen in hypertension in the vasculature. Also, aging increases the vascular dysfunction that occurs in hypertension. L‐arginase is a ureohydrolase enzyme that converts L‐arginine to L‐ornithine and urea. Arginase action reduces substrate (L‐arginine) availability for the formation of nitric oxide (NO). This reduces the level of NO and leads to reduced vasodilation and ultimately, vascular dysfunction. Hypothesis This study tests the hypothesis that the age dependent vascular dysfunction in SHRs is mediated by arginase. Methods Young (12–14 weeks) and old (11–12 months) male Wistar and spontaneously hypertensive rats (SHR) were used in this study. Mean arterial pressure (MAP) was measured in the rats. They were then euthanized and 5ml of blood was drawn from the heart to obtain serum for the assay of arginase activity. Mesenteric resistance arteries (MRAs) and thoracic aortae were excised and placed in ice‐cold physiological salt solution (PSS). Arterial segments were either snap‐frozen in liquid nitrogen and stored for immunoblotting studies or cut into 2mm rings for reactivity studies. Cumulative concentration‐response curves to phenylephrine (PE; 10‐9‐3×10‐5M), acetylcholine (Ach; 10‐9 – 3×10‐5M) and sodium nitroprusside (SNP; 10‐12 – 3×10‐5 M) were performed in the absence or presence (30‐minute exposure) of various agents: L‐arginase, 0.05U/ML (MRA) or 0.5U/ML (aorta); Rho kinase inhibitor, Y27632 − 10‐5mmol/L; or 0.5U/ML L‐arginase + 10‐5mmol/L Y27632 (aorta). All chemicals were obtained from Sigma‐Aldrich MO, USA. Data are expressed as mean + S.E.M. of 6 rats per group. Statistical differences were calculated using Student’s t‐test and two‐way ANOVA with repeated measures followed by Bonferroni post hoc test. Significance was set at p<0.05. Results MAP increased during aging in the SHRs (132.2±10.2 vs 166.2±1.9mmHg p<0.05.) but not in the Wistar rats (104.4±3.0 vs 92.0±1.5mmHg). Arginase impaired the endothelium‐dependent relaxation responses of thoracic aortic and MRA arterial rings to Ach in the old Wistars (Emax aorta: 68.66248±1.96% vs 56.46116±3.42%) and SHRs (Emax aorta: 29.41753±2.19% vs 7.943045±1.86%). Arginase also impaired endothelium‐independent relaxation response to SNP in the old SHRs only (Emax aorta: 88.62396±4.10% vs 31.45081±10.61%). Correspondingly, arginase potentiated contractile responses of thoracic aortic and MRA arterial rings to PE in the old SHRs (Emax MRA: 25.24835±1.93mN vs 36.43248±2.99mN) which was attenuated by the Rho Kinase inhibitor (Y26732) in the presence or absence of arginase. We also observed no differences in the serum arginase activity in the four groups of rats. On the contrary, arginase activity in the thoracic aortae of young Wistar rats was reduced compared to the other groups. Conclusions The results of this study suggest that arginase impairs both endothelium‐dependent and –independent vaso...

Drug-coated balloon therapy is a minimally-invasive endovascular approach to treat obstructive arterial disease, with increasing utilization in the peripheral circulation due to improved outcomes as compared to alternative interventional modalities. Broader clinical use of drug-coated balloons is limited by an incomplete understanding of device- and patient-specific determinants of treatment efficacy, including late outcomes that are mediated by post-interventional maladaptive inward arterial remodeling. To address this knowledge gap, we propose a predictive mathematical model of pressure-mediated femoral artery remodeling following drug-coated balloon deployment, with account of drug-based modulation of resident vascular cell phenotype and common patient co-morbidities, namely hypertension and endothelial cell dysfunction. Our results elucidate how post-interventional arterial remodeling outcomes are altered by the delivery of a traditional anti-proliferative drug, as well as by co-delivery with an anti-contractile drug. Our findings suggest that co-delivery of anti-proliferative and anti-contractile drugs could improve patient outcomes following drug-coated balloon therapy, motivating further consideration of novel payloads in next-generation devices.

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