Vascular hyperacetylation is associated with vascular smooth muscle dysfunction in a rat model of non-obese type 2 diabetes.

BACKGROUND: Advanced type 2 diabetes mellitus (T2DM) accelerates vascular smooth muscle cell (VSMC) dysfunction which contributes to the development of vasculopathy, associated with the highest degree of morbidity of T2DM. Lysine acetylation, a post-translational modification (PTM), has been associated with metabolic diseases and its complications. Whether levels of global lysine acetylation are altered in vasculature from advanced T2DM remains undetermined. We hypothesized that VSMC undergoes dysregulation in advanced T2DM which is associated with vascular hyperacetylation. METHODS: Aged male Goto Kakizaki (GK) rats, a non-obese murine model of T2DM, and age-matched male Wistar rats (control group) were used in this study. Thoracic aortas were isolated and examined for measurement of global levels of lysine acetylation, and vascular reactivity studies were conducted using a wire myograph. Direct arterial blood pressure was assessed by carotid catheterization. Cultured human VSMCs were used to investigate whether lysine acetylation participates in high glucose-induced reactive oxygen species (ROS), a crucial factor triggering diabetic vascular dysfunction. RESULTS: The GK rats exhibited marked glucose intolerance as well as insulin resistance. Cardiovascular complications in GK rats were confirmed by elevated arterial blood pressure and reduced VSMC-dependent vasorelaxation. These complications were correlated with high levels of vascular global lysine acetylation. Human VSMC cultures incubated under high glucose conditions displayed elevated ROS levels and increased global lysine acetylation. Inhibition of hyperacetylation by garcinol, a lysine acetyltransferase and p300/CBP association factor (PCAF) inhibitor, reduced high glucose-induced ROS production in VSMC. CONCLUSION: This study provides evidence that vascular hyperacetylation is associated with VSMC dysfunction in advanced T2DM. Understanding lysine acetylation regulation in blood vessels from diabetics may provide insight into the mechanisms of diabetic vascular dysfunction, and opportunities for novel therapeutic approaches to treat diabetic vascular complications.

FOAM ROLLING AND INDICES OF AUTONOMIC RECOVERY FOLLOWING EXERCISE-INDUCED MUSCLE DAMAGE.

BACKGROUND: With the increased popularity of foam rolling as a recovery tool, it is important to explore possible mechanisms of action toward mitigating soreness and restoring athletic performance. PURPOSE: The purpose of the present experiment was to assess the influence of foam rolling on gross measures of physical performance and indices of autonomic function following exercise-induced muscle damage (EIMD). METHOD: In a between-group design, 40 participants performed a session of 40x15 meter sprints, inducing muscle damage. Immediately following sprinting and in the four days following, heart rate variability and pulse wave velocity were recorded, in addition to perceived muscle soreness, vertical jump, and agility. Nineteen subjects (mean±sd; age 23.1±5.0 yrs; BMI 25.6±3.3 kg.m-2) foam rolled their quadricep, gluteal, and gastrocnemius areas prior to testing each day, while 21 (mean±sd; age 24.2±3.4 yrs; BMI 26.3±4.0 kg.m-2) served as a control. Mean values from three days of baseline testing were compared to the area under the curve during five days of recovery after the performance of the repeated sprint protocol. The area under the curve was calculated by summing all five values recorded the recovery days, then these data were compared by condition using a two-tailed Mann-Whitney U test (alpha level = 0.05). RESULTS: Following EIMD, neither heart rate variability, pulse wave velocity, agility, nor vertical jumping performance versus previously measured baseline differed significantly between groups (p>0.05). Perceived muscle soreness was significantly diminished in the foam rolling condition (p<0.05). Mean Day 1 to Day 5 values for perceived muscle soreness in controls were 16.52, 30.24, 24.48, 17.19, and 11.10. Mean Day 1 to Day 5 values in foam rolling subjects were 12.63, 24.63, 21.79, 15.05, and 10.16. CONCLUSION: Foam rolling may be useful for reducing soreness following damaging exercise, but according to the outcomes measured in the present experiment, the effect does not appear to be mediated by the autonomic nervous system. LEVEL OF EVIDENCE: 2c.

Ellagic Acid Alleviates Hepatic Oxidative Stress and Insulin Resistance in Diabetic Female Rats.

Non-alcoholic fatty liver disease (NAFLD) affects more than 70% of patients with type 2 diabetes mellitus (T2DM) and has become one of the most common metabolic liver diseases worldwide. To date, treatments specifically targeting NAFLD do not exist. Oxidative stress and insulin resistance have been implicated in the pathogenesis of NAFLD in diabetes. Accordingly, the goal of this present study was to determine whether Ellagic acid (EA), a natural antioxidant polyphenol found in berries and nuts, mitigates hepatic oxidative stress and insulin resistance in T2DM rats, and thus alleviates NAFLD. Using adult female Goto Kakizaki (GK) rats, a non-obese and spontaneous model of T2DM, we found that EA treatment significantly lowered fasting blood glucose and reduced insulin resistance, as shown by a 21.8% reduction in the homeostasis model assessment index of insulin resistance (HOMA-IR), while triglyceride and total cholesterol levels remained unchanged. Increased hepatic lipid accumulation and oxidative stress present in diabetic GK rats was markedly reduced with EA treatment. This effect was associated with a downregulation of the NADPH oxidase subunit, p47-phox, and overexpression of NF-E2-related factor-2 (NRF2). Moreover, EA was able to decrease the hepatic expression of hypoxia-inducible factor (HIF-α), a transcription factor linked to hypoxia and hepatic steatosis. We further showed that EA treatment activated an insulin signaling pathway in the liver, as evidenced by increased levels of phosphorylated Akt (Ser 473). In conclusion, our results demonstrate that EA diminishes blood glucose levels and potently suppress NAFLD in diabetic rats via mechanisms that involve reductions in p47-phox and HIF-α, upregulation of NRF2 and enhancement of the Akt signaling pathway in the liver. Together, these results reveal that EA improves hepatic insulin sensitivity and lipid metabolism as a result of its antioxidant effects. This implies an anti-diabetic effect of EA with beneficial effects for the treatment of hepatic complications in T2DM.