Endothelial dysfunction associated with hypercholesterolemia is an early event in atherosclerosis characterized by redox imbalance associated with high superoxide production and reduced nitric oxide (NO) and hydrogen peroxide (H2O2) production. Aerobic exercise training (AET) has been demonstrated to ameliorate atherosclerotic lesions and oxidative stress in advanced atherosclerosis. However, whether AET protects against the early mechanisms of endothelial dysfunction in familial hypercholesterolemia remains unclear. This study investigated the effects of AET on endothelial dysfunction and vascular redox status in the aortas of LDL receptor knockout mice (LDLr−/−), a genetic model of familial hypercholesterolemia. Twelve-week-old C57BL/6J (WT) and LDLr−/− mice were divided into sedentary and exercised (AET on a treadmill 1 h/5 × per week) groups for 4 weeks. Changes in lipid profiles, endothelial function, and aortic NO, H2O2 and superoxide production were examined. Total cholesterol and triglycerides were increased in sedentary and exercised LDLr−/− mice. Endothelium-dependent relaxation induced by acetylcholine was impaired in aortas of sedentary LDLr−/− mice but not in the exercised group. Inhibition of NO synthase (NOS) activity or H2O2 decomposition by catalase abolished the differences in the acetylcholine response between the animals. No changes were noted in the relaxation response induced by NO donor sodium nitroprusside or H2O2. Neuronal NOS expression and endothelial NOS phosphorylation (Ser1177), as well as NO and H2O2 production, were reduced in aortas of sedentary LDLr−/− mice and restored by AET. Incubation with apocynin increased acetylcholine-induced relaxation in sedentary, but not exercised LDLr−/− mice, suggesting a minor participation of NADPH oxidase in the endothelium-dependent relaxation after AET. Consistent with these findings, Nox2 expression and superoxide production were reduced in the aortas of exercised compared to sedentary LDLr−/− mice. Furthermore, the aortas of sedentary LDLr−/− mice showed reduced expression of superoxide dismutase (SOD) isoforms and minor participation of Cu/Zn-dependent SODs in acetylcholine-induced, endothelium-dependent relaxation, abnormalities that were partially attenuated in exercised LDLr−/− mice. The data gathered by this study suggest AET as a potential non-pharmacological therapy in the prevention of very early endothelial dysfunction and redox imbalance in familial hypercholesterolemia via increases in NO bioavailability and H2O2 production.

Endothelial dysfunction precedes atherosclerosis and is an independent predictor of cardiovascular events. Cholesterol levels and oxidative stress are key contributors to endothelial damage, whereas high levels of plasma high-density lipoproteins (HDL) could prevent it. Cholesteryl ester transfer protein (CETP) is one of the most potent endogenous negative regulators of HDL-cholesterol. However, whether and to what degree CETP expression impacts endothelial function, and the molecular mechanisms underlying the vascular effects of CETP on endothelial cells, have not been addressed. Acetylcholine-induced endothelium-dependent relaxation of aortic rings was impaired in human CETP-expressing transgenic mice, compared to their non-transgenic littermates. However, endothelial nitric oxide synthase (eNOS) activation was enhanced. The generation of superoxide and hydrogen peroxide was increased in aortas from CETP transgenic mice, while silencing CETP in cultured human aortic endothelial cells effectively decreased oxidative stress promoted by all major sources of ROS: mitochondria and NOX2. The endoplasmic reticulum stress markers, known as GADD153, PERK, and ARF6, and unfolded protein response effectors, were also diminished. Silencing CETP reduced endothelial tumor necrosis factor (TNF) α levels, intercellular cell adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1) expression, diminishing monocyte adhesion. These results support the notion that CETP expression negatively impacts endothelial cell function, revealing a new mechanism that might contribute to atherosclerosis.

Polymeric materials capable of releasing nitric oxide (NO) locally have potential uses in various biomedical applications. One of the main challenges in this field is obtaining materials that allow the modulation of NO release rates through the incorporation of different NO donor molecules. Herein, we describe the synthesis of materials composed of poly(2-hydroxyethyl methacrylate) (PHEMA) crosslinked by a polysilsesquioxane (PSS) network through sol–gel polymerization and photocrosslinking. Increasing the PSS content from 5 to 20 wt% led to an increase in the glass transition temperature from 107 °C to 133 °C. Swelling studies in phosphate buffer saline solution and ethanol revealed that higher siloxane content reduced the solvent uptake of the hybrids, while surface contact angle measurements confirmed that all compositions remained hydrophilic (60–70°). These hybrids enabled, for the first time, the incorporation of two structurally distinct NO donors, hydrophilic S-nitrosoglutathione (GSNO) and hydrophobic S-nitroso-N-acetyl-DL-penicillamine (SNAP), via absorption from aqueous and ethanolic solutions, respectively. Computational modeling showed that GSNO forms multiple hydrogen bonds with PHEMA hydroxyl groups, while SNAP interacts hydrophobically with its methyl groups. Real-time NO measurements showed that SNAP spontaneously releases NO at a flow rate 2 to 10 times higher than that of GSNO in the first 30 min after hydration of the hybrids, likely due to its weaker intermolecular interactions and higher mobility upon hydration. The hydrophilic nature of the hybrids, tunable NO release, and lack of cytotoxicity toward cultured endothelial cells position them as promising candidates for the manufacturing of antithrombotic blood-contacting medical devices.

The myostatin/follistatin pathway modulates skeletal muscle trophism. Physical exercise has an important role in the heart failure treatment. In this study we evaluated the effects of moderate aerobic physical training on myostatin and follistatin gene expression and trophism in the gastrocnemius of spontaneously hypertensive rats with heart failure. Sixteen‐month‐old SHRs and normotensive Wistar‐Kyoto (WKY) rats were assigned to sedentary or trained groups. Exercise was performed on treadmill, 30 min/day, 5 days/week, 12 m/min for 4 months. Transthoracic echocardiogram was performed at the end of experiment. Gene expression was evaluated by real time RT‐PCR. Fiber cross‐sectional area was measured in HE‐stained histological sections. Statistical analysis: two‐way ANOVA and Tukey. Results: Echocardiography showed left cardiac chambers dilation and left ventricular systolic and diastolic dysfunction in both SHR groups compared to the WKY groups. Gene expression of myostatin and follistatin did not differ between groups. Cross‐sectional area was reduced in both SHR groups compared to WKY and was not changed by exercise. Conclusion: Physical exercise does not modulate skeletal muscle trophism and myostatin and follistatin gene expression in spontaneously hypertensive rats with heart failure.