Protective Effects of PARP-1 Knockout on Dyslipidemia-Induced Autonomic and Vascular Dysfunction in ApoE−/− Mice: Effects on eNOS and Oxidative Stress

The aims of this study were to investigate the role of poly(ADP-ribose) polymerase (PARP)-1 in dyslipidemia-associated vascular dysfunction as well as autonomic nervous system dysregulation. Apolipoprotein (ApoE)−/− mice fed a high-fat diet were used as a model of atherosclerosis. Vascular and autonomic functions were measured in conscious mice using telemetry. The study revealed that PARP-1 plays an important role in dyslipidemia-associated vascular and autonomic dysfunction. Inhibition of this enzyme by gene knockout partially restored baroreflex sensitivity in ApoE−/− mice without affecting baseline heart-rate and arterial pressure, and also improved heart-rate responses following selective blockade of the autonomic nervous system. The protective effect of PARP-1 gene deletion against dyslipidemia-induced endothelial dysfunction was associated with preservation of eNOS activity. Dyslipidemia induced PARP-1 activation was accompanied by oxidative tissue damage, as evidenced by increased expression of iNOS and subsequent protein nitration. PARP-1 gene deletion reversed these effects, suggesting that PARP-1 may contribute to vascular and autonomic pathologies by promoting oxidative tissue injury. Further, inhibition of this oxidative damage may account for protective effects of PARP-1 gene deletion on vascular and autonomic functions. This study demonstrates that PARP-1 participates in dyslipidemia-mediated dysregulation of the autonomic nervous system and that PARP-1 gene deletion normalizes autonomic and vascular dysfunctions. Maintenance of eNOS activity may be associated with the protective effect of PARP-1 gene deletion against dyslipidemia-induced endothelial dysfunction

ACE2-Mediated Reduction of Oxidative Stress in the Central Nervous System Is Associated with Improvement of Autonomic Function

Oxidative stress in the central nervous system mediates the increase in sympathetic tone that precedes the development of hypertension. We hypothesized that by transforming Angiotensin-II (AngII) into Ang-(1–7), ACE2 might reduce AngII-mediated oxidative stress in the brain and prevent autonomic dysfunction. To test this hypothesis, a relationship between ACE2 and oxidative stress was first confirmed in a mouse neuroblastoma cell line (Neuro2A cells) treated with AngII and infected with Ad-hACE2. ACE2 overexpression resulted in a reduction of reactive oxygen species (ROS) formation. In vivo, ACE2 knockout (ACE2−/y) mice and non-transgenic (NT) littermates were infused with AngII (10 days) and infected with Ad-hACE2 in the paraventricular nucleus (PVN). Baseline blood pressure (BP), AngII and brain ROS levels were not different between young mice (12 weeks). However, cardiac sympathetic tone, brain NADPH oxidase and SOD activities were significantly increased in ACE2−/y. Post infusion, plasma and brain AngII levels were also significantly higher in ACE2−/y, although BP was similarly increased in both genotypes. ROS formation in the PVN and RVLM was significantly higher in ACE2−/y mice following AngII infusion. Similar phenotypes, i.e. increased oxidative stress, exacerbated dysautonomia and hypertension, were also observed on baseline in mature ACE2−/y mice (48 weeks). ACE2 gene therapy to the PVN reduced AngII-mediated increase in NADPH oxidase activity and normalized cardiac dysautonomia in ACE2−/y mice. Altogether, these data indicate that ACE2 gene deletion promotes age-dependent oxidative stress, autonomic dysfunction and hypertension, while PVN-targeted ACE2 gene therapy decreases ROS formation via NADPH oxidase inhibition and improves autonomic function. Accordingly, ACE2 could represent a new target for the treatment of hypertension-associated dysautonomia and oxidative stress

Polylactic Acid Improves the Rheological Properties, and Promotes the Degradation of Sodium Carboxymethyl Cellulose-Modified Alkali-Activated Cement

In consideration of the insolubility in water, sensitivity to heat and wide application in the oil and gas industry as a degradable additive, this paper introduces polylactic acid (PLA) to a self-degradable temporary sealing material (SDTSM) to investigate its effect on the SDTSM performance and evaluate its potential to improve the rheological properties and further promote the self-degradation of the material. The thermal degradation of PLA, the rheological properties, compressive strength, hydrated products and water absorption of SDTSMs with different PLA dosages were tested. The analysis showed that the addition of 2% PLA increased the fluidity by 13.18% and reduced the plastic viscosity by 38.04%, when compared to those of the SDTSM without PLA. PLA increased the water absorption of 200 °C-heated SDTSM and had small effect on the types but decreased the hydrate products of 85 °C-cured SDTSM, and created plenty of pores in 200 °C-heated SDTSM. PLA enhanced the self-degradation level of SDTSM by generating a large amount of pores in cement. These pores worked in two ways: one was such a large amount of pores led to a looser microstructure; the other was these pores made the water impregnate the cement more easily, and then made the dissolution of substances in the 200 °C-heated SDTSM progress faster to generate heat and to destruct the microstructure

A Study on the Effects of Starches on the Properties of Alkali-Activated Cement and the Potential of Starch as a Self-Degradable Additive

An urgent problem of geothermal energy source development is how to cut down the production costs. The use of temporary sealing materials can reduce the costs associated with the circulation lost by plugging, and increase the production by self-degradation. Based on the utilization of starches as self-degradable additives in the medical field, this paper investigated the effects of three kinds of starches, namely corn starch (CS), hydroxypropyl starch (HPS) and carboxymethyl starch (CMS) on the properties of alkali-activated cement (AAC). In addition, the thermal properties of starch, the compressive strength and microstructures of the cement with starch were tested, to evaluate the potentiality of starch as self-degradable additive for geothermal cement. The analysis showed that: (1) all the starches have the effect of increasing the apparent viscosity, prolonging the setting time and reducing the static fluid loss of alkali-activated cement; (2) the addition of starch increased the number of pores in 200 °C-heated cement, facilitated the leaching process, and thus promoted the self-degradation; and (3) among the three starches, CMS has the most potential as a self-degradable additive

Angiotensin-converting enzyme 2: a new target for neurogenic hypertension

Overactivity of the renin-angiotensin system (RAS) is involved in the pathogenesis of hypertension, and an overactive brain RAS has been highlighted in several genetic and experimental models. Until now, angiotensin II (Ang II) was thought to be the main effector of this system, and the angiotensin-converting enzyme (ACE)-Ang II-Ang II type 1 receptor axis was the main target for antihypertensive therapies. A new member of the RAS, ACE2 (angiotensin-converting enzyme type 2), has been identified in organs and tissues related to cardiovascular function (e.g. heart, kidney and blood vessels) and appears to be part of a counter-regulatory pathway to buffer the excess of Ang II. We recently identified the ACE2 protein in brain regions involved in the central regulation of blood pressure and showed that it regulates, and is regulated by, other components of the RAS. Here, we present evidence for the involvement of brain ACE2 in the central regulation of blood pressure, autonomic and cardiac function. We show that lack of ACE2 is deleterious for the central regulation of blood pressure and that brain ACE2 gene therapy can restore baroreflex and autonomic functions and prevent the development of hypertension. Additionally, and independently of a reduction in Ang II levels, we will highlight some of the mechanisms responsible for the beneficial effects of central ACE2 in cardiovascular function

The Self-Degradation Mechanism of Polyvinyl Chloride-Modified Slag/Fly Ash Binder for Geothermal Wells

Polyvinyl chloride (PVC) releases hydrochloric acid (HCl) during its thermal degradation, and hydrochloric acid can react with hydration products of alkali-activated binders. According to this characteristic of PVC and the temperature change that occurs during the development of a geothermal well, the PVC was added into slag/fly ash binder to develop self-degradable materials. The thermal degradation properties of PVC, compressive strength, hydration products, and microstructure of binders at different stages were tested, in order to study the degradation mechanism of the material. It was found that 20% PVC reduced the compressive strength, decreasing the level of binder from 13.95% to 76.63%. The mechanism of PVC promoting the material degradation mainly includes the following: (1) the thermal degradation of PVC increases the number of multiple damage pores in the material, at a high temperature; (2) HCl generated by the PVC thermal degradation reacts with the binder gels, and breaks them into particles; and (3) HCl also reacts with other substances in the binder, including CaCO3 and NaOH in the pore solution