Mineralocorticoid Receptor Blockade Attenuates Chronic Overexpression of the Renin-Angiotensin- Aldosterone System Stimulation of Reduced Nicotinamide Adenine Dinucleotide Phosphate Oxidase and Cardiac Remodeling

doi: 10.1210/en.2006-1691The renin-angiotensin-aldosterone system contributes to cardiac remodeling, hypertrophy, and left ventricular dysfunction. Angiotensin II and aldosterone (corticosterone in rodents) together generate reactive oxygen species (ROS) via reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, which likely facilitate this hypertrophy and remodeling. This investigation sought to determine whether cardiac oxidative stress and cellular remodeling could be attenuated by in vivo mineralocorticoid receptor (MR) blockade in a rodent model of the chronically elevated tissue renin-angiotensin-aldosterone system, the transgenic TG (mRen2) 27 rat (Ren2). The Ren2 overexpresses the mouse renin transgene with resultant hypertension, insulin resistance, proteinuria, and cardiovascular damage. Young (6- to 7-wk-old) male Ren2 and age-matched Sprague-Dawley rats were treated with spironolactone or placebo for 3 wk. Heart tissue ROS, immunohistochemical analysis of 3-nitrotyrosine,and NADPH oxidase (NOX) subunits (gp91phox recently renamed NOX2, p22phox, Rac1, NOX1, and NOX4) were measured. Structural changes were assessed with cine-magnetic resonance imaging, transmission electron microscopy, and light microscopy. Significant increases in Ren2 septal wall thickness (cine-magnetic resonance imaging) were accompanied by perivascular fibrosis, increased mitochondria, and other ultrastructural changes visible by light microscopy and transmission electron microscopy. Although there was no significant reduction in systolic blood pressure, significant improvements were seen with MR blockade on ROS formation and NOX subunits (each P < 0.05). Collectively, these data suggest that MR blockade, independent of systolic blood pressure reduction, improves cardiac oxidative stress-induced structural and functional changes, which are driven, in part, by angiotensin type 1 receptor-mediated increases in NOX.This research was supported by National Institutes of Health (NIH) Grants R01 HL73101-01A1 (to J.R.S.) and P01 HL-51952 (to C.F.), the Veterans Affairs Merit System (0018) (to J.R.S.), and Advanced Research Career Development (to C.S.). Male transgenic Ren2 rats and male Sprague-Dawley controls were kindly provided by C.F. through the Transgenic Core Facility supported in part by NIH Grant HL-51952

European Red List of Marine Fishes

The European Red List is a review of the conservation status of European species according to IUCN regional Red Listing guidelines. It identifies those species that are threatened with extinction at the regional level, so that appropriate conservation action can be taken to improve their status. This Red List publication summarises results for all described native European marine fishes.Postprin

Coherent Assessments of Europe’s Marine Fishes Show Regional Divergence and Megafauna Loss

Europe has a long tradition of exploiting marine fishes and is promoting marine economic activity through its Blue Growth strategy. This increase in anthropogenic pressure, along with climate change, threatens the biodiversity of fishes and food security. Here, we examine the conservation status of 1,020 species of European marine fishes and identify factors that contribute to their extinction risk. Large fish species (greater than 1.5 m total length) are most at risk; half of these are threatened with extinction, predominantly sharks, rays and sturgeons. This analysis was based on the latest International Union for Conservation of Nature (IUCN) European regional Red List of marine fishes, which was coherent with assessments of the status of fish stocks carried out independently by fisheries management agencies: no species classified by IUCN as threatened were considered sustainable by these agencies. A remarkable geographic divergence in stock status was also evident: in northern Europe, most stocks were not overfished, whereas in the Mediterranean Sea, almost all stocks were overfished. As Europe proceeds with its sustainable Blue Growth agenda, two main issues stand out as needing priority actions in relation to its marine fishes: the conservation of marine fish megafauna and the sustainability of Mediterranean fish stocks

Hindlimb muscle glucose uptake and metabolism in rats exposed to simulated microgravity.

Over the last 30 years data from manned spaceflight missions have indicated that microgravity affects a number of physiological systems including the skeletal muscles. The purpose of the experiments in this dissertation was to examine the influence of 14 days of simulated microgravity on insulin and exercise stimulated glucose utilization in rat hindlimb muscles. To accomplish this aim, male Sprague-Dawley rats (250-325 g) were suspended in a head down position (SUS) so that one or both hindlimbs were non-weight bearing. The results from hindlimb perfusion experiments indicated that glucose uptake rates for the entire hindquarter at both submaximally and maximally stimulating insulin concentrations were significantly higher (p ≤ 0.05) in the SUS rats (77% and 15%, respectively) than the cage control rats (CC), suggesting increases in insulin sensitivity and responsiveness. Insulin sensitivity for ¹⁴C glucose incorporation into glycogen was also increased for the soleus (SOL), plantaris (PL), and extensor digitorum longus (EDL) muscles in the SUS rats. When the suspended (SUS-E) and control (CC-E) rats were exposed to acute treadmill exercise at 80-90% of VO₂ max, hindlimb glucose uptake and its incorporation into glycogen in the absence of insulin were higher in the PL, EDL, and white gastrocnemius (GW) muscles from the SUS-E rats. However, hindlimb muscle responses to insulin appeared to be impaired after exercise for the SUS-E rats when compared to the CC-E rats, especially in the SOL muscle. To examine the influence of non-weight bearing per se on muscles during simulated microgravity, rats were suspended with the left hindlimb non-weight bearing (NWB) and the right hindlimb bearing 20% of pre-suspension body mass (WB). The results indicated that ³H 2-deoxyglucose uptake was significantly higher for the SOL, PL, EDL and GW muscles (21-80%), at a maximally stimulating insulin concentration, in both SUS-NWB and SUS-WB hindlimbs despite the prevention of SOL and PL muscle mass losses in the SUS-WB hindlimbs. Collectively, the results from this dissertation indicate that the suspension of the rat with hindlimbs non-weight bearing leads to enhanced muscle responses to insulin for glucose uptake and metabolism, and suggest that systemic influences may be involved. In addition, exercise induced glucose and glycogen utilization increase to a greater extent in the hindlimb muscles of suspended rats when compared to their controls; but, there was evidence that muscle responses to insulin were attenuated with exercise in the suspended animals

Physical Activity in the Prevention of Chronic Kidney Disease

Chronic kidney disease (CKD) is an important risk factor for cardiovascular disease (CVD) and mortality. The increase in CKD in recent decades has paralleled increases in obesity, diabetes, and the metabolic syndrome. Physical inactivity is a modifiable risk factor that may affect the development and course of CKD. It is well established that exercise training improves a number of metabolic factors, including blood pressure and insulin resistance, which would be expected to preserve renal function as well as lower CVD risk. Epidemiological studies have suggested that partaking in vigorous physical activity may protect against kidney disease. However, to date few studies have rigorously measured physical activity levels. Instead, investigators have relied on subjective measures of physical activity and patient recall. This is particularly problematic when attempting to capture low- and very-low-intensity physical activity and in quantifying sedentary behavior. Improvements in vascular endothelial function, insulin sensitivity, adipocytokine profiles, and oxidative stress likely mediate the benefits of physical activity on the kidney. While formal exercise recommendations have been published for diabetes and hypertension, guidelines regarding the optimal type, frequency, intensity and duration of physical activity for preventing CKD have yet to be formalized

The Connection Building Theodicy

In this chapter, I present a new theodicy, which I call the connection building theodicy. The basic idea behind this theodicy is that virtuous responses to evil allow for certain types of ongoing, intrinsically valuable connections of appreciation, contribution, and what I call “intimacy” between personal agents. Because of their ongoing character, arguably, the value of these connections will eventually outweigh the disvalue of the evils that God must allow in order for them to exist. After presenting the basic idea of the theodicy, I consider a series of objections, and argue for its philosophical, theological, and practical fruitfulness. I do not claim this theodicy offers the sole reason why God allows evil, only that it provides an important and neglected set of reasons