Endothelial mineralocorticoid receptor activation mediates endothelial dysfunction in diet-induced obesity.

AIMS: Aldosterone plays a crucial role in cardiovascular disease. 'Systemic' inhibition of its mineralocorticoid receptor (MR) decreases atherosclerosis by reducing inflammation and oxidative stress. Obesity, an important cardiovascular risk factor, is an inflammatory disease associated with increased plasma aldosterone levels. We have investigated the role of the 'endothelial' MR in obesity-induced endothelial dysfunction, the earliest stage in atherogenesis. METHODS AND RESULTS: C57BL/6 mice were exposed to a normal chow diet (ND) or a high-fat diet (HFD) alone or in combination with the MR antagonist eplerenone (200 mg/kg/day) for 14 weeks. Diet-induced obesity impaired endothelium-dependent relaxation in response to acetylcholine, whereas eplerenone treatment of obese mice prevented this. Expression analyses in aortic endothelial cells isolated from these mice revealed that eplerenone attenuated expression of pro-oxidative NADPH oxidase (subunits p22phox, p40phox) and increased expression of antioxidative genes (glutathione peroxidase-1, superoxide dismutase-1 and -3) in obesity. Eplerenone did not affect obesity-induced upregulation of cyclooxygenase (COX)-1 or prostacyclin synthase. Endothelial-specific MR deletion prevented endothelial dysfunction in obese (exhibiting high 'endogenous' aldosterone) and in 'exogenous' aldosterone-infused lean mice. Pre-incubation of aortic rings from aldosterone-treated animals with the COX-inhibitor indomethacin restored endothelial function. Exogenous aldosterone administration induced endothelial expression of p22phox in the presence, but not in the absence of the endothelial MR. CONCLUSION: Obesity-induced endothelial dysfunction depends on the 'endothelial' MR and is mediated by an imbalance of oxidative stress-modulating mechanisms. Therefore, MR antagonists may represent an attractive therapeutic strategy in the increasing population of obese patients to decrease vascular dysfunction and subsequent atherosclerotic complications.

Evolutionary switch and genetic convergence on rbcL following the evolution of C4 photosynthesis.

Rubisco is responsible for the fixation of CO2 into organic compounds through photosynthesis and thus has a great agronomic importance. It is well established that this enzyme suffers from a slow catalysis, and its low specificity results into photorespiration, which is considered as an energy waste for the plant. However, natural variations exist, and some Rubisco lineages, such as in C4 plants, exhibit higher catalytic efficiencies coupled to lower specificities. These C4 kinetics could have evolved as an adaptation to the higher CO2 concentration present in C4 photosynthetic cells. In this study, using phylogenetic analyses on a large data set of C3 and C4 monocots, we showed that the rbcL gene, which encodes the large subunit of Rubisco, evolved under positive selection in independent C4 lineages. This confirms that selective pressures on Rubisco have been switched in C4 plants by the high CO2 environment prevailing in their photosynthetic cells. Eight rbcL codons evolving under positive selection in C4 clades were involved in parallel changes among the 23 independent monocot C4 lineages included in this study. These amino acids are potentially responsible for the C4 kinetics, and their identification opens new roads for human-directed Rubisco engineering. The introgression of C4-like high-efficiency Rubisco would strongly enhance C3 crop yields in the future CO2-enriched atmosphere.

Oligocene CO2 decline promoted C4 photosynthesis in grasses.

C4 photosynthesis is an adaptation derived from the more common C3 photosynthetic pathway that confers a higher productivity under warm temperature and low atmospheric CO2 concentration [1, 2]. C4 evolution has been seen as a consequence of past atmospheric CO2 decline, such as the abrupt CO2 fall 32-25 million years ago (Mya) [3-6]. This relationship has never been tested rigorously, mainly because of a lack of accurate estimates of divergence times for the different C4 lineages [3]. In this study, we inferred a large phylogenetic tree for the grass family and estimated, through Bayesian molecular dating, the ages of the 17 to 18 independent grass C4 lineages. The first transition from C3 to C4 photosynthesis occurred in the Chloridoideae subfamily, 32.0-25.0 Mya. The link between CO2 decrease and transition to C4 photosynthesis was tested by a novel maximum likelihood approach. We showed that the model incorporating the atmospheric CO2 levels was significantly better than the null model, supporting the importance of CO2 decline on C4 photosynthesis evolvability. This finding is relevant for understanding the origin of C4 photosynthesis in grasses, which is one of the most successful ecological and evolutionary innovations in plant history.

The origins of C4 grasslands: integrating evolutionary and ecosystem science.

The evolution of grasses using C4 photosynthesis and their sudden rise to ecological dominance 3 to 8 million years ago is among the most dramatic examples of biome assembly in the geological record. A growing body of work suggests that the patterns and drivers of C4 grassland expansion were considerably more complex than originally assumed. Previous research has benefited substantially from dialog between geologists and ecologists, but current research must now integrate fully with phylogenetics. A synthesis of grass evolutionary biology with grassland ecosystem science will further our knowledge of the evolution of traits that promote dominance in grassland systems and will provide a new context in which to evaluate the relative importance of C4 photosynthesis in transforming ecosystems across large regions of Earth.

Measurement of 13CO2 in expired air as an index of compliance to a high carbohydrate diet naturally enriched in 13C.

The aim of this study was to determine whether breath 13CO2 measurements could be used to assess the compliance to a diet containing carbohydrates naturally enriched in 13C. The study was divided into two periods: Period 1 (baseline of 4 days) with low 13C/12C ratio carbohydrates. Period 2 (5 days) isocaloric diet with a high 13C/12C ratio (corn, cane sugar, pineapple, millet) carbohydrates. Measurements were made of respiratory gas exchange by indirect calorimetry, urinary nitrogen excretion and breath 13CO2 every morning in post-absorptive conditions, both in resting state and during a 45-min low intensity exercise (walking on a treadmill). The subjects were 10 healthy lean women (BMI 20.4 +/- 1.7 kg/m2, % body fat 24.4 +/- 1.3%), the 13C enrichment of oxidized carbohydrate and breath 13CO2 were compared to the enrichment of exogenous dietary carbohydrates. At rest the enrichment of oxidized carbohydrate increased significantly after one day of 13C carbohydrate enriched diet and reached a steady value (103 +/- 16%) similar to the enrichment of exogenous carbohydrates. During exercise, the 13C enrichment of oxidized carbohydrate remained significantly lower (68 +/- 17%) than that of dietary carbohydrates. The compliance to a diet with a high content of carbohydrates naturally enriched in 13C may be assessed from the measurement of breath 13CO2 enrichment combined with respiratory gas exchange in resting, postabsorptive conditions.

Renal responses to three types of renin-angiotensin system blockers in patients with diabetes mellitus on a high-salt diet: a need for higher doses in diabetic patients?

Objective Activation of the renal renin-angiotensin system in patients with diabetes mellitus appears to contribute to the risk of nephropathy. Recently, it has been recognized than an elevation of prorenin in plasma also provides a strong indication of risk of nephropathy. This study was designed to examine renin-angiotensin system control mechanisms in the patient with diabetes mellitus.Methods We enrolled 43 individuals with type 2 diabetes mellitus. All individuals were on a high-salt diet to minimize the contribution of the systemic renin-angiotensin system. After an acute exposure to captopril (25 mg), they were randomized to treatment with either irbesartan (300 mg) or aliskiren (300 mg) for 2 weeks.Results All agents acutely lowered blood pressure and plasma aldosterone, and increased renal plasma flow and glomerular filtration rate. Yet, only captopril and aliskiren acutely increased plasma renin and decreased plasma angiotensin II, whereas irbesartan acutely affected neither renin nor angiotensin II. Plasma renin and angiotensin II subsequently did increase upon chronic irbesartan treatment. When given on day 14, irbesartan and aliskiren again induced the above hemodynamic, renal and adrenal effects, yet without significantly changing plasma renin. Irbesartan at that time did not affect plasma angiotensin II, whereas aliskiren lowered it to almost zero.Conclusion The relative resistance of the renal renin response to acute (irbesartan) and chronic (irbesartan and aliskiren) renin-angiotensin system blockade supports the concept of an activated renal renin-angiotensin system in diabetes, particularly at the level of the juxtaglomerular cell, and implies that diabetic patients might require higher doses of renin-angiotensin system blockers to fully suppress the renal renin-angiotensin system. J Hypertens 29: 2454-2461 (C) 2011 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.