Berry-Enriched Diet in Salt-Sensitive Hypertensive Rats: Metabolic Fate of (Poly)Phenols and the Role of Gut Microbiota.

Diets rich in (poly)phenols are associated with a reduced reduction in the incidence of cardiovascular disorders. While the absorption and metabolism of (poly)phenols has been described, it is not clear how their metabolic fate is affected under pathological conditions. This study evaluated the metabolic fate of berry (poly)phenols in an in vivo model of hypertension as well as the associated microbiota response. Dahl salt-sensitive rats were fed either a low-salt diet (0.26% NaCl) or a high-salt diet (8% NaCl), with or without a berry mixture (blueberries, blackberries, raspberries, Portuguese crowberry and strawberry tree fruit) for 9 weeks. The salt-enriched diet promoted an increase in the urinary excretion of berry (poly)phenol metabolites, while the abundance of these metabolites decreased in faeces, as revealed by UPLC-MS/MS. Moreover, salt and berries modulated gut microbiota composition as demonstrated by 16S rRNA analysis. Some changes in the microbiota composition were associated with the high-salt diet and revealed an expansion of the families Proteobacteria and Erysipelotrichaceae. However, this effect was mitigated by the dietary supplementation with berries. Alterations in the metabolic fate of (poly)phenols occur in parallel with the modulation of gut microbiota in hypertensive rats. Thus, beneficial effects of (poly)phenols could be related with these interlinked modifications, between metabolites and microbiota environments.

Low-Intensity Running and High-Intensity Swimming Exercises Differentially Improve Energy Metabolism in Mice With Mild Spinal Muscular Atrophy.

Spinal Muscular Atrophy (SMA), an autosomal recessive neurodegenerative disease characterized by the loss of spinal-cord motor-neurons, is caused by mutations on Survival-of-Motor Neuron (SMN)-1 gene. The expression of SMN2, a SMN1 gene copy, partially compensates for SMN1 disruption due to exon-7 excision in 90% of transcripts subsequently explaining the strong clinical heterogeneity. Several alterations in energy metabolism, like glucose intolerance and hyperlipidemia, have been reported in SMA at both systemic and cellular level, prompting questions about the potential role of energy homeostasis and/or production involvement in disease progression. In this context, we have recently reported the tolerance of mild SMA-like mice (SmnΔ7/Δ7; huSMN2 +/+) to 10 months of low-intensity running or high-intensity swimming exercise programs, respectively involving aerobic and a mix aerobic/anaerobic muscular metabolic pathways. Here, we investigated whether those exercise-induced benefits were associated with an improvement in metabolic status in mild SMA-like mice. We showed that untrained SMA-like mice exhibited a dysregulation of lipid metabolism with an enhancement of lipogenesis and adipocyte deposits when compared to control mice. Moreover, they displayed a high oxygen consumption and energy expenditure through ß-oxidation increase yet for the same levels of spontaneous activity. Interestingly, both exercises significantly improved lipid metabolism and glucose homeostasis in SMA-like mice, and enhanced oxygen consumption efficiency with the maintenance of a high oxygen consumption for higher levels of spontaneous activity. Surprisingly, more significant effects were obtained with the high-intensity swimming protocol with the maintenance of high lipid oxidation. Finally, when combining electron microscopy, respiratory chain complexes expression and enzymatic activity measurements in muscle mitochondria, we found that (1) a muscle-specific decreased in enzymatic activity of respiratory chain I, II, and IV complexes for equal amount of mitochondria and complexes expression and (2) a significant decline in mitochondrial maximal oxygen consumption, were reduced by both exercise programs. Most of the beneficial effects were obtained with the high-intensity swimming protocol. Taking together, our data support the hypothesis that active physical exercise, including high-intensity protocols, induces metabolic adaptations at both systemic and cellular levels, providing further evidence for its use in association with SMN-overexpressing therapies, in the long-term care of SMA patients.

CSRP3 mediates polyphenols-induced cardioprotection in hypertension.

Berries contain bioactive polyphenols, whose capacity to prevent cardiovascular diseases has been established recently in animal models as well in human clinical trials. However, cellular processes and molecular targets of berries polyphenols remain to be identified. The capacity of a polyphenol-enriched diet (i.e., blueberries, blackberries, raspberries, strawberry tree fruits and Portuguese crowberries berries mixture) to promote animal survival and protect cardiovascular function from salt-induced hypertension was evaluated in a chronic salt-sensitive Dahl rat model. The daily consumption of berries improved survival of Dahl/salt-sensitive rats submitted to high-salt diet and normalized their body weight, renal function and blood pressure. In addition, a prophylactic effect was observed at the level of cardiac hypertrophy and dysfunction, tissue cohesion and cardiomyocyte hypertrophy. Berries also protected the aorta from fibrosis and modulated the expression of aquaporin-1, a channel involved in endothelial water and nitric oxide permeability. Left ventricle proteomics analysis led to the identification of berries and salt metabolites targets, including cystein and glycin-rich protein 3 (CSRP3), a protein involved in myocyte cytoarchitecture. In neonatal rat ventricular cardiomyocytes, CSRP3 was validated as a target of a berries-derived polyphenol metabolite, 4-methylcatechol sulfate, at micromolar concentrations, mimicking physiological conditions of human plasma circulation. Accordingly, siRNA silencing of CSRP3 and 4-methylcatechol sulfate pretreatment reversed cardiomyocyte hypertrophy and CSRP3 overexpression induced by phenylephrine. Our systemic study clearly supports the modulation of CSRP3 by a polyphenol-rich berries diet as an efficient cardioprotective strategy in hypertension-induced heart failure.

Phenolic Metabolites Modulate Cardiomyocyte Beating in Response to Isoproterenol.

Cardiovascular disease (CVD) is a public health concern, and the third cause of death worldwide. Several epidemiological studies and experimental approaches have demonstrated that consumption of polyphenol-enriched fruits and vegetables can promote cardioprotection. Thus, diet plays a key role in CVD development and/or prevention. Physiological ß-adrenergic stimulation promotes beneficial inotropic effects by increasing heart rate, contractility and relaxation speed of cardiomyocytes. Nevertheless, chronic activation of ß-adrenergic receptors can cause arrhythmias, oxidative stress and cell death. Herein the cardioprotective effect of human metabolites derived from polyphenols present in berries was assessed in cardiomyocytes, in response to chronic ß-adrenergic stimulation, to disclose some of the underlying molecular mechanisms. Ventricular cardiomyocytes derived from neonate rats were treated with three human bioavailable phenolic metabolites found in circulating human plasma, following berries' ingestion (catechol-O-sulphate, pyrogallol-O-sulphate, and 1-methylpyrogallol-O-sulphate). The experimental conditions mimic the physiological concentrations and circulating time of these metabolites in the human plasma (2 h). Cardiomyocytes were then challenged with the ß-adrenergic agonist isoproterenol (ISO) for 24 h. The presence of phenolic metabolites limited ISO-induced mitochondrial oxidative stress. Likewise, phenolic metabolites increased cell beating rate and synchronized cardiomyocyte beating population, following prolonged ß-adrenergic receptor activation. Finally, phenolic metabolites also prevented ISO-increased activation of PKA-cAMP pathway, modulating Ca2+ signalling and rescuing cells from an arrhythmogenic Ca2+ transients' phenotype. Unexpected cardioprotective properties of the recently identified human-circulating berry-derived polyphenol metabolites were identified. These metabolites modulate cardiomyocyte beating and Ca2+ transients following ß-adrenergic prolonged stimulation.

Pure Polyphenols Applications for Cardiac Health and Disease.

Polyphenols are natural compounds present in fruits and vegetables that can exert beneficial effects on human health and notably, on the cardiovascular system. Some of these compounds showed significant protective activities toward atherosclerosis, hypertension, myocardial infarction, anthracyclin-induced cardiomyopathy, angiogenesis as well as heart failure. Polyphenols can act through systemic effects as well as through modulation of signaling pathways such as redox signaling, inflammation, autophagy and cell death in the heart and vessels. These effects can be mediated by changes in expression level and by post-translational modifications of proteins (e.g. Stat1, CaMKII, Sirtuins, BCL-2 family members, PDEs, TRF2, eNOS and SOD). This non-comprehensive short review aims to summarize recent knowledge on the main pharmacological effects and mechanisms of cardioprotection of pure polyphenols, using different approaches such as cell culture, animal models and human studies.

Hippocampal neurogenesis response: What can we expect from two different models of hypertension?

Hypertension is associated with cerebrovascular disease, white matter lesion and cognitive deficit, both in experimental models and clinical observations. Furthermore, in non-clinical models it is shown that hippocampus is affected by hypertension and hypoxia. Herein, two distinct hypertension models were used to study neurogenic response in hippocampus. Dahl salt sensitive (DSS) rat model is a genetic based idiopathic model, while chronic intermittent hypoxia (CIH) mimics the hypertension observed in patients with obstructive sleep apnea (OSA). Both models are chronic and trigger hypertension. No macroscopic alterations based on histological analysis were found in hippocampus derived from DSS and CIH exposure rats. Nevertheless, in hippocampus derived from CIH-induced hypertensive rats, there was a decrease on neuronal population (MAP2 and NeuN positive cells) and an increase on astrocytic marker GFAP. Accordingly, a higher increase on Ki67 expressing cells was found in dentate gyrus (DG) region, suggesting an enhancement of cell proliferation, concomitantly with an increase of Nestin staining, which indicates the presence of immature neurons under differentiation. While, in hippocampus of DSS rats with or without high salt diet, there was no remarkable difference indicating potential neuronal loss, astrocytic activation or neurogenesis. Furthermore, in both models hypertension did not alter the levels of expression of the stress response enzyme heme oxygenase-1 in DG. These data indicate that intermittent hypoxia might be the key factor involved in neurogenesis modulation in hippocampus. Furthermore, two hypotheses can be explored: (i) activation of neurogenesis is a response against neuronal loss induced by hypertension and/or hypoxia or (ii) neurogenesis can be directly stimulated by hypoxia as a neuroprotective mechanism.

Left ventricular mass changes after renal transplantation: influence of dietary sodium and change in serum uric acid.

BACKGROUND: We hypothesized that dietary sodium may modulate the effect of systolic blood pressure and other nonhemodynamic factors, such as high uric acid and renal dysfunction, on changes in the left ventricular mass after renal transplantation. The objective of the present 3-year follow-up longitudinal study was to assess the concomitant influence of these factors on changes in the left ventricular mass after renal transplantation. METHODS: Twenty-four-hour urinary sodium excretion, glomerular filtration rate (isotopic clearance), and left ventricular mass (echocardiography) assessment were done in 165 renal transplant patients during the first year and after a follow-up of 3 years after renal transplantation. RESULTS: At follow-up, therapy of hypertension was associated with normalization of blood pressure in 64% and a decrease in the prevalence of left ventricular hypertrophy from 66% to 56%. At baseline and follow-up, systolic blood pressure, sodium intake, and serum uric acid emerged as independent and significant determinants of the final left ventricular mass index. When the population was divided according to sex-specific tertiles of the final 24-hr urinary sodium excretion, the relationship between change in serum uric acid during follow-up, final left ventricular mass index, and final glomerular filtration rate was significant only on the highest tertile of 24-hr urinary sodium excretion. CONCLUSION: The decrease in the prevalence of left ventricular hypertrophy after renal transplantation is blunted by high sodium intake. Persistence of the left ventricular hypertrophy may result from the combined adverse influences of excessive dietary sodium intake and increased serum uric acid during follow-up despite pharmacological control of blood pressure.

Dietary sodium restriction prevents kidney damage in high fructose-fed rats.

Sodium depletion has a protective effect on target-organ damage in hypertension independent of blood pressure. Here we tested whether chronic dietary sodium restriction may prevent the development of renal alterations associated with insulin resistance by reducing the inflammatory and oxidant state. Rats were fed normal-salt-60% fructose, low-salt-60% fructose, or control normal-salt diet for 12 weeks. Insulin resistance induced by high-fructose diet was associated with an increase in albuminuria, tubular and glomerular hypertrophy, and inflammation of kidney and adipose tissue. The low-salt diet improved insulin sensitivity and prevented kidney damage. These beneficial effects of sodium depletion were associated with a decrease in renal inflammation (macrophage infiltration, IL-6, TNF-α) and oxidative stress (NADPH oxidase activity), and a prevention of histologic changes in retroperitoneal fat induced by high fructose. Thus, dietary salt depletion has beneficial effects on renal and metabolic alterations associated with a high-fructose diet in rats.

Early detection of isolated left ventricular diastolic dysfunction in high-risk differentiated thyroid carcinoma patients on TSH-suppressive therapy.

OBJECTIVE: L-Thyroxine-suppressive therapy benefits high-risk differentiated thyroid cancer patients by decreasing recurrence rates and cancer-related mortality. However, fully suppressed serum thyroid-stimulating hormone (TSH) implies a state of subclinical hyperthyroidism (SCH) with associated adverse cardiac effects. Because left ventricular (LV) diastolic dysfunction may be the first manifestation of more severe LV failure, and to balance the risks from thyroid cancer recurrence with risks of cardiac failure, the purpose of this study was to analyse new parameters of LV function in asymptomatic patients with exogenous SCH. DESIGN: Case-control study with 24 patients on TSH-suppressive therapy of short duration (≤ 4 years) after thyroid ablative therapy for differentiated thyroid carcinoma and 20 age- and sex-matched subjects. MEASUREMENTS: LV function [LV global strain and strain rate (SR) curves] was assessed by speckle tracking imaging echocardiography in each subject. RESULTS: Patients and controls do not differ in body mass index, systolic blood pressure and heart rate. No significant differences were observed in LV morphology (LV mass and relative wall thickness), cardiac output and parameters of LV systolic function between patients on suppressive therapy and controls. When compared with controls, patients with exogenous SCH had a significantly impaired longitudinal protodiastolic strain, SR and strain diastolic index but preserved radial strain and SR function. CONCLUSIONS: In subjects with SCH at the early phase of TSH-suppressive therapy, evidence of isolated longitudinal LV diastolic dysfunction was observed, despite a normal LV morphology. Further prospective studies to clarify the prognosis of picking-up early diastolic dysfunction in asymptomatic patients are needed before serial measurements could be recommended.

Cardiac function during exercise in obese prepubertal boys: effect of degree of obesity.

The purpose of the study was to evaluate the dynamics of diastolic and systolic function from rest to maximal exercise using conventional echocardiography and tissue Doppler imaging (TDI) in obese prepubertal boys compared to age-matched lean controls. Eighteen obese (10 with first degree obesity and 8 with second degree obesity according to French curves, BMI: 23.3+/-1.8 and 29.0+/-2.0 kg/m2, respectively) and 17 lean controls (BMI=17.6+/-0.6 kg/m2, P<0.001), aged 10-12 years were recruited. After resting echocardiography, all children performed a maximal exercise test. Regional diastolic and systolic myocardial velocities were acquired at rest and each workload. Stroke volume and cardiac output were calculated. At rest, obese boys had greater left ventricular (LV) diameters and LV mass. Boys in the first degree group showed no diastolic or systolic dysfunction, whereas boys with second degree obesity showed subtle diastolic dysfunction. During exercise, both obese groups showed greater stroke volume and cardiac output. First degree obese boys exhibited greater systolic and diastolic tissue Doppler velocities than controls, whereas second degree obese boys had lower diastolic tissue velocities irrespective of exercise intensity and lower fractional shortening at high exercise intensities than controls. In conclusion, no impairment in diastolic or systolic function is noticed in prepubertal boys with first degree of obesity. Enhanced regional myocardial function response to exercise was also demonstrated in this population, suggesting adaptive compensatory cardiac changes in mild obesity. However, when obesity becomes more severe, impaired global and regional cardiac function at rest and during exercise can be observed.