ER stress improvement by aerobic training or enalapril differently ameliorates pathological cardiac remodeling in obese mice.

Overactivation of the classic arm of the renin-angiotensin system (RAS) is one of the main mechanisms involved in obesity-related cardiac remodeling, and a possible relationship between RAS and ER stress in the cardiovascular system have been described. Thus, the aim of this study is to evaluate if activating the protective arm of the RAS by ACE inhibition or aerobic exercise training could overturn diet-induced pathological cardiac hypertrophy by attenuating ER stress. Male C57BL/6 mice were fed a control (SC) or a high-fat diet (HF) for 16 weeks. In the 8th week, HF-fed animals were randomly divided into HF, enalapril treatment (HF-En), and aerobic exercise training (HF-Ex) groups. Body mass (BM), food and energy intake, plasma analyzes, systolic blood pressure (SBP), physical conditioning, and plasma ACE and ACE2 activity were evaluated. Cardiac morphology, and protein expression of hypertrophy, cardiac metabolism, RAS, and ER stress markers were assessed. Data presented as mean ± standard deviation and analyzed by one-way ANOVA with Holm-Sidak post-hoc. HF group had increased BM and SBP, and developed pathological concentric cardiac hypertrophy, with overactivation of the classic arm of the RAS, and higher ER stress. Both interventions reverted the increase in BM, and SBP, and favored the protective arm of the RAS. Enalapril treatment improved pathological cardiac hypertrophy with partial reversal of the concentric pattern, and slightly attenuated cardiac ER stress. In contrast, aerobic exercise training induced physiological eccentric cardiac hypertrophy, and fully diminished ER stress.

Comparison between aerobic exercise training and enalapril treatment as tools to improve diet-induced metabolic-associated fatty liver disease: Effects on endoplasmic reticulum stress markers.

AIMS: Endoplasmic reticulum (ER) stress poses a new pathological mechanism for metabolic-associated fatty liver disease (MAFLD). MAFLD treatment has encompassed renin-angiotensin system (RAS) blockers and aerobic exercise training, but their association with hepatic ER stress is not well known. Therefore, we aimed to compare the effects of hepatic RAS modulation by enalapril and/or aerobic exercise training over ER stress in MAFLD caused by a diet-induced obesity model. MAIN METHODS: C57BL/6 mice were fed a standard-chow (CON, n = 10) or a high-fat (HF, n = 40) diet for 8 weeks. HF group was then randomly divided into: HF (n = 10), HF + Enalapril (EN, n = 10), HF + Aerobic exercise training (AET, n = 10), and HF + Enalapril+Aerobic exercise training (EN + AET, n = 10) for 8 more weeks. Body mass (BM) and glucose profile were evaluated. In the liver, ACE and ACE2 activity, morphology, lipid profile, and protein expression of ER stress and metabolic markers were assessed. KEY FINDINGS: Both enalapril and aerobic exercise training provided comparable efficacy in improving diet-induced MAFLD through modulation of RAS and ER stress, but the latter was more efficient in improving ER stress, liver damage and metabolism. SIGNIFICANCE: This is the first study to evaluate pharmacological (enalapril) and non-pharmacological (aerobic exercise training) RAS modulators associated with ER stress in a diet-induced MAFLD model.

Impact of Brazil Nut (Bertholletia excelsa, H.B.K.) Supplementation on Body Composition, Blood Pressure, and the Vascular Reactivity of Wistar Rats When Submitted to a Hypersodium Diet.

Introdution: Endothelium integrity is a key that maintains vascular homeostasis but it can suffer irreversible damage by blood pressure changes, reflecting an imbalance in the maintenance of vascular homeostasis.Objective: The aim of this study was to investigate the impact of Brazil nut (Bertholletia excelsa, H.B.K.) (BN) supplementation (10% in chow, wt/wt) on the vascular reactivity of Wistar rats during chronic exposure to a sodium overload (1% in water).Methods: First, male Wistar rats were allocated into two groups: Control Group (CG) and the Hypersodic Group (HG) for 4 weeks. Afterward, the CG was divided into the Brazil Nut Group (BNG) and the HG Group into the Hypersodic Brazil Nut Group (HBNG) for a further 8 weeks, totaling 4 groups. Blood pressure was measured during the protocol. At the end of the protocol, the vascular reactivity procedure was performed. Glucose, lipid profile, lipid peroxidation, and platelet aggregation were analyzed in the serum. Body composition was determined by the carcass technique.Results: The groups that were supplemented with the BN chow presented less body mass gain and body fat mass, together with lower serum glucose levels. The HG Group presented an increase in blood pressure and a higher platelet aggregation, while the BN supplementation was able to blunt this effect. The HG Group also showed an increase in contractile response that was phenylephrine-induced and a decrease in maximum relaxation that was acetylcholine-induced when compared to the other groups.Conclusion: The BN supplementation was able to prevent an impaired vascular function in the early stages of arterial hypertension, while also improving body composition, serum glucose, and platelet aggregation.

Evaluation of the effects produced by subacute tributyltin administration on vascular reactivity of male wistar rats.

Tributyltin chloride (TBT) is an organotin compound widely used in several high biocides for agroindustrial applications, such as fungicides, and marine antifouling paints leading to endocrine disrupting actions, such as imposex development in mollusks. In female rats, TBT has been shown to promote ovarian dysfunction, reduction of estrogen protective effect in the vascular morphophysiology, at least in part by oxidative stress consequences. Estrogen causes coronary endothelium-dependent and independent vasodilation. However, the TBT effects on cardiovascular system of male rats are not fully understood. The aim of this study was to evaluate the effects of subacute TBT exposure in aorta vascular reactivity from male wistar rats. Rats were randomly divided into three groups: control (C), TBT 500 ng/kg/day and TBT 1000 ng/kg/day. TBT was administered daily for 30 days by oral gavage. We found that TBT exposure enhanced testosterone serum levels and it was also observed obesogenic properties. TBT exposure evoked an increase in endothelium-dependent and independent phenylephrine-induced contraction, associated to an inhibition in eNOS activity. On the other hand, it was observed an enhancement of iNOS and NF-kB protein expression. We also observed an increase in oxidative stress parameters, such as superoxide dismutase (SOD) and catalase expression, and also an increase in malondialdehyde production. Finally, TBT exposure produced aortic intima-media thickness. Taken together, these data suggest a potential cardiovascular toxicological effect after subacute TBT exposure in male rats.

Crosstalk between the renin-angiotensin system and the endoplasmic reticulum stress in the cardiovascular system: Lessons learned so far.

The renin-angiotensin (Ang) system (RAS) is a complex hormonal system present locally in several tissues such as cardiovascular organs. RAS deregulation through overactivation of the classical arm [Ang-converting enzyme (ACE)/Ang-II/Ang type 1 receptor (AT1R)] has been linked to the development of cardiovascular diseases and activation of endoplasmic reticulum (ER) stress pathways. The ER stress is a condition that, if unresolved, might lead to heart failure, atherosclerosis, hypertension, and endothelial dysfunction. Accumulated evidence has shown that the RAS modulates the UPR activation. Several studies reported increased ER stress markers in response to Ang-II treatment, in both in vivo and in vitro models. Evidence has also pointed that targeting the RAS classical arm through RAS blockers, gene silencing or genetic models leads to lower levels of ER stress markers. Few studies demonstrated protective effects of the counter-regulatory arm (ACE-2/Ang-(1-7)/Mas receptor) over ER stress. However, the crosstalk mechanisms between the arms of the RAS and ER stress remain unclear. In this review, we sought to explore the classical arm of the RAS as a key mechanism in UPR activation and to suggest a possible protective role of the counter-regulatory arm in mitigating ER stress.

Modulation of cardiac renin-angiotensin system, redox status and inflammatory profile by different volumes of aerobic exercise training in obese rats.

Overactivation of the classical arm of the renin-angiotensin (Ang) system (RAS) occurs during inflammation, oxidative stress and obesity-induced cardiomyopathy. The activation of the protective arm of RAS may act to counterbalance the deleterious effects of the classical RAS. Although aerobic exercise training (AET) shifts the balance of the RAS towards the protective arm, little is known about the molecular adaptations to different volumes of AET. The aim of this study was to evaluate the impact of AET volume on the modulation of RAS, as well as on cardiac biomarkers of oxidative stress and inflammation, in a diet-induced obesity model. Male Wistar rats were fed either control (CON) or high fat (HF) diet for 32 weeks. At week 20, HF group was subdivided into sedentary, low (LEV, 150 min/week) or high (HEV, 300 min/week) exercise volume. After 12 weeks of exercise, body mass gain, systolic blood pressure and heart rate were evaluated, as well as RAS, oxidative stress and inflammation in the heart. Body mass gain, systolic blood pressure and heart rate were higher in HF group when compared with SC group. Both trained groups restored systolic blood pressure and heart rate, but only HEV reduced body mass gain. Regarding the cardiac RAS, the HF group exhibited favoring of the classical arm and both trained groups shifted the balance towards the counterregulatory protective arm. The HF group had higher B1R expression and lower B2R expression than the control group, and B2R expression was reverted in both trained groups. The HF group also presented oxidative stress. The LEV and HEV groups improved the cardiac redox status by reducing Nox 2 and nitrotyrosine expression, but only the LEV group was able to increase the antioxidant defense by increasing Nrf2 signaling. While the HF group presented higher TNF-α, IL-6 and NFκB expression, and lower IL-10 expression, than the SC group, both training protocols improved the inflammatory profile. Although both trained groups improved the deleterious changes related to obesity cardiomyopathy, it is clear that the molecular mechanisms differ between them. Our results suggest that different exercise volumes might reach different molecular targets, and this could be a relevant factor when using exercise to manage obesity.

Effects of short-term high-intensity interval and continuous exercise training on body composition and cardiac function in obese sarcopenic rats.

AIM: We investigated the effects of high-intensity interval and continuous short-term exercise on body composition and cardiac function after myocardial ischemia-reperfusion injury (IRI) in obese rats. METHODS: Rats fed with a standard chow diet (SC) or high-fat diet (HFD) for 20 weeks underwent systolic blood pressure (SBP), glycemia and dual-energy X-ray absorptiometry analyses. Then, animals fed with HFD were subdivided into three groups: sedentary (HFD-SED); moderate-intensity continuous training (HFD-MICT); and high-intensity interval training (HFD-HIIT). Exercised groups underwent four isocaloric aerobic exercise sessions, in which HFD-MICT maintained the intensity continuously and HFD-HIIT alternated it. After exercise sessions, all groups underwent global IRI and myocardial infarct size (IS) was determined histologically. Fat and muscle mass were weighted, and protein levels involved in muscle metabolism were assessed in skeletal muscle. RESULTS: HFD-fed versus SC-fed rats reduced lean body mass by 31% (P < 0.001), while SBP, glycemia and body fat percentage were increased by 10% (P = 0.04), 30% (P = 0.006) and 54% (P < 0.001); respectively. HFD-induced muscle atrophy was restored in exercised groups, as only HFD-SED presented lower gastrocnemius (32%; P = 0.001) and quadriceps mass (62%; P < 0.001) than SC. PGC1-α expression was 2.7-fold higher in HFD-HIIT versus HFD-SED (P = 0.04), whereas HFD-HIIT and HFD-MICT exhibited 1.7-fold increase in p-mTORSer2481 levels compared to HFD-SED (P = 0.04). Although no difference was detected among groups for IS (P = 0.30), only HFD-HIIT preserved left-ventricle developed pressure after IRI (+0.7 mmHg; P = 0.9). SIGNIFICANCE: Short-term exercise, continuous or HIIT, restored HFD-induced muscle atrophy and increased mTOR expression, but only HIIT maintained myocardial contractility following IRI in obese animals.

Exercise-induced cardiac opioid system activation attenuates apoptosis pathway in obese rats.

AIM: To compare the effect of 150 min vs. 300 min of weekly moderate intensity exercise training on the activation of the opioid system and apoptosis in the hearts of a diet-induced obesity model. METHODS: Male Wistar rats were fed with either control (CON) or high fat (HF) diet for 32 weeks. At the 20th week, HF group was subdivided into sedentary, low (LEV, 150 min·week-1) or high (HEV, 300 min·week-1) exercise volume. After 12 weeks of exercise, body mass gain, adiposity index, systolic blood pressure, cardiac morphometry, apoptosis biomarkers and opioid system expression were evaluated. RESULTS: Sedentary animals fed with HF presented pathological cardiac hypertrophy and higher body mass gain, systolic blood pressure and adiposity index than control group. Both exercise volumes induced physiological cardiac hypertrophy, restored systolic blood pressure and improved adiposity index, but only 300 min·week-1 reduced body mass gain. HF group exhibited lower proenkephalin, PI3K, ERK and GSK-3ß expression, and greater activated caspase-3 expression than control group. Compared to HF, no changes in the cardiac opioid system were observed in the 150 min·week-1 of exercise training, while 300 min·week-1 showed greater proenkephalin, DOR, KOR, MOR, Akt, ERK and GSK-3ß expression, and lower activated caspase-3 expression. CONCLUSION: 300 min·week-1 of exercise training triggered opioid system activation and provided greater cardioprotection against obesity than 150 min·week-1. Our findings provide translational aspect with clinical relevance about the critical dose of exercise training necessary to reduce cardiovascular risk factors caused by obesity.