Publications by authors named "Massimiliano Caprio"

69 Publications

SIRT5 Inhibition Induces Brown Fat-Like Phenotype in 3T3-L1 Preadipocytes.

Cells 2021 May 7;10(5). Epub 2021 May 7.

Laboratory of Cardiovascular Endocrinology, IRCCS San Raffaele Pisana, 00163 Rome, Italy.

Brown adipose tissue (BAT) activity plays a key role in regulating systemic energy. The activation of BAT results in increased energy expenditure, making this tissue an attractive pharmacological target for therapies against obesity and type 2 diabetes. Sirtuin 5 (SIRT5) affects BAT function by regulating adipogenic transcription factor expression and mitochondrial respiration. We analyzed the expression of SIRT5 in the different adipose depots of mice. We treated 3T3-L1 preadipocytes and mouse primary preadipocyte cultures with the SIRT5 inhibitor MC3482 and investigated the effects of this compound on adipose differentiation and function. The administration of MC3482 during the early stages of differentiation promoted the expression of brown adipocyte and mitochondrial biogenesis markers. Upon treatment with MC3482, 3T3-L1 adipocytes showed an increased activation of the AMP-activated protein kinase (AMPK), which is known to stimulate brown adipocyte differentiation. This effect was paralleled by an increase in autophagic/mitophagic flux and a reduction in lipid droplet size, mediated by a higher lipolytic rate. Of note, MC3482 increased the expression and the activity of adipose triglyceride lipase, without modulating hormone-sensitive lipase. Our findings reveal that SIRT5 inhibition stimulates brown adipogenesis in vitro, supporting this approach as a strategy to stimulate BAT and counteract obesity.
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http://dx.doi.org/10.3390/cells10051126DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8148511PMC
May 2021

Long-Term Iron and Vitamin B12 Deficiency Are Present after Bariatric Surgery, Despite the Widespread Use of Supplements.

Int J Environ Res Public Health 2021 04 25;18(9). Epub 2021 Apr 25.

Department of Systems Medicine, Tor Vergata University, 00133 Rome, Italy.

There are few long-term nutritional studies in subjects undergoing bariatric surgery that have assessed weight regain and nutritional deficiencies. In this study, we report data 8 years after surgery on weight loss, use of dietary supplements and deficit of micronutrients in a cohort of patients from five centres in central and northern Italy. The study group consisted of 52 subjects (age: 38.1 ± 10.6 y, 42 females): 16 patients had Roux-en-Y gastric bypass (RYGB), 25 patients had sleeve gastrectomy (SG) and 11 subjects had adjustable gastric banding (AGB). All three bariatric procedures led to sustained weight loss: the average percentage excess weight loss, defined as weight loss divided by excess weight based on ideal body weight, was 60.6% ± 32.3. Despite good adherence to prescribed supplements, 80.7% of subjects (72.7%, AGB; 76.7%, SG; 93.8 %, RYGB) reported at least one nutritional deficiency: iron (F 64.3% vs. M 30%), vitamin B12 (F 16.6% vs. M 10%), calcium (F 33.3% vs. M 0%) and vitamin D (F 38.1% vs. M 60%). Long-term nutritional deficiencies were greater than the general population among men for iron and among women for vitamin B12.
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http://dx.doi.org/10.3390/ijerph18094541DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8123142PMC
April 2021

Association of Urinary and Plasma Levels of Trimethylamine N-Oxide (TMAO) with Foods.

Nutrients 2021 Apr 23;13(5). Epub 2021 Apr 23.

Section of Clinical Nutrition and Nutrigenomic, Department of Biomedicine and Prevention, University of Tor Vergata, via Montpellier 1, 00133 Rome, Italy.

Introduction: Trimethylamine N-oxide (TMAO) may play a key mediator role in the relationship between the diet, gut microbiota and cardiovascular diseases, particularly in people with kidney failure. The aim of this review is to evaluate which foods have a greater influence on blood or urinary trimethylamine N-oxide (TMAO) levels.

Methods: 391 language articles were screened, and 27 were analysed and summarized for this review, using the keywords "TMAO" AND "egg" OR "meat" OR "fish" OR "dairy" OR "vegetables" OR "fruit" OR "food" in December 2020.

Results: A strong correlation between TMAO and fish consumption, mainly saltwater fish and shellfish, but not freshwater fish, has been demonstrated. Associations of the consumption of eggs, dairy and meat with TMAO are less clear and may depend on other factors such as microbiota or cooking methods. Plant-based foods do not seem to influence TMAO but have been less investigated.

Discussion: Consumption of saltwater fish, dark meat fish and shellfish seems to be associated with an increase in urine or plasma TMAO values. Further studies are needed to understand the relationship between increased risk of cardiovascular disease and plasma levels of TMAO due to fish consumption. Interventions coupled with long-term dietary patterns targeting the gut microbiota seem promising.
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http://dx.doi.org/10.3390/nu13051426DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8145508PMC
April 2021

Nutritional guidelines for the management of insulin resistance.

Crit Rev Food Sci Nutr 2021 Apr 2:1-14. Epub 2021 Apr 2.

Dipartimento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia, Università "Federico II" di Napoli, Via Sergio Pansini, 5, Naples, Italy.

Obesity and its related co-morbidities, namely type 2 diabetes (T2D), pose a significant global public health problem. Insulin resistance (IR) in muscle and liver is the core pathophysiologic defect that underlies obesity preceding and predicting the onset of T2D in susceptible humans. There is a broad population with IR that has no indication for prescription of medications, who still need medical consultation and specific advice in this respect. This prevalent need can be achieved by appropriate diet, exercise, and other behavioral therapies for lifestyle interventions. Despite a well-recognized role of IR in the progression to metabolic diseases, no specific nutritional recommendations exist to manage this condition, to the best of our knowledge. An international panel of experts reviewed and critically appraised the updated literature published about this topic. This review primarily examines the evidence for areas of consensus and ongoing uncertainty or controversy about diet and exercise approaches for IR. The aim of this article is to present the most common IR states, namely obesity and Polycystic Ovary Syndrome (PCOS), and provide nutritional advice to manage IR, hyperinsulinemia, and reactive hypoglycemia. These nutritional guidelines could prevent progression or worsening of IR with resultant beta-cell failure and, as a result, T2D.
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http://dx.doi.org/10.1080/10408398.2021.1908223DOI Listing
April 2021

Very-Low-Calorie Ketogenic Diet as a Safe and Valuable Tool for Long-Term Glycemic Management in Patients with Obesity and Type 2 Diabetes.

Nutrients 2021 Feb 26;13(3). Epub 2021 Feb 26.

Laboratory of Cardiovascular Endocrinology, IRCCS San Raffaele Pisana, 00166 Rome, Italy.

Obesity-related type 2 diabetes represents one of the most difficult challenges for the healthcare system. This retrospective study aims to determine the efficacy, safety and durability of a very-low-calorie ketogenic diet (VLCKD), compared to a standard low-calorie diet (LCD) on weight-loss, glycemic management, eating behavior and quality of life in patients with type 2 diabetes (T2DM) and obesity. Thirty patients with obesity and T2DM, aged between 35 and 75 years, who met the inclusion criteria and accepted to adhere to a VLCKD or a LCD nutritional program, were consecutively selected from our electronic database. Fifteen patients followed a structured VLCKD protocol, fifteen followed a classical LCD. At the beginning of the nutritional protocol, all patients were asked to stop any antidiabetic medications, with the exception of metformin. Data were collected at baseline and after 3 (T1) and 12 (T2) months. At T1 and T2, BMI was significantly reduced in the VLCKD group ( < 0.001), whereas it remained substantially unchanged in the LCD group. HbA1c was significantly reduced in the VLCKD group ( = 0.002), whereas a slight, although not significant, decrease was observed in the LCD group. Quality of life and eating behavior scores were improved in the VLCKD group, whereas no significant changes were reported in the LCD group, both at T1 and T2. At the end of the study, in the VLCKD group 26.6% of patients had stopped all antidiabetic medications, and 73.3% were taking only metformin, whereas 46.6% of LCD patients had to increase antidiabetic medications. The study confirms a valuable therapeutic effect of VLCKD in the long-term management of obesity and T2DM and its potential contribution to remission of the disease.
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http://dx.doi.org/10.3390/nu13030758DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7996853PMC
February 2021

Effects of Two Months of Very Low Carbohydrate Ketogenic Diet on Body Composition, Muscle Strength, Muscle Area, and Blood Parameters in Competitive Natural Body Builders.

Nutrients 2021 Jan 26;13(2). Epub 2021 Jan 26.

Department of Biomedical Sciences, University of Padua, 35131 Padua, Italy.

: Ketogenic diet (KD) is a nutritional approach that restricts daily carbohydrates, replacing most of the reduced energy with fat, while maintaining an adequate quantity of protein. Despite the widespread use of KD in weight loss in athletes, there are still many concerns about its use in sports requiring muscle mass accrual. Thus, the present study sought to investigate the influence of a KD in competitive natural body builders. : Nineteen volunteers (27.4 ± 10.5 years) were randomly assigned to ketogenic diet (KD) or to a western diet (WD). Body composition, muscle strength and basal metabolic rate were measured before and after two months of intervention. Standard blood biochemistry, testosterone, IGF-1, brain-derived neurotrophic factor (BDNF) and inflammatory cytokines (IL6, IL1β, TNFα) were also measured. : Body fat significantly decreased in KD ( = 0.030); whilst lean mass increased significantly only in WD ( < 0.001). Maximal strength increased similarly in both groups. KD showed a significant decrease of blood triglycerides ( < 0.001), glucose ( = 0.001), insulin ( < 0.001) and inflammatory cytokines compared to WD whilst BDNF increased in both groups with significant greater changes in KD ( < 0.001). : KD may be used during body building preparation for health and leaning purposes but with the caution that hypertrophic muscle response could be blunted.
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http://dx.doi.org/10.3390/nu13020374DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7911670PMC
January 2021

Tyrosol May Prevent Obesity by Inhibiting Adipogenesis in 3T3-L1 Preadipocytes.

Oxid Med Cell Longev 2020 9;2020:4794780. Epub 2020 Dec 9.

Department of Systems Medicine, University of Rome Tor Vergata, Rome 00133, Italy.

Tyrosol (TR), a major polyphenol found in extra virgin olive oil (EVOO), exerts several antioxidant effects. However, only scarce evidences are present regarding its activity on adipocytes and obesity. This study evaluated the role of TR in adipogenesis. Murine 3T3-L1 preadipocytes were incubated with TR (300 and 500 M), and TR administration inhibited adipogenesis by downregulation of several adipogenic factors (leptin and aP2) and transcription factors (C/EBP, PPAR, SREBP1c, and Glut4) and by modulation of the histone deacetylase sirtuin 1. After complete differentiation, adipocytes treated with 300 and 500 M TR showed a reduction of 20% and 30% in lipid droplets, respectively. Intracellular triglycerides were significantly reduced after TR treatment ( < 0.05). Mature adipocytes treated with TR at 300 and 500 M showed a marked decrease in the inflammatory state and oxidative stress as shown by the modulation of specific biomarkers (TNF, IL6, ROS, and SOD2). TR treatment also acted on the early stage of differentiation by reducing cell proliferation (~40%) and inducing cell cycle arrest during Mitotic Expansion Clonal (first 48 h of differentiation), as shown by the increase in both S1 phase and p21 protein expression. We also showed that TR induced lipolysis by activating the AMPK-ATGL-HSL pathway. In conclusion, we provided evidence that TR reduces 3T3-L1 differentiation through downregulation of adipogenic proteins, inflammation, and oxidative stress. Moreover, TR may trigger adipose tissue browning throughout the induction of the AMPK-ATGL-UCP1 pathway and, subsequently, may have promise as a potential therapeutic agent for the treatment and prevention of obesity.
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http://dx.doi.org/10.1155/2020/4794780DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7746459PMC
December 2020

Could ketogenic diet "starve" cancer? Emerging evidence.

Crit Rev Food Sci Nutr 2020 Dec 4:1-22. Epub 2020 Dec 4.

Dipartimento di Medicina Clinica e Chirurgia, Unit of Endocrinology, Federico II University Medical School of Naples, Naples, Italy.

Cancer cells (CCs) predominantly use aerobic glycolysis (Warburg effect) for their metabolism. This important characteristic of CCs represents a potential metabolic pathway to be targeted in the context of tumor treatment. Being this mechanism related to nutrient oxidation, dietary manipulation has been hypothesized as an important strategy during tumor treatment. Ketogenic diet (KD) is a dietary pattern characterized by high fat intake, moderate-to-low protein consumption, and very-low-carbohydrate intake (<50 g), which in cancer setting may target CCs metabolism, potentially influencing both tumor treatment and prognosis. Several mechanisms, far beyond the originally proposed inhibition of glucose/insulin signaling, can underpin the effectiveness of KD in cancer management, ranging from oxidative stress, mitochondrial metabolism, and inflammation. The role of a qualified Nutritionist is essential to reduce and manage the short and long-term complications of this dietary therapy, which must be personalized to the individual patient for the planning of tailored KD protocol in cancer patients. In the present review, we summarize the proposed antitumor mechanisms of KD, the application of KD in cancer patients with obesity and cachexia, and the preclinical and clinical evidence on KD therapy in cancer.
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http://dx.doi.org/10.1080/10408398.2020.1847030DOI Listing
December 2020

The dark side of the spoon - glucose, ketones and COVID-19: a possible role for ketogenic diet?

J Transl Med 2020 11 20;18(1):441. Epub 2020 Nov 20.

Laboratory of Cardiovascular Endocrinology, IRCCS San Raffaele Pisana, Via di Val Cannuta, 247, 00166, Rome, Italy.

The novel coronavirus disease (COVID-19) is posing a serious challenge to the health-care systems worldwide, with an enormous impact on health conditions and loss of lives. Notably, obesity and its related comorbidities are strictly related with worse clinical outcomes of COVID-19 disease. Recently, there is a growing interest in the clinical use of ketogenic diets (KDs), particularly in the context of severe obesity with related metabolic complications. KDs have been proven effective for a rapid reduction of fat mass, preserving lean mass and providing an adequate nutritional status. In particular, the physiological increase in plasma levels of ketone bodies exerts important anti-inflammatory and immunomodulating effects, which may reveal as precious tools to prevent infection and potential adverse outcomes of COVID-19 disease. We discuss here the importance of KDs for a rapid reduction of several critical risk factors for COVID-19, such as obesity, type 2 diabetes and hypertension, based on the known effects of ketone bodies on inflammation, immunity, metabolic profile and cardiovascular function. We do believe that a rapid reduction of all modifiable risk factors, especially obesity with its metabolic complications, should be a pillar of public health policies and interventions, in view of future waves of SARS-CoV-2 infection.
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http://dx.doi.org/10.1186/s12967-020-02600-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7677746PMC
November 2020

Losing Weight after Menopause with Minimal Aerobic Training and Mediterranean Diet.

Nutrients 2020 Aug 17;12(8). Epub 2020 Aug 17.

Department of Human Sciences and Promotion of the Quality of Life, San Raffaele Roma Open University, 00166 Rome, Italy.

Objective: It is a common belief that menopausal women have greater difficulty losing weight. The aim of this study was to assess the efficacy of a Mediterranean diet (MD) to promote weight loss in postmenopausal women. All participants were prescribed a hypocaloric traditional MD, tailored to the individual. Subjects were asked not to begin any kind of physical activity. Body composition was measured at the beginning and after 8 weeks of treatment. In total, 89 women (age 52.8 ± 4.5 years, BMI 30.0 ± 5.2 kg/m, fat mass 31.6 ± 10.5 kg) were divided into two groups: the first group consisted of fertile women over 45 years of age, the second group consisted of those diagnosed as menopausal. All women had an improvement in body composition (fat mass -2.3 ± 2.1 kg, < 0.001; protein -0.1 ± 0.7 kg, = 0.190) and blood pressure values. No differences were found between the two groups except for a higher reduction of low-density lipoprotein in the menopausal group ( = 0.035). A positive significant correlation between plant to animal protein ratio and fat-free mass variation was found in the menopausal group. These data suggest that a high adherence to a traditional MD would enable menopausal women to lose fat mass and maintain muscle mass with no significant difference to younger women. Fat mass reduction provides menopausal women with improved cardiovascular and metabolic risk factors.
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http://dx.doi.org/10.3390/nu12082471DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7468767PMC
August 2020

Neuroendocrine and Metabolic Effects of Low-Calorie and Non-Calorie Sweeteners.

Front Endocrinol (Lausanne) 2020 16;11:444. Epub 2020 Jul 16.

Laboratory of Cardiovascular Endocrinology, IRCCS San Raffaele Pisana, Rome, Italy.

Since excessive sugar consumption has been related to the development of chronic metabolic diseases prevalent in the western world, the use of sweeteners has gradually increased worldwide over the last few years. Although low- and non-calorie sweeteners may represent a valuable tool to reduce calorie intake and prevent weight gain, studies investigating the safety and efficacy of these compounds in the short- and long-term period are scarce and controversial. Therefore, future studies will need to elucidate the potential beneficial and/or detrimental effects of different types of sweeteners on metabolic health (energy balance, appetite, body weight, cardiometabolic risk factors) in healthy subjects and patients with diabetes, obesity and metabolic syndrome. In this regard, the impact of different sweeteners on central nervous system, gut hormones and gut microbiota is important, given the strong implications that changes in such systems may have for human health. The aim of this narrative review is to summarize the current evidence for the neuroendocrine and metabolic effects of sweeteners, as well as their impact on gut microbiota. Finally, we briefly discuss the advantages of the use of sweeteners in the context of very-low calorie ketogenic diets.
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http://dx.doi.org/10.3389/fendo.2020.00444DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7378387PMC
June 2021

The novel non-steroidal MR antagonist finerenone improves metabolic parameters in high-fat diet-fed mice and activates brown adipose tissue via AMPK-ATGL pathway.

FASEB J 2020 09 30;34(9):12450-12465. Epub 2020 Jul 30.

Laboratory of Cardiovascular Endocrinology, IRCCS San Raffaele Pisana, Rome, Italy.

Mineralocorticoid receptor antagonists (MRAs) are recommended for the treatment of heart failure and hypertension, mainly due to their natriuretic and anti-fibrotic mode of action. Rodent studies have shown that MRAs can prevent adverse metabolic consequences of obesity but an elucidation of underlying molecular mechanisms is missing. Here, we investigated metabolic effects of the novel non-steroidal MRA finerenone (FIN) in a mouse model of high-fat diet (HFD)-induced obesity and the signaling pathways activated by MR antagonism at level of interscapular brown adipose tissue (iBAT). C57BL/6J male mice were fed a normal diet or a HFD (with60% kcal from fat) containing or not FIN for 3 months. Metabolic parameters, adipose tissue morphology, gene and protein expression analysis were assessed. We also used brown adipocyte cultures (T37i cells) to investigate the effects of FIN-mediated MR antagonism upon lipid and mitochondrial metabolism. HFD + FIN-treated mice showed improved glucose tolerance together with increased multilocularity and higher expression of thermogenic markers at the level of iBAT, without differences in white adipose depots, suggesting an iBAT-specific effect of FIN. Mechanistically, FIN increased activation of AMP-activated protein kinase which, in turn, stimulated adipose triglyceride lipase activation, with subsequent increased expression of uncoupling protein-1 in brown adipocytes.
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http://dx.doi.org/10.1096/fj.202000164RDOI Listing
September 2020

Hydroxychloroquine in the COVID-19 pandemic era: in pursuit of a rational use for prophylaxis of SARS-CoV-2 infection.

Expert Rev Anti Infect Ther 2021 01 16;19(1):5-16. Epub 2020 Aug 16.

Division of Endocrinology, CTO Andrea Alesini Hospital, ASL Roma 2, Department of Systems Medicine, University of Rome "Tor Vergata" , Rome, Italy.

Introduction: Over the last few months, coronavirus disease 2019 (COVID-19) pandemic caused by the novel coronavirus SARS-CoV-2 has posed a serious threat to public health on a global scale. Given the current lack of an effective vaccine, several drugs have been repurposed for treatment and prophylaxis of COVID-19 in an attempt to find an effective cure.

Areas Covered: The antimalarial drug hydroxychloroquine (HCQ) initially garnered widespread attention following the publication of preliminary results showing that this drug exerts an anti-SARS-CoV-2 activity in vitro.

Expert Opinion: To date, clinical evidence suggests lack of benefit from HCQ use for the treatment of hospitalized patients with COVID-19. In such patients, HCQ also appears to be associated with an increased risk of QT interval prolongation and potentially lethal ventricular arrhythmias. Therefore, FDA has recently revoked the Emergency Use Authorization (EUA) for emergency use of HCQ and chloroquine to treat COVID-19. Conversely, whether HCQ use may represent an effective prophylactic strategy against COVID-19 is a separate question that still remains to be answered. In addition, relevant aspects regarding the potential risks and benefits of HCQ need to be clarified, in pursuit of a rational use of this drug in the COVID-19 pandemic era.
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http://dx.doi.org/10.1080/14787210.2020.1799785DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7441799PMC
January 2021

Effects of Quality and Quantity of Protein Intake for Type 2 Diabetes Mellitus Prevention and Metabolic Control.

Curr Nutr Rep 2020 12;9(4):329-337

Department of Human Sciences and Promotion of the Quality of Life, San Raffaele Open University, Via di Val Cannuta, 247, 00166, Rome, Italy.

Purpose Of Review: The aim of this review is to evaluate the ideal protein quality and quantity and the dietary composition for the prevention and metabolic control of type 2 diabetes mellitus (T2DM).

Introduction: Although some reviews demonstrate the advantages of a diet with a higher protein intake, other reviews have observed that a diet high in carbohydrates, with low-glycaemic index carbohydrates and good fibre intake, is equally effective in improving insulin sensitivity.

Methods: Over 2831 articles were screened, and 24 from the last 5 years were analysed and summarised for this review, using the protein, diabetes and insulin glucose metabolic keywords in Pubmed in June 2019.

Results: Eleven studies demonstrate that a higher consumption of proteins has a positive effect on insulin sensitivity. A higher intake of animal protein seems to be related to an increased risk of T2DM. Four studies show that consumption of meat has a deleterious effect. Higher intake of plant protein and dairy products is associated with a modestly reduced risk.

Discussion: Based on the results obtained, for the prevention of T2DM and all disorders related to metabolic syndrome, no ideal dietary composition has yet been found. The advantage of plant protein sources may be related to the foods' low-glycaemic index due to the high fibre content. However, the right protein quality (animal and plant) and the quantity for T2DM prevention and metabolic control are unclear and need to be investigated with further long-term studies.
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http://dx.doi.org/10.1007/s13668-020-00324-2DOI Listing
December 2020

From glucose lowering to treatment of cardiovascular disease: the repositioning of glucose-lowering agents.

Eur Heart J Cardiovasc Pharmacother 2021 Mar;7(2):83-85

Department of Cardiovascular and Respiratory Sciences, IRCCS San Raffaele, Roma, Italy.

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http://dx.doi.org/10.1093/ehjcvp/pvaa019DOI Listing
March 2021

Altered Tregs Differentiation and Impaired Autophagy Correlate to Atherosclerotic Disease.

Front Immunol 2020 13;11:350. Epub 2020 Mar 13.

Unit of Histology and Medical Embryology, Department of Anatomy, Histology, Forensic Medicine and Orthopaedics, Sapienza University of Rome, Rome, Italy.

Atherosclerosis is a progressive vascular disease representing the primary cause of morbidity and mortality in developed countries. Formerly, atherosclerosis was considered as a mere passive accumulation of lipids in blood vessels. However, it is now clear that atherosclerosis is a complex and multifactorial disease, in which the involvement of immune cells and inflammation play a key role. A variety of studies have shown that autophagy-a cellular catalytic mechanism able to remove injured cytoplasmic components in response to cellular stress-may be proatherogenic. So far, in this context, its role has been investigated in smooth muscle cells, macrophages, and endothelial cells, while the function of this catabolic protective process in lymphocyte functionality has been overlooked. The few studies carried out so far, however, suggested that autophagy modulation in lymphocyte subsets may be functionally related to plaque formation and development. Therefore, in this research, we aimed at better clarifying the role of lymphocyte subsets, mainly regulatory T cells (Tregs), in human atherosclerotic plaques and in animal models of atherosclerosis investigating the contribution of autophagy on immune cell homeostasis. Here, we investigate basal autophagy in a mouse model of atherosclerosis, apolipoprotein E (ApoE)-knockout (KO) mice, and we analyze the role of autophagy in driving Tregs polarization. We observed defective maturation of Tregs from ApoE-KO mice in response to tumor growth factor-β (TGFβ). TGFβ is a well-known autophagy inducer, and Tregs maturation defects in ApoE-KO mice seem to be related to autophagy impairment. In this work, we propose that autophagy underlies Tregs maturation, advocating that the study of this process in atherosclerosis may open new therapeutic strategies.
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http://dx.doi.org/10.3389/fimmu.2020.00350DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7082762PMC
March 2021

The different daily distribution of proteins does not influence the variations in body composition in a sample of subjects undergoing a low-calorie Mediterranean-type diet.

Minerva Gastroenterol (Torino) 2021 Jun 24;67(2):183-189. Epub 2020 Mar 24.

Department of Human Sciences and Promotion of the Quality of Life, San Raffaele Roma Open University, Rome, Italy.

Background: Controversy exists regarding whether the different daily balances of proteins between meals and snacks in a low-calorie diet may influence the effects on body composition (BC) results. Aim of this study is to evaluate BC changes made by a lifestyle intervention in a randomized homogeneous sample of two groups with equal daily caloric reduction but different protein distributions between meals.

Methods: Forty-seven men and women (mean age: 32±10 years; Body Mass Index: 28.4±2.4 kg/m) consumed an energy-restricted diet (788 kcal/d below the requirement) for eight weeks in a free-living contest. Subjects consumed 90.1 g protein/d (1.10±0.16 g/kg/day) and were randomized in an EVEN (16.7% at breakfast, 32.8% at lunch, 31.3% at dinner, 19.2% at snacks; N.=23) or UNEVEN (15.4% at breakfast, 36.6% at lunch, 34.9% at dinner, 12.4% at snacks; N.=24) distribution pattern. The nutritional characteristics and caloric deficit of the two diets were similar.

Results: The total sample had an overall improvement in both BMI (-0.9±0.6) and fat mass (FM: -2.3±1.5), while lean body mass was preserved (LBM: 0.0±0.7). There were no significant differences between the two groups in variations in BC.

Conclusions: In overweight and obese subjects undergoing a Mediterranean-type low-calorie diet, a different distribution of daily protein intake between meals and snacks does not result in significant differences in terms of FM loss and LBM maintenance. This is one of the first studies showing that nutritional dietary plans with different daily protein distribution show no particular differences in fat loss and lean mass maintenance.
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http://dx.doi.org/10.23736/S1121-421X.20.02694-XDOI Listing
June 2021

Effects of a ketogenic diet in overweight women with polycystic ovary syndrome.

J Transl Med 2020 02 27;18(1):104. Epub 2020 Feb 27.

Laboratory of Cardiovascular Endocrinology, IRCCS San Raffaele Pisana, Rome, Italy.

Background: Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women during reproductive age. It is characterised clinically by oligo-ovulation or anovulation, hyper-androgenism, and the presence of polycystic ovaries. It is associated with an increased prevalence of metabolic syndrome, cardiovascular disease and type 2 diabetes. The onset of PCOS has been associated to several hereditary and environmental factors, but insulin resistance plays a key pathogenetic role. We sought to investigate the effects of a ketogenic diet (KD) on women of childbearing age with a diagnosis of PCOS.

Methods: Fourteen overweight women with diagnosis of PCOS underwent to a ketogenic Mediterranean diet with phyoextracts (KEMEPHY) for 12 week. Changes in body weight, body mass index (BMI), fat body mass (FBM), lean body mass (LBM), visceral adipose tissue (VAT), insulin, glucose, HOMA-IR, total cholesterol, low density lipoprotein (LDL), high density lipoprotein (HDL), triglycerides (TGs), total and free testosterone, luteinizing hormone (LH), follicle stimulating hormone (FSH); dehydroepiandrosterone sulfate (DHEAs), estradiol, progesterone, sex hormone binding globulin (SHBG) and Ferriman Gallwey score were evaluated.

Results: After 12 weeks, anthropometric and body composition measurements revealed a significant reduction of body weight (- 9.43 kg), BMI (- 3.35), FBM (8.29 kg) and VAT. There was a significant, slightly decrease of LBM. A significant decrease in glucose and insulin blood levels were observed, together with a significant improvement of HOMA-IR. A significant decrease of triglycerides, total cholesterol and LDL were observed along with a rise in HDL levels. The LH/FSH ratio, LH total and free testosterone, and DHEAS blood levels were also significantly reduced. Estradiol, progesterone and SHBG increased. The Ferriman Gallwey Score was slightly, although not significantly, reduced.

Conclusions: Our results suggest that a KD may be considered as a valuable non pharmacological treatment for PCOS. Longer treatment periods should be tested to verify the effect of a KD on the dermatological aspects of PCOS. Trial registration Clinicaltrial.gov, NCT04163120, registrered 10 November 2019, retrospectively registered, https://clinicaltrials.gov.
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http://dx.doi.org/10.1186/s12967-020-02277-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7045520PMC
February 2020

Design and Rationale of the ERA-CVD Consortium PREMED-CAD-Precision Medicine in Coronary Artery Disease.

Biomolecules 2020 01 11;10(1). Epub 2020 Jan 11.

Clinic for Cardiology, University Medical Center Eppendorf, 20246 Hamburg, Germany.

Cardiovascular diseases (CVDs) comprise 45% of all deaths in Europe and causes 3.9 million deaths annually. Coronary artery disease (CAD) which includes myocardial infarction (MI) represents the most common form of CVD. A relevant proportion of MI cases seems preventable since reports claim that up to two-thirds of these patients exhibit symptoms suggestive for MI within 12 months prior to the acute MI event. An early identification of these at-risk subjects is necessary to manage an early and efficient treatment during the ischemic phase. The aim of the PRecision MEDicine in Coronary Artery Disease (PREMED-CAD) consortium is to apply a system medicine approach towards studying and identifying an ischemia specific 'biomarker signature' that improves the identification of individuals 'at-risk' for acute MI. The consortium will take an interdisciplinary and translational approach integrating knowledge from CAD epidemiology, imaging, bioinformatics, statistics and molecular biology, as well as existing phenotypic, blood-based and clinical biomarker data of distinct CAD and subclinical MI phenotypes. This biomarker signature will be validated through atherosclerosis-prone mouse models and human cohorts. The validated signature will be translated in a real-world clinical setting using an ongoing clinical trial comprising patients with subclinical ischemia. The aim of the knowledge obtained from this project is to aid in early MI detection and reduce the mortality and morbidity rate in these at-risk MI individuals.
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http://dx.doi.org/10.3390/biom10010125DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7022893PMC
January 2020

Mineralocorticoid Receptors in Metabolic Syndrome: From Physiology to Disease.

Trends Endocrinol Metab 2020 03 14;31(3):205-217. Epub 2019 Dec 14.

Laboratory of Cardiovascular Endocrinology, IRCCS San Raffaele Pisana, Rome, Italy; Department of Human Sciences and Promotion of the Quality of Life, San Raffaele Roma Open University, Rome, Italy. Electronic address:

Over the past decade, several studies have shown that activity of extra-renal mineralocorticoid receptors (MR) regulates vascular tone, adipogenesis, adipose tissue function, and cardiomyocyte contraction. In mice, abnormal activation of MR in the vasculature and in adipose tissue favors the occurrence of several components of the metabolic syndrome (MetS), such as hypertension, obesity, and glucose intolerance. Accordingly, high levels of aldosterone are associated with obesity and MetS in humans, suggesting that altered activation of aldosterone-MR system in extra-renal tissues leads to profound metabolic dysfunctions. In this context, in addition to the classical indications for heart failure and hypertension, MR antagonists (MRAs) nowadays represent a promising approach to tackle cardiovascular and metabolic disorders occurring in the MetS.
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http://dx.doi.org/10.1016/j.tem.2019.11.006DOI Listing
March 2020

Influence of Vitamin D on Islet Autoimmunity and Beta-Cell Function in Type 1 Diabetes.

Nutrients 2019 Sep 11;11(9). Epub 2019 Sep 11.

Department of Systems Medicine, University of Rome "Tor Vergata", Via Montpellier 1, 00133 Rome, Italy.

Type 1 diabetes (T1D) is a chronic autoimmune disease leading to immune-mediated destruction of pancreatic beta cells, resulting in the need for insulin therapy. The incidence of T1D is increasing worldwide, thus prompting researchers to investigate novel immunomodulatory strategies to halt autoimmunity and modify disease progression. T1D is considered as a multifactorial disease, in which genetic predisposition and environmental factors interact to promote the triggering of autoimmune responses against beta cells. Over the last decades, it has become clear that vitamin D exerts anti-inflammatory and immunomodulatory effects, apart from its well-established role in the regulation of calcium homeostasis and bone metabolism. Importantly, the global incidence of vitamin D deficiency is also dramatically increasing and epidemiologic evidence suggests an involvement of vitamin D deficiency in T1D pathogenesis. Polymorphisms in genes critical for vitamin D metabolism have also been shown to modulate the risk of T1D. Moreover, several studies have investigated the role of vitamin D (in different doses and formulations) as a potential adjuvant immunomodulatory therapy in patients with new-onset and established T1D. This review aims to present the current knowledge on the immunomodulatory effects of vitamin D and summarize the clinical interventional studies investigating its use for prevention or treatment of T1D.
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http://dx.doi.org/10.3390/nu11092185DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6769474PMC
September 2019

Role of Aldosterone and Mineralocorticoid Receptor in Cardiovascular Aging.

Front Endocrinol (Lausanne) 2019 23;10:584. Epub 2019 Aug 23.

Laboratory of Cardiovascular Endocrinology, IRCCS San Raffaele Pisana, Rome, Italy.

The mineralocorticoid receptor (MR) was originally identified as a regulator of blood pressure, able to modulate renal sodium handling in response to its principal ligand aldosterone. MR is expressed in several extra-renal tissues, including the heart, vasculature, and adipose tissue. More recent studies have shown that extra-renal MR plays a relevant role in the control of cardiovascular and metabolic functions and has recently been implicated in the pathophysiology of aging. MR activation promotes vasoconstriction and acts as a potent pro-fibrotic agent in cardiovascular remodeling. Aging is associated with increased arterial stiffness and vascular tone, and modifications of arterial structure and function are responsible for these alterations. MR activation contributes to increase blood pressure with aging by regulating myogenic tone, vasoconstriction, and vascular oxidative stress. Importantly, aging represents an important contributor to the increased prevalence of cardiometabolic syndrome. In the elderly, dysregulation of MR signaling is associated with hypertension, obesity, and diabetes, representing an important cause of increased cardiovascular risk. Clinical use of MR antagonists is limited by the adverse effects induced by MR blockade in the kidney, raising the risk of hyperkalaemia in older patients with reduced renal function. Therefore, there is an unmet need for the enhanced understanding of the role of MR in aging and for development of novel specific MR antagonists in the context of cardiovascular rehabilitation in the elderly, in order to reduce relevant side effects.
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http://dx.doi.org/10.3389/fendo.2019.00584DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6716354PMC
August 2019

Endothelial Mineralocorticoid Receptors Contribute to Vascular Inflammation in Atherosclerosis in a Sex-Specific Manner.

Arterioscler Thromb Vasc Biol 2019 08 11;39(8):1588-1601. Epub 2019 Jul 11.

From the Molecular Cardiology Research Institute, Tufts Medical Center, Boston, MA (M.E.M., Q.L., S.L.I., I.Z.J.).

Objective: MR (mineralocorticoid receptor) activation is associated with cardiovascular ischemia in humans. This study explores the role of the MR in atherosclerotic mice of both sexes and identifies a sex-specific role for endothelial cell (EC)-MR in vascular inflammation. Approach and Results: In the AAV-PCSK9 (adeno-associated virus-proprotein convertase subtilisin/kexin type 9) mouse atherosclerosis model, MR inhibition attenuated vascular inflammation in males but not females. Further studies comparing male and female littermates with intact MR or EC-MR deletion revealed that although EC-MR deletion did not affect plaque size in either sex, it reduced aortic arch inflammation specifically in male mice as measured by flow cytometry. Moreover, MR-intact females had larger plaques but were protected from vascular inflammation compared with males. Intravital microscopy of the mesenteric vasculature demonstrated that EC-MR deletion attenuated TNFα (tumor necrosis factor α)-induced leukocyte slow rolling and adhesion in males, while females exhibited fewer leukocyte-endothelial interactions with no additional effect of EC-MR deletion. These effects corresponded with decreased TNFα-induced expression of the endothelial adhesion molecules ICAM-1 (intercellular adhesion molecule-1) and E-selectin in males with EC-MR deletion compared with MR-intact males and females of both genotypes. These observations were also consistent with MR and estrogen regulation of ICAM-1 transcription and E-selectin expression in primary cultured mouse ECs and human umbilical vein ECs.

Conclusions: In male mice, EC-MR deletion attenuates leukocyte-endothelial interactions, plaque inflammation, and expression of E-selectin and ICAM-1, providing a potential mechanism by which the MR promotes vascular inflammation. In females, plaque inflammation and leukocyte-endothelial interactions are decreased relative to males and EC-MR deletion is not protective.
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http://dx.doi.org/10.1161/ATVBAHA.119.312954DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6656626PMC
August 2019

Comment on "mineralocorticoid antagonism enhances brown adipose tissue function in humans: A randomized placebo-controlled cross-over study".

Diabetes Obes Metab 2019 08 26;21(8):2024-2026. Epub 2019 May 26.

Laboratory of Cardiovascular Endocrinology, IRCCS San Raffaele Pisana, Rome, Italy.

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http://dx.doi.org/10.1111/dom.13756DOI Listing
August 2019

Adipocyte Mineralocorticoid Receptor.

Vitam Horm 2019 21;109:189-209. Epub 2018 Dec 21.

Laboratory of Cardiovascular Endocrinology, IRCCS San Raffaele Pisana, Rome, Italy; Department of Human Sciences and Promotion of the Quality of Life, San Raffaele Roma Open University, Rome, Italy. Electronic address:

Mineralocorticoid receptor (MR) has been recently identified in adipose tissue, where its excessive activation contributes to several metabolic derangements often observed in obesity and metabolic syndrome. Recent findings support the existence of a bidirectional cross-talk between adipose tissue and adrenal glands, contributing to obesity-related hyperaldosteronism and subsequent adipocyte MR excessive activation. In this regard, MR pharmacological blockade has led to prevention of weight gain and metabolic benefits in murine models of genetic or diet-induced obesity. However, there is still a lack of knowledge on the potential metabolic effects of MR antagonists in clinical settings. Hence, larger clinical studies are deemed necessary to clarify the role of MR antagonism in obesity and metabolic syndrome in humans.
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http://dx.doi.org/10.1016/bs.vh.2018.10.005DOI Listing
April 2019

RANKL/RANK/OPG system beyond bone remodeling: involvement in breast cancer and clinical perspectives.

J Exp Clin Cancer Res 2019 Jan 8;38(1):12. Epub 2019 Jan 8.

Unit of Endocrinology and Metabolic Diseases, Department of Systems Medicine, CTO A. Alesini Hospital, ASL Roma 2, University Tor Vergata, Via San Nemesio, 21, 00145, Rome, Italy.

RANKL/RANK/OPG system consists of three essential signaling molecules: i) the receptor activator of nuclear factor (NF)-kB-ligand (RANKL), ii) the receptor activator of NF-kB (RANK), and iii) the soluble decoy receptor osteoprotegerin (OPG). Although this system is critical for the regulation of osteoclast differentiation/activation and calcium release from the skeleton, different studies have elucidated its specific role in mammary gland physiology and hormone-driven epithelial proliferation during pregnancy. Of note, several data suggest that progesterone induces mammary RANKL expression in mice and humans. In turn, RANKL controls cell proliferation in breast epithelium under physiological conditions typically associated with higher serum progesterone levels, such as luteal phase of the menstrual cycle and pregnancy. Hence, RANKL/RANK system can be regarded as a major downstream mediator of progesterone-driven mammary epithelial cells proliferation, potentially contributing to breast cancer initiation and progression. Expression of RANKL, RANK, and OPG has been detected in breast cancer cell lines and in human primary breast cancers. To date, dysregulation of RANKL/RANK/OPG system at the skeletal level has been widely documented in the context of metastatic bone disease. In fact, RANKL inhibition through the RANKL-blocking human monoclonal antibody denosumab represents a well-established therapeutic option to prevent skeletal-related events in metastatic bone disease and adjuvant therapy-induced bone loss in breast cancer. On the other hand, the exact role of OPG in breast tumorigenesis is still unclear. This review focuses on molecular mechanisms linking RANKL/RANK/OPG system to mammary tumorigenesis, highlighting pre-clinical and clinical evidence for the potential efficacy of RANKL inhibition as a prevention strategy and adjuvant therapy in breast cancer settings.
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http://dx.doi.org/10.1186/s13046-018-1001-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6325760PMC
January 2019

Omega-3 PUFAs and vitamin D co-supplementation as a safe-effective therapeutic approach for core symptoms of autism spectrum disorder: case report and literature review.

Nutr Neurosci 2020 Oct 13;23(10):779-790. Epub 2018 Dec 13.

Unit of Endocrinology and Metabolic Diseases, Department of Systems Medicine, CTO Andrea Alesini Hospital, University Tor Vergata, Rome, Italy.

Autism spectrum disorder (ASD) is a group of neurodevelopmental disorders characterized by abnormal development of cognitive, social, and communicative skills. Although ASD aetiology and pathophysiology are still unclear, various nutritional factors have been investigated as potential risk factors for ASD development, including omega-3 polyunsaturated fatty acids (PUFAs) and vitamin D deficiency. In fact, both omega-3 PUFAs and vitamin D are important for brain development and function. Herein, we report the case of a 23-year-old young adult male with autism who was referred to our Unit due to a 12-month history of cyclic episodes of restlessness, agitation, irritability, oppositional and self-injurious behaviours. Laboratory tests documented a markedly altered omega-6/omega-3 balance, along with a vitamin D deficiency, as assessed by serum levels of 25-hydroxyvitamin D. Omega-3 and vitamin D co-supplementation was therefore started, with remarkable improvements in ASD symptoms throughout a 24-month follow-up period. A brief review of the literature for interventional studies evaluating the efficacy of omega-3 or vitamin D supplementation for the treatment of ASD-related symptoms is also provided. To our knowledge, this is the first case reporting remarkable beneficial effects on ASD symptoms deriving from omega-3 and vitamin D combination therapy. This case report suggests omega-3 and vitamin D co-supplementation as a potential safe-effective therapeutic strategy to treat core symptoms of ASD. However, larger studies are needed to evaluate the real efficacy of such therapeutic approach in a broader sample of ASD patients.
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http://dx.doi.org/10.1080/1028415X.2018.1557385DOI Listing
October 2020

Canrenone on cardiovascular mortality in congestive heart failure: CanrenOne eFFects on cardiovascular mortality in patiEnts with congEstIve hearT failure: The COFFEE-IT study.

Pharmacol Res 2019 03 28;141:46-52. Epub 2018 Nov 28.

Medical and Surgery Sciences Department, University of Bologna, Bologna, Italy.

Aim: To evaluate canrenone effects compared to other therapies on cardiovascular mortality in patients with chronic heart failure (CHF) and preserved systolic function after 10 years of evaluation.

Methods: We enrolled 532 patients with CHF and preserved systolic function. Patients were followed with a mean follow-up of 10 years: 166 patients were in therapy with canrenone, while 336 patients were in conventional therapy. We re-evaluated these data after 10 years, together with the rate of death and survival.

Results: Systolic and diastolic blood pressure were lower with canrenone compared to the group not treated with canrenone, both in supine and orthostatism. In the group treated with canrenone we recorded a lower value of fasting plasma glucose and glycated hemoglobin. Uric acid was lower in the group treated with canrenone, no differences were observed regarding creatinine, sodium, potassium, brain natriuretic peptide (BNP), pro-BNP or plasma renin activity (PRA), while aldosterone levels were reduced in canrenone group compared to control. After 10 years, left ventricular mass was lower in canrenone group. We recorded a more pronounced progression of NYHA class in controls compared to patients treated with canrenone, with also a higher number of deaths. A higher number of deaths was recorded in control group in the 68-83 years range compared to canrenone. A higher incidence of death was reported among patients without hypercholesterolemia in control group; this was not significant in patients treated with canrenone. A longer survival was observed in patients treated with canrenone.

Conclusion: Administered to patients with CHF and preserved systolic fraction, reduced mortality and extended the life.
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http://dx.doi.org/10.1016/j.phrs.2018.11.037DOI Listing
March 2019

Induction of Atherosclerotic Plaques Through Activation of Mineralocorticoid Receptors in Apolipoprotein E-deficient Mice.

J Vis Exp 2018 09 26(139). Epub 2018 Sep 26.

Laboratory of Cardiovascular Endocrinology, IRCCS San Raffaele Pisana, Rome, Italy; Department of Human Sciences and Promotion of the Quality of Life, San Raffaele Roma Open University, Rome, Italy;

Atherosclerosis is due to a chronic inflammatory response affecting vascular endothelium and is promoted by several factors such as hypertension, dyslipidemia, and diabetes. To date, there is evidence to support a role for circulating aldosterone as a risk factor for the development of cardiovascular disease. Transgenic mouse models have been generated to study cellular and molecular processes leading to atherosclerosis. In this manuscript, we describe a protocol that takes advantage of continuous infusion of aldosterone in ApoE mice and generates atherosclerotic plaques in the aortic root after 4 weeks of treatment. We, therefore, illustrate a method for quantification and characterization of atherosclerotic lesions at the aortic root level. The added value of aldosterone infusion is represented by the generation of atherosclerotic lesions rich in lipid and inflammatory cells after 4 weeks of treatment. We describe in detail the staining procedures to quantify lipid and macrophage content within the plaque. Notably, in this protocol, we perform heart tissue-embedding in OCT in order to preserve the antigenicity of cardiac tissue and facilitate detectability of antigens of interest. Analysis of the plaque phenotype represents a valid approach to study the pathophysiology of atherosclerosis development and to identify novel pharmacological targets for the development of anti-atherogenic drugs.
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http://dx.doi.org/10.3791/58303DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6235332PMC
September 2018

Mineralocorticoid Receptor and Aldosterone-Related Biomarkers of End-Organ Damage in Cardiometabolic Disease.

Biomolecules 2018 09 18;8(3). Epub 2018 Sep 18.

Laboratory of Cardiovascular Endocrinology, IRCCS San Raffaele Pisana, Via di Val Cannuta 247, 00166 Rome, Italy.

The mineralocorticoid receptor (MR) was first identified as a blood pressure regulator, modulating renal sodium handling in response to its principal ligand aldosterone. The mineralocorticoid receptor is also expressed in many tissues other than the kidney, such as adipose tissue, heart and vasculature. Recent studies have shown that MR plays a relevant role in the control of cardiovascular and metabolic function, as well as in adipogenesis. Dysregulation of aldosterone/MR signaling represents an important cause of disease as high plasma levels of aldosterone are associated with hypertension, obesity and increased cardiovascular risk. Aldosterone displays powerful vascular effects and acts as a potent pro-fibrotic agent in cardiovascular remodeling. Mineralocorticoid receptor activation regulates genes involved in vascular and cardiac fibrosis, calcification and inflammation. This review focuses on the role of novel potential biomarkers related to aldosterone/MR system that could help identify cardiovascular and metabolic detrimental conditions, as a result of altered MR activation. Specifically, we discuss: (1) how MR signaling regulates the number and function of different subpopulations of circulating and intra-tissue immune cells; (2) the role of aldosterone/MR system in mediating cardiometabolic diseases induced by obesity; and (3) the role of several MR downstream molecules as novel potential biomarkers of cardiometabolic diseases, end-organ damage and rehabilitation outcome.
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http://dx.doi.org/10.3390/biom8030096DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6165349PMC
September 2018