Publications by authors named "Manfredi Tesauro"

93 Publications

Vasodilator Dysfunction in Human Obesity: Established and Emerging Mechanisms.

J Cardiovasc Pharmacol 2021 Dec;78(Suppl 6):S40-S52

Department of Aging, Policlinico A. Gemelli IRCCS, Rome, Italy.

Abstract: Human obesity is associated with insulin resistance and often results in a number of metabolic abnormalities and cardiovascular complications. Over the past decades, substantial advances in the understanding of the cellular and molecular pathophysiological pathways underlying the obesity-related vascular dysfunction have facilitated better identification of several players participating in this abnormality. However, the complex interplay between the disparate mechanisms involved has not yet been fully elucidated. Moreover, in medical practice, the clinical syndromes stemming from obesity-related vascular dysfunction still carry a substantial burden of morbidity and mortality; thus, early identification and personalized clinical management seem of the essence. Here, we will initially describe the alterations of intravascular homeostatic mechanisms occurring in arteries of obese patients. Then, we will briefly enumerate those recognized causative factors of obesity-related vasodilator dysfunction, such as vascular insulin resistance, lipotoxicity, visceral adipose tissue expansion, and perivascular adipose tissue abnormalities; next, we will discuss in greater detail some emerging pathophysiological mechanisms, including skeletal muscle inflammation, signals from gut microbiome, and the role of extracellular vesicles and microRNAs. Finally, it will touch on some gaps in knowledge, as well as some current acquisitions for specific treatment regimens, such as glucagon-like peptide-1 enhancers and sodium-glucose transporter2 inhibitors, that could arrest or slow the progression of this abnormality full of unwanted consequences.
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http://dx.doi.org/10.1097/FJC.0000000000001108DOI Listing
December 2021

Impact of Physical Activity and Natural Bioactive Compounds on Endothelial Dysfunction in Chronic Kidney Disease.

Life (Basel) 2021 Aug 17;11(8). Epub 2021 Aug 17.

UOC of Internal Medicine-Center of Hypertension and Nephrology Unit, Department of Systems Medicine, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy.

Chronic kidney disease (CKD) represents a world-wide public health problem. Inflammation, endothelial dysfunction (ED) and vascular calcifications are clinical features of CKD patients that increase cardiovascular (CV) mortality. CKD-related CV disease pathogenic mechanisms are not only associated with traditional factors such as arterial hypertension and dyslipidemia, but also with ED, oxidative stress and low-grade inflammation. The typical comorbidities of CKD contribute to reduce the performance and the levels of the physical activity in nephropathic patients compared to healthy subjects. Currently, the effective role of physical activity on ED is still debated, but the available few literature data suggest its positive contribution. Another possible adjuvant treatment of ED in CKD patients is represented by natural bioactive compounds (NBCs). Among these, minor polar compounds of extra virgin olive oil (hydroxytyrosol, tyrosol and oleocanthal), polyphenols, and vitamin D seem to exert a beneficial role on ED in CKD patients. The objective of the review is to evaluate the effectiveness of physical exercise protocols and/or NBCs on ED in CKD patients.
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http://dx.doi.org/10.3390/life11080841DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8402113PMC
August 2021

Variable Changes of Circulating ANGPTL3 and ANGPTL4 in Different Obese Phenotypes: Relationship with Vasodilator Dysfunction.

Biomedicines 2021 Aug 18;9(8). Epub 2021 Aug 18.

Department of Aging, Policlinico A. Gemelli IRCCS, 00168 Roma, Italy.

Obesity associates with premature atherosclerosis and an increased burden of cardiovascular disease, especially when accompanied by abnormalities of lipid and glucose metabolism. Angiopoietin-like (ANGPTL)3 and ANGPTL4 are metabolic regulators, whose upregulation is associated with dyslipidemia, insulin resistance and atherosclerosis. We analyzed, therefore, changes in circulating ANGPTL3 and ANGPTL4 in obese patients with different metabolic phenotypes and their relation with impaired vasodilator reactivity, an early abnormality in atherosclerosis. Compared to the lean subjects ( = 42), circulating ANGPTL3 was elevated (both > 0.001) in the patients with metabolically unhealthy obesity (MUO; = 87) and type 2 diabetes (T2D; = 31), but not in those with metabolically healthy obesity (MHO; = 48, > 0.05). Circulating ANGPTL4, by contrast, was increased in all obese subgroups (all < 0.001 vs. lean subjects). Vasodilator responses to both acetylcholine and sodium nitroprusside were reduced in the three obese subgroups vs. lean subjects (all < 0.001), with greater impairment in the patients with T2D than in those with MHO and MUO (all < 0.05). In the whole population, an inverse relationship ( = 0.27; = 0.003) was observed between circulating ANGPTL4 and endothelium-dependent vasorelaxation. Circulating ANGPTL3 and ANGPTL4 undergo variable changes in obese patients with different metabolic phenotypes; changes in ANGPTL4 relate to endothelial dysfunction, making this protein a possible target for vascular prevention in these patients.
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http://dx.doi.org/10.3390/biomedicines9081037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8393675PMC
August 2021

Global mapping of cancers: The Cancer Genome Atlas and beyond.

Mol Oncol 2021 11 20;15(11):2823-2840. Epub 2021 Jul 20.

Department of Experimental Medicine, Torvergata Oncoscience Research Centre of Excellence, TOR, University of Rome Tor Vergata, Italy.

Cancer genomes have been explored from the early 2000s through massive exome sequencing efforts, leading to the publication of The Cancer Genome Atlas in 2013. Sequencing techniques have been developed alongside this project and have allowed scientists to bypass the limitation of costs for whole-genome sequencing (WGS) of single specimens by developing more accurate and extensive cancer sequencing projects, such as deep sequencing of whole genomes and transcriptomic analysis. The Pan-Cancer Analysis of Whole Genomes recently published WGS data from more than 2600 human cancers together with almost 1200 related transcriptomes. The application of WGS on a large database allowed, for the first time in history, a global analysis of features such as molecular signatures, large structural variations and noncoding regions of the genome, as well as the evaluation of RNA alterations in the absence of underlying DNA mutations. The vast amount of data generated still needs to be thoroughly deciphered, and the advent of machine-learning approaches will be the next step towards the generation of personalized approaches for cancer medicine. The present manuscript wants to give a broad perspective on some of the biological evidence derived from the largest sequencing attempts on human cancers so far, discussing advantages and limitations of this approach and its power in the era of machine learning.
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http://dx.doi.org/10.1002/1878-0261.13056DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8564642PMC
November 2021

Gut Dysbiosis and Western Diet in the Pathogenesis of Essential Arterial Hypertension: A Narrative Review.

Nutrients 2021 Apr 1;13(4). Epub 2021 Apr 1.

UOC of Internal Medicine-Center of Hypertension and Nephrology Unit, Department of Systems Medicine, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy.

Metabolic syndrome is a cluster of the most dangerous cardiovascular (CV) risk factors including visceral obesity, insulin resistance, hyperglycemia, alterations in lipid metabolism and arterial hypertension (AH). In particular, AH plays a key role in the complications associated with metabolic syndrome. High salt intake is a well-known risk factor for AH and CV diseases. Vasoconstriction, impaired vasodilation, extracellular volume expansion, inflammation, and an increased sympathetic nervous system (SNS) activity are the mechanisms involved in the pathogenesis of AH, induced by Western diet. Gut dysbiosis in AH is associated with reduction of short chain fatty acid-producing bacteria: acetate, butyrate and propionate, which activate different pathways, causing vasoconstriction, impaired vasodilation, salt and water retention and a consequent high blood pressure. Moreover, increased trimethylamine N-oxide and lipopolysaccharides trigger chronic inflammation, which contributes to endothelial dysfunction and target organs damage. Additionally, a high salt-intake diet impacts negatively on gut microbiota composition. A bidirectional neuronal pathway determines the "brain-gut" axis, which, in turn, influences blood pressure levels. Then, we discuss the possible adjuvant novel treatments related to gut microbiota modulation for AH control.
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http://dx.doi.org/10.3390/nu13041162DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8066853PMC
April 2021

Health-related quality of life in patients with advanced colorectal cancer: a predictive nomogram including BMI, sex and age.

Ann Palliat Med 2021 Apr 1;10(4):4252-4261. Epub 2021 Apr 1.

Medical Oncology Unit, Department of Systems Medicine, Tor Vergata University Hospital, Rome, Italy.

Background: Health-related quality of life (HRQoL) is not universally assessed in metastatic colorectal cancer (mCRC) patients. We tried to identify patient subgroups for whom HRQoL assessment should be strongly encouraged.

Methods: Consecutive mCRC patients who had been deemed candidates for first-line chemotherapy were enrolled in a prospective study (NCT03873064) and asked to complete the HRQoL questionnaire EORTC QLQ-C30. Primary endpoint was the Global Health Status (GHS) of EORTC QLQ-C30. A nomogram was built for prediction of low GHS (i.e., <67%).

Results: Among recruited patients (n=173), a univariable logistic regression analysis (LRA) found that body mass index (BMI <23), age (>65 years) and sex (female) were significantly associated with low GHS. The multivariable LRA confirmed they were independently associated with the outcome (P values of 0.04-0.004). BMI, age and sex were included in a final predictive model (C-statistics, 67%; P=0.001) and used to build a nomogram. A total nomogram score ≥72 was associated with a risk of 28% or higher of having a low GHS. The 28% risk cut-off had a sensitivity of 90% and a specificity of 34% for identifying low GHS. A decision curve analysis revealed that a risk threshold of 28% of the model was associated to an added net benefit of ≥4% when using the nomogram. Low GHS was recorded in 58% vs. 23% of patients with >28% vs. <28% risk according to the nomogram, respectively (odds ratio 3.54, P=0.0004).

Conclusions: High BMI together with young age and male sex were protective against HRQoL deterioration. In centers where HRQoL is not routinely assessed, such an assessment should be at least made for mCRC patients at risk according to the proposed nomogram (i.e., over 65-year-old females with BMI <23).
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http://dx.doi.org/10.21037/apm-20-2194DOI Listing
April 2021

Association of Gut Hormones and Microbiota with Vascular Dysfunction in Obesity.

Nutrients 2021 Feb 13;13(2). Epub 2021 Feb 13.

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

In the past few decades, obesity has reached pandemic proportions. Obesity is among the main risk factors for cardiovascular diseases, since chronic fat accumulation leads to dysfunction in vascular endothelium and to a precocious arterial stiffness. So far, not all the mechanisms linking adipose tissue and vascular reactivity have been explained. Recently, novel findings reported interesting pathological link between endothelial dysfunction with gut hormones and gut microbiota and energy homeostasis. These findings suggest an active role of gut secretome in regulating the mediators of vascular function, such as nitric oxide (NO) and endothelin-1 (ET-1) that need to be further investigated. Moreover, a central role of brain has been suggested as a main player in the regulation of the different factors and hormones beyond these complex mechanisms. The aim of the present review is to discuss the state of the art in this field, by focusing on the processes leading to endothelial dysfunction mediated by obesity and metabolic diseases, such as insulin resistance. The role of perivascular adipose tissue (PVAT), gut hormones, gut microbiota dysbiosis, and the CNS function in controlling satiety have been considered. Further understanding the crosstalk between these complex mechanisms will allow us to better design novel strategies for the prevention of obesity and its complications.
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http://dx.doi.org/10.3390/nu13020613DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7918888PMC
February 2021

Anti-Inflammatory and Proliferative Properties of Luteolin-7-O-Glucoside.

Int J Mol Sci 2021 Jan 28;22(3). Epub 2021 Jan 28.

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

Flavonoids display a broad range of structures and are responsible for the major organoleptic characteristics of plant-derived foods and beverages. Recent data showed their activity, and in particular of luteolin-7-O-glucoside (LUT-7G), in reduction of oxidative stress and inflammatory mechanisms in different physiological systems. In this paper, we tried to elucidate how LUT-7G could exert both antioxidant and anti-inflammatory effects in endothelial cells cultured in vitro. Here, we showed that LUT-7G is able to inhibit the STAT3 pathway, to have an antiproliferative action, and an important antioxidant property in HUVEC cells. These properties are exerted by the flavone in endothelial through the transcriptional repression of a number of inflammatory cytokines and their receptors, and by the inhibition of ROS generation. ROS and STAT3 activation has been correlated with the production of oxysterols and other hydroxylated fatty acids, and they have been recognized important as players of atherogenesis and cardiocirculatory system diseases. The analysis of the general production pathway of these hydroxylated species, showed a strong decrease of cholesterol hydroxylated species such as 7-alpha-hydroxicholesterol, 7-beta-hydroxicholesterol by the treatment with LUT-7G. This confirms the anti-inflammatory properties of LUT-7G also in the endothelial district, showing for the first time the molecular pathway that verify previous postulated cardiovascular benefits of this flavone.
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http://dx.doi.org/10.3390/ijms22031321DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7865871PMC
January 2021

Preoperative Immunonutrition vs. Standard Dietary Advice in Normo-Nourished Patients Undergoing Fast-Track Laparoscopic Colorectal Surgery.

J Clin Med 2021 Jan 22;10(3). Epub 2021 Jan 22.

Department of Surgical Science, University Tor Vergata, 00133 Rome, Italy.

Immunonutrition (IN) appears to reduce infective complications and in-hospital length of stay (LOS) after major gastrointestinal surgery, but its use in normo-nourished patients is still controversial. The primary aim of this comparative observational study was to evaluate if pre-operative IN reduces in-hospital stay in patients undergoing laparoscopic colorectal resection for cancer under an enhanced recovery after surgery (ERAS) program. The influence of IN on time to first bowel movements, time to full oral diet tolerance, number and type of complications, reasons of prolonged LOS and readmission rate was evaluated as secondary outcome. Patients undergoing ERAS laparoscopic colorectal resection between December 2016 and December 2019 were reviewed. Patients who have received preoperative IN (group A) were compared to those receiving standard dietary advice (group B). Mean in-hospital LOS was significantly shorter in patients receiving preoperative IN than standard dietary advice (4.85 ± 2.25 days vs. 6.06 ± 3.95 days; < 0.0492). No differences in secondary outcomes were observed. Preoperative IN associated with ERAS protocol in normo-nourished patients undergoing laparoscopic colorectal cancer resection seems to reduce LOS.
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http://dx.doi.org/10.3390/jcm10030413DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7865842PMC
January 2021

Mechanisms of SGLT2 (Sodium-Glucose Transporter Type 2) Inhibition-Induced Relaxation in Arteries From Human Visceral Adipose Tissue.

Hypertension 2021 02 28;77(2):729-738. Epub 2020 Dec 28.

Department of Translational Medicine and Surgery, Università Cattolica del Sacro Cuore, Roma, Italy (G.V., C.C.).

As novel drug treatments for diabetes have shown favorable cardiovascular effects, interest has mounted with regard to their possible vascular actions, particularly in relation to visceral adipose tissue perfusion and remodeling in obesity. The present study tested the vasorelaxing effect of the SGLT2 (sodium-glucose transporter type 2) inhibitor canagliflozin in arteries from visceral adipose tissue of either nonobese or obese humans and investigated the underlying mechanisms. Also, the vasorelaxing effect of canagliflozin and the GLP-1 (glucagon-like peptide 1) agonist liraglutide were compared in arteries from obese patients. To these purposes, small arteries (116-734 μm) isolated from visceral adipose tissue were studied ex vivo in a wire myograph. Canagliflozin elicited a higher concentration-dependent vasorelaxation in arterioles from obese than nonobese individuals (=0.02). The vasorelaxing response to canagliflozin was not modified (=0.93) by inhibition of nitric oxide synthase (L-NAME) or prostacyclin (indomethacin), or by HO scavenging (catalase); also, canagliflozin-induced relaxation was similar (=0.23) in endothelium-intact or -denuded arteries precontracted with high potassium concentration, thereby excluding an involvement of endothelium-derived hyperpolarizing factors. The vasorelaxing response to canagliflozin was similar to that elicited by the Na/H exchanger 1 inhibitor BIX (=0.67), but greater than that to the Na/Ca exchanger inhibitor SEA 0400 (=0.001), hinting a role of Na/H exchanger inhibition in canagliflozin-induced relaxation. In arterioles from obese patients, the vasorelaxing response to canagliflozin was greater than that to liraglutide (=0.004). These findings demonstrate that canagliflozin induces endothelium-independent vasorelaxation in arterioles from human visceral adipose tissue, thereby suggesting that SGLT2 inhibition might favorably impact the processes linking visceral adipose burden to vascular disease in obesity.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.120.16466DOI Listing
February 2021

Liquid biopsies and cancer omics.

Cell Death Discov 2020 Nov 26;6(1):131. Epub 2020 Nov 26.

Torvergata Oncoscience Research Centre of Excellence, TOR, Department of Experimental Medicine, University of Rome Tor Vergata, 00133, Rome, Italy.

The development of the sequencing technologies allowed the generation of huge amounts of molecular data from a single cancer specimen, allowing the clinical oncology to enter the era of the precision medicine. This massive amount of data is highlighting new details on cancer pathogenesis but still relies on tissue biopsies, which are unable to capture the dynamic nature of cancer through its evolution. This assumption led to the exploration of non-tissue sources of tumoral material opening the field of liquid biopsies. Blood, together with body fluids such as urines, or stool, from cancer patients, are analyzed applying the techniques used for the generation of omics data. With blood, this approach would allow to take into account tumor heterogeneity (since the circulating components such as CTCs, ctDNA, or ECVs derive from each cancer clone) in a time dependent manner, resulting in a somehow "real-time" understanding of cancer evolution. Liquid biopsies are beginning nowdays to be applied in many cancer contexts and are at the basis of many clinical trials in oncology.
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http://dx.doi.org/10.1038/s41420-020-00373-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7691330PMC
November 2020

Serological determinants of COVID-19.

Biol Direct 2020 11 2;15(1):21. Epub 2020 Nov 2.

UOC of Internal Medicine-Center of Hypertension and Nephrology Unit, Department of Systems Medicine, University of Rome Tor Vergata, via Montpellier 1, 00133, Rome, Italy.

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection spreaded rapidly worldwide, as far as it has become a global pandemic. Therefore, the introduction of serological tests for determination of IgM and IgG antibodies has become the main diagnostic tool, useful for tracking the spread of the virus and for consequently allowing its containment. In our study we compared point of care test (POCT) lateral flow immunoassay (FIA) vs automated chemiluminescent immunoassay (CLIA), in order to assess their specificity and sensibility for COVID-19 antibodies detection.

Results: We find that different specificities and sensitivities for IgM and IgG tests. Notably IgM POCT FIA method vs CLIA method (gold standard) has a low sensitivity (0.526), while IgG POCT FIA method vs CLIA method (gold standard) test has a much higher sensitivity (0.937); further, with respect of IgG, FIA and CLIA could arguably provide equivalent information.

Conclusions: FIA method could be helpful in assessing in short time, the possible contagiousness of subjects that for work reasons cannot guarantee "social distancing".
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http://dx.doi.org/10.1186/s13062-020-00276-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7605129PMC
November 2020

ACTH-Independent Cushing's Syndrome Associated with Left Adrenocortical Oncocytoma of Uncertain Malignant Potential.

Case Rep Endocrinol 2020 26;2020:8816527. Epub 2020 Sep 26.

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

Adrenocortical oncocytomas are rare and mostly nonfunctioning neoplasms. We report the case of a 27-year-old woman diagnosed with an ACTH-independent Cushing's syndrome due to left adrenal oncocytoma. She underwent laparoscopic adrenalectomy. Histopathological examination revealed an oncocytoma of uncertain malignant potential with a low Ki-67 proliferation index, inhibin A positivity, and chromogranin A negativity. Electron micrographs confirmed adrenal oncocytoma cells, characterized by the presence of a large amount of mitochondria. The postoperative course was uneventful, and the patient experienced a progressive regression of Cushing-related symptoms. Periodical follow-ups with MRI and cortisol dosage are required due to the neoplasm's uncertain malignant potential. Considerations on the diagnosis, pathology findings, clinical remarks, and interventions are made.
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http://dx.doi.org/10.1155/2020/8816527DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7537674PMC
September 2020

Cancer predictive studies.

Biol Direct 2020 10 14;15(1):18. Epub 2020 Oct 14.

Torvergata Oncoscience Research Centre of Excellence, TOR, Department of Experimental Medicine, University of Rome Tor Vergata, via Montpellier 1, 00133, Rome, Italy.

The identification of individual or clusters of predictive genetic alterations might help in defining the outcome of cancer treatment, allowing for the stratification of patients into distinct cohorts for selective therapeutic protocols. Neuroblastoma (NB) is the most common extracranial childhood tumour, clinically defined in five distinct stages (1-4 & 4S), where stages 3-4 define chemotherapy-resistant, highly aggressive disease phases. NB is a model for geneticists and molecular biologists to classify genetic abnormalities and identify causative disease genes. Despite highly intensive basic research, improvements on clinical outcome have been predominantly observed for less aggressive cancers, that is stages 1,2 and 4S. Therefore, stages 3-4 NB are still complicated at the therapeutic level and require more intense fundamental research. Using neuroblastoma as a model system, here we herein outline how cancer prediction studies can help at steering preclinical and clinical research toward the identification and exploitation of specific genetic landscape. This might result in maximising the therapeutic success and minimizing harmful effects in cancer patients.
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http://dx.doi.org/10.1186/s13062-020-00274-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7557058PMC
October 2020

Increased fractalkine and vascular dysfunction in obesity and in type 2 diabetes. Effects of oral antidiabetic treatment.

Vascul Pharmacol 2020 May - Jun;128-129:106676. Epub 2020 Mar 26.

Policlinico A. Gemelli IRCCS, Roma, Italy; Department of Internal Medicine, Università Cattolica del Sacro Cuore, Roma, Italy. Electronic address:

Activation of fractalkine and other chemokines plays an important role in atherogenesis and, in conjunction with endothelial dysfunction, promotes premature vascular damage in obesity and diabetes. We hypothesized that increased circulating fractalkine coexists with impaired vasomotor function in metabolically healthy or unhealthy obesity, and that treatment with antidiabetic drugs may impact these abnormalities in type 2 diabetes. Compared to lean subjects, in both obese groups the vasodilator responses to acetylcholine and sodium nitroprusside were impaired (both P < .001); ET-receptor blockade resulted in greater vasodilation (both P < .001); and plasma levels of fractalkine, E-selectin and monocyte chemoattractant protein (MCP)-1 were increased (all P < .05). In diabetic patients, oral antidiabetic drugs (glyburide, metformin or pioglitazone) reduced circulating levels fractalkine and E-selectin (both P < .05), without affecting vascular responses (all P > .05). Our findings indicate that insulin resistant states are associated with elevated atherogenic chemokines and impaired vascular reactivity. Antidiabetic treatment results in lower circulating fractalkine, which may provide cardiovascular benefits.
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http://dx.doi.org/10.1016/j.vph.2020.106676DOI Listing
October 2020

Peroxiredoxin 6 Is a Key Antioxidant Enzyme in Modulating the Link between Glycemic and Lipogenic Metabolism.

Oxid Med Cell Longev 2019 19;2019:9685607. Epub 2019 Dec 19.

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

Insulin action and often glucose-stimulated insulin secretion are reduced in obesity. In addition, the excessive intake of lipids increases oxidative stress leading to overt type 2 diabetes mellitus (T2DM). Among the antioxidative defense systems, peroxiredoxin 6 (PRDX6) is able to reduce HO and short chain and phospholipid hydroperoxides. Increasing evidences suggest that PRDX6 is involved in the pathogenesis of atherosclerosis and T2DM, but its role in the etiopathology of obesity and its complications is still not known. Therefore, in the present study, we sought to investigate this association by using PRDX6 knockout mice (PRDX6). Metabolic parameters, like carbon dioxide (VCO) production, oxygen consumption (VO), and the respiratory exchange ratio (RER), were determined using metabolic cages. Intraperitoneal insulin and glucose tolerance tests were performed to evaluate insulin sensitivity and glucose tolerance, respectively. Liver and pancreas histochemical analyses were also evaluated. The expression of enzymes involved in lipid and glucose metabolism was analyzed by real-time PCR. Following 24 weeks of high-fat-diet (HFD), PRDX6 mice showed weight gain and higher food and drink intake compared to controls. VO consumption and VCO production decreased in PRDX6 mice, while the RER was lower than 0.7 indicating a prevalent lipid metabolism. PRDX6 mice fed with HFD showed a further deterioration on insulin sensitivity and glucose-stimulated insulin secretion. Furthermore, in PRDX6 mice, insulin did not suppress adipose tissue lipolysis with consequent hepatic lipid overload and higher serum levels of ALT, cholesterol, and triglycerides. Interestingly, in PRDX6 mice, liver and adipose tissue were associated with proinflammatory gene upregulation. Finally, PRDX6 mice showed a higher rate of nonalcoholic steatohepatitis (NASH) compared to control. Our results suggest that PRDX6 may have a functional and protective role in the development of obesity-related metabolic disorders such as liver diseases and T2DM and may be considered a potential therapeutic target against these illnesses.
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http://dx.doi.org/10.1155/2019/9685607DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6948322PMC
June 2020

Calcification biomarkers and vascular dysfunction in obesity and type 2 diabetes: influence of oral hypoglycemic agents.

Am J Physiol Endocrinol Metab 2019 10 13;317(4):E658-E666. Epub 2019 Aug 13.

Internal Medicine, Policlinico A. Gemelli Istituto di Ricovero e Cura a Carattere Scientifico, Rome, Italy.

Vascular aging in obesity and type 2 diabetes (T2D) is associated with progressive vascular calcification, an independent predictor of morbidity and mortality. Pathways for vascular calcification modulate bone matrix deposition, thus regulating calcium deposits. We investigated the association between biomarkers of vascular calcification and vasodilator function in obesity or T2D, and whether antidiabetic therapies favorably impact those markers. Circulating levels of proteins involved in vascular calcification, such as osteopontin (OPN), osteoprotegerin (OPG), regulated on activation, normal T cell expressed and secreted (RANTES), and fetuin-A were measured in lean subjects, individuals with metabolically healthy obesity (MHO), and patients with metabolically unhealthy obesity (MUO) or T2D. Vasodilator function was assessed by infusion of ACh and sodium nitroprusside (SNP). Circulating levels of OPN were higher in the MUO/T2D group than in lean subjects ( < 0.05); OPG and RANTES were higher in MUO/T2D group than in the other groups (both < 0.001); fetuin-A was not different between groups ( > 0.05); vasodilator responses to either ACh or SNP were impaired in both MUO/T2D and MHO compared with lean subjects (all < 0.001). In patients with T2D who were enrolled in the intervention trial, antidiabetic treatment with glyburide, metformin, or pioglitazone resulted in a significant reduction of circulating OPG ( = 0.001), without changes in the other biomarkers and vasodilator responses (all > 0.05). In conclusion, obese patients with MUO/T2D have elevated circulating OPN, OPG, and RANTES; in these patients, antidiabetic treatment reduces only circulating OPG. Further study is needed to better understand the mechanisms of vascular calcifications in obesity and diabetes.
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http://dx.doi.org/10.1152/ajpendo.00204.2019DOI Listing
October 2019

Lp-PLA, a new biomarker of vascular disorders in metabolic diseases.

Int J Immunopathol Pharmacol 2019 Jan-Dec;33:2058738419827154

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

Metabolic diseases are chronic disorders correlated to a greater risk of cardiovascular event and death. Recently, many data have sustained the biological link between microvascular dysfunction, oxidative stress, vascular inflammation, and metabolic diseases. The determination of new and specific blood biomarkers of vascular inflammation associated with obesity-related metabolic syndrome (MetS) and diabetes such as lipoprotein-associated phospholipase A (Lp-PLA) could be useful to identify subject with high risk of cardiovascular events. Lp-PLA participates by a crucial role in microvascular dysfunction and oxidative stress showing positive association with metabolic disorders. In this review, we will argue the evolving role of Lp-PLA in predicting cardiovascular events in metabolic disease patients.
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http://dx.doi.org/10.1177/2058738419827154DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6360470PMC
March 2019

Corrigendum to "Analysis of the Power of Common Diagnostic Tools in the Management of Acute Pancreatitis".

Gastroenterol Res Pract 2018 24;2018:4929275. Epub 2018 Jun 24.

Medizinische Klinik I, Universitaetsklinikum Hamburg-Eppendorf, 20246 Hamburg, Germany.

[This corrects the article DOI: 10.1155/2014/438697.].
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http://dx.doi.org/10.1155/2018/4929275DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6035827PMC
June 2018

Circulating MicroRNAs in Elderly Type 2 Diabetic Patients.

Int J Endocrinol 2018 10;2018:6872635. Epub 2018 Apr 10.

Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy.

The circulating microRNAs (miRNAs) associated with type 2 diabetes (T2D) in elderly patients are still being defined. To identify novel miRNA biomarker candidates for monitoring responses to sitagliptin in such patients, we prospectively studied 40 T2D patients (age > 65) with HbA1c levels of 7.5-9.0% on metformin. After collection of baseline blood samples (), the dipeptidyl peptidase-IV (DPP-IV) inhibitor (DPP-IVi) sitagliptin was added to the metformin regimen, and patients were followed for 15 months. Patients with HbA1c < 7.5% or HbA1c reduction > 0.5% after 3 and 15 months of therapy were classified as "responders" (group R, = 34); all others were classified as "nonresponders" (group NR, = 6). Circulating miRNA profiling was performed on plasma collected in each group before and after 15 months of therapy ( and ). Intra- and intergroup comparison of miRNA profiles pinpointed three miRNAs that correlated with responses to sitagliptin: miR-378, which is a candidate biomarker of resistance to this DPP-IVi, and miR-126-3p and miR-223, which are associated with positive responses to the drug. The translational implications are as immediate as evident, with the possibility to develop noninvasive diagnostic tools to predict drug response and development of chronic complications.
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http://dx.doi.org/10.1155/2018/6872635DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5914089PMC
April 2018

Effects of fenoldopam on renal blood flow in hypertensive chronic kidney disease.

J Nephrol 2019 Feb 15;32(1):75-81. Epub 2018 May 15.

Division of Hypertension and Nephrology, Department of Systems Medicine, University of Rome "Tor Vergata", Viale Oxford 81, 00133, Rome, Italy.

Background And Aim: The synthetic drug fenoldopam mesylate (FM) may have a renoprotective role, and a "renal dose" of 0.1 µg/kg/min intravenous (IV) infusion of FM has been reported as able to increase renal blood flow without affecting systemic blood pressure. But conclusive data are still lacking. We aimed to investigate by color-Doppler ultrasonography the effects of IV administration of FM at this dosage in hypertensive chronic kidney disease (CKD) patients, and verify whether it may induce any systemic hemodynamic alteration.

Methods: In 60 hypertensive CKD patients, we measured by duplex Doppler ultrasonography, at baseline and during infusion of 0.1 µg/kg/min of FM, the systolic and diastolic flow velocity (sampled at the renal hilum, intermediate section and origin of both renal arteries) and the intra-parenchymal renal resistive index (RRI) sampled on interlobular arteries of both kidneys. Patients were divided into four subgroups (I-IV) according to classification of National Kidney Foundation Kidney Disease Outcomes Quality Initiative (NKF-DOQI).

Results: Infusion of 0.1 µg/kg/min FM significantly decreased the RRI (0.73 ± 0.05 vs. 0.65 ± 0.06; p < 0.0001) and increased the systolic and diastolic flow velocities in all renal artery tracts examined. No single episode of systemic hypotension was observed.

Conclusions: Very low-dose FM may significantly increase renal blood flow and exert a renal protective effect in hypertensive CKD patients. Infusion of FM at such low dosage appears also to be quite safe, even in CKD and hypertensive patients.
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http://dx.doi.org/10.1007/s40620-018-0496-0DOI Listing
February 2019

Lower Heart Rate Variability Is Associated with Lower Pulse Pressure Amplification: Role of Obesity.

Pulse (Basel) 2018 Mar 7;5(1-4):99-105. Epub 2017 Sep 7.

Hypertension Unit, Department of Internal Medicine, Policinico Tor Vergata, Università di Roma Tor Vergata, Rome, Italy.

Background: Heart rate variability (HRV), pulse pressure amplification, and obesity represent risk factors for cardiovascular events. The aims of the present study are (1) to explore the impact of HRV on pulse pressure amplification and (2) to investigate whether the association between HRV and pulse pressure amplification differs in obese and lean subjects.

Methods: A total of 342 patients (age 61 ± 11 years) were enrolled. HRV was analyzed concerning both the frequency and time domain as well as concerning the HRV triangular index. Pulse pressure amplification was estimated as the ratio between brachial and carotid pulse pressure, the latter measured with SphygmoCor.

Results: Time domain HRV indices were directly correlated with pulse pressure amplification (the lower the HRV indices, the lower the pulse pressure amplification). This association was stronger in obese than in lean subjects after controlling for age and sex.

Conclusion: Larger controlled studies are needed to provide a more detailed insight into the relation between HRV and pulse pressure amplification and to determine which pathways are differentially activated in lean and obese subjects.
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http://dx.doi.org/10.1159/000479701DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5939841PMC
March 2018

An operational definition of SHATS (Systemic Hemodynamic Atherosclerotic Syndrome): Role of arterial stiffness and blood pressure variability in elderly hypertensive subjects.

Int J Cardiol 2018 07;263:132-137

Hypertension and Nephrology Unit, Department of Medicine, Policinico Tor Vergata, Universita'di Roma Tor Vergata -, Rome, Italy.

Background: CV risk exponentially increases as the number of damaged organs increases The Systemic Hemodynamic Atherosclerotic Syndrome (SHATS) represents a novel conceptualization of the CV continuum focusing on simultaneous multi-organ alteration. This is the first study operationally defining SHATS and aimed at identifying its determinants.

Methods: Left Ventricular Hypertrophy (echocardiography), Common Carotid Artery plaque and increased thickness (ultrasound), and Chronic Kidney Disease (estimated Glomerular Filtration Rate) indexed selective target organ damage. SHATS was operationally defined as their simultaneous presence in a patient. PWV was measured by Sphygmocor® and BP variability by 24 h ABPM.

Results: SHATS affected 19.9% of the 367 studied subjects. Subjects with SHATS had a similar prevalence in diabetes mellitus, but a greater prevalence of very stiff artery (84.9 vs 64.3%, p < 0.01) and use of antihypertensive medications. In the presence of similar office BP, SHATS was associated with higher 24 h SBP and lower 24 h DBP (a greater pulsatile pressure!), reduced nighttime SBP fall, and a twofold greater prevalence of reverse dipper status (48.2 vs 20.2%, p < 0.001). BMI (positive correlation) and DBP (negative correlation) were the only traditional CV risk factors significantly associated with the odds of having SHATS. Very stiff artery and BP variability were significant independent determinants of SHATS, with highly predictive accuracy.

Conclusion: SHATS, the simultaneous damage of multiple target organs, may easily operationally defined. Very stiff artery and BP variability represent key factors for SHATS. The present results support the hypothesis of SHATS as a systemic condition, needing further characterization.
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http://dx.doi.org/10.1016/j.ijcard.2018.03.117DOI Listing
July 2018

Brachial flow-mediated dilation predicts glycemia worsening in normoglycemic young subjects.

Acta Diabetol 2018 Apr 26;55(4):387-389. Epub 2018 Feb 26.

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

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http://dx.doi.org/10.1007/s00592-018-1108-0DOI Listing
April 2018

Metabolic profiling of visceral adipose tissue from obese subjects with or without metabolic syndrome.

Biochem J 2018 03 15;475(5):1019-1035. Epub 2018 Mar 15.

Department of Experimental Medicine and Surgery, University of Rome 'Tor Vergata', 00133 Rome, Italy.

Obesity represents one of the most complex public health challenges and has recently reached epidemic proportions. Obesity is also considered to be primarily responsible for the rising prevalence of metabolic syndrome, defined as the coexistence in the same individual of several risk factors for atherosclerosis, including dyslipidemia, hypertension and hyperglycemia, as well as for cancer. Additionally, the presence of three of the five risk factors (abdominal obesity, low high-density lipoprotein cholesterol, high triglycerides, high fasting glucose and high blood pressure) characterizes metabolic syndrome, which has serious clinical consequences. The current study was conducted in order to identify metabolic differences in visceral adipose tissue (VAT) collected from obese (body mass index 43-48) human subjects who were diagnosed with metabolic syndrome, obese individuals who were metabolically healthy and nonobese healthy controls. Extensive gas chromatography/mass spectrometry (GC/MS) and liquid chromatography/mass spectrometry (LC/MS/MS) analyses were used to obtain the untargeted VAT metabolomic profiles of 481 metabolites belonging to all biochemical pathways. Our results indicated consistent increases in oxidative stress markers from the pathologically obese samples in addition to subtle markers of elevated glucose levels that may be consistent with metabolic syndrome. In the tissue derived from the pathologically obese subjects, there were significantly elevated levels of plasmalogens, which may be increased in response to oxidative changes in addition to changes in glycerolphosphorylcholine, glycerolphosphorylethanolamine glycerolphosphorylserine, ceramides and sphingolipids. These data could be potentially helpful for recognizing new pathways that underlie the metabolic-vascular complications of obesity and may lead to the development of innovative targeted therapies.
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http://dx.doi.org/10.1042/BCJ20170604DOI Listing
March 2018

Favorable Vascular Actions of Angiotensin-(1-7) in Human Obesity.

Hypertension 2018 01 4;71(1):185-191. Epub 2017 Dec 4.

From the Policlinico A. Gemelli, Rome, Italy (F.S., A.V., N.M., C.C.); Department of Internal Medicine, University of Tor Vergata, Rome, Italy (M.T., N.D.D.); and Departments of Surgery (A.V.), Pharmacology (N.M.), and Internal Medicine (C.C.), Catholic University, Rome, Italy.

Obese patients have vascular dysfunction related to impaired insulin-stimulated vasodilation and increased endothelin-1-mediated vasoconstriction. In contrast to the harmful vascular actions of angiotensin (Ang) II, the angiotensin-converting enzyme 2 product Ang-(1-7) has shown to exert cardiovascular and metabolic benefits in experimental models through stimulation of the Mas receptor. We, therefore, examined the effects of exogenous Ang-(1-7) on vasodilator tone and endothelin-1-dependent vasoconstriction in obese patients. Intra-arterial infusion of Ang-(1-7) (10 nmol/min) resulted in significant increase in unstimulated forearm flow (=0.03), an effect that was not affected by the Mas receptor antagonist A779 (10 nmol/min; >0.05). In the absence of hyperinsulinemia, however, forearm flow responses to graded doses of acetylcholine and sodium nitroprusside were not different during Ang-(1-7) administration compared with saline (both >0.05). During infusion of regular insulin (0.15 mU/kg per minute), by contrast, endothelium-dependent vasodilator response to acetylcholine was significantly enhanced by Ang-(1-7) (=0.04 versus saline), whereas endothelium-independent response to sodium nitroprusside was not modified (=0.91). Finally, Ang-(1-7) decreased the vasodilator response to endothelin A receptor blockade (BQ-123; 10 nmol/min) compared with saline (6±1% versus 93±17%; <0.001); nitric oxide inhibition by l--monomethylarginine (4 µmol/min) during concurrent endothelin A antagonism resulted in similar vasoconstriction in the absence or presence of Ang-(1-7 Ang-(1-7) (=0.69). Our findings indicate that in obese patients Ang-(1-7) has favorable effects not only to improve insulin-stimulated endothelium-dependent vasodilation but also to blunt endothelin-1-dependent vasoconstrictor tone. These findings provide support for targeting Ang-(1-7) to counteract the hemodynamic abnormalities of human obesity.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.117.10280DOI Listing
January 2018

Hypertension in kidney transplantation is associated with an early renal nerve sprouting.

Nephrol Dial Transplant 2017 Jun;32(6):1053-1060

Hypertension and Nephrology Unit, Department of Systems Medicine, Tor Vergata University, Rome, Italy.

Background.: Normalization of arterial pressure occurs in just a few patients with hypertensive chronic kidney disease undergoing kidney transplantation. Hypertension in kidney transplant recipients may be related to multiple factors. We aimed to assess whether hypertension in kidney-transplanted patients may be linked to reinnervation of renal arteries of the transplanted kidney.

Methods.: We investigated renal arteries innervation from native and transplanted kidneys in three patients 5 months, 2 years and 11 years after transplantation, respectively. Four transplanted kidneys from non-hypertensive patients on immunosuppressive treatment without evidence of hypertensive arteriolar damage were used as controls.

Results: . Evidence of nerve sprouting was observed as early as 5 months following transplantation, probably originated from ganglions of recipient patient located near the arterial anastomosis and was associated with mild hypertensive arteriolar damage. Regeneration of periadventitial nerves was already complete 2 years after transplantation. Nerve density tended to reach values observed in native kidney arteries and was associated with hypertension-related arteriolar lesions in transplanted kidneys. Control kidneys, albeit on an immunosuppressive regimen, presented only a modest regeneration of sympathetic nerves.

Conclusions: . Our results suggest that the considerable increase in sympathetic nerves, as found in patients with severe arterial damage, may be correlated to hypertension rather than to immunosuppressive therapy, thus providing a morphological basis for hypertension recurrence despite renal denervation.
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http://dx.doi.org/10.1093/ndt/gfx069DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5837349PMC
June 2017

Beneficial Effects of Apelin on Vascular Function in Patients With Central Obesity.

Hypertension 2017 05 13;69(5):942-949. Epub 2017 Mar 13.

From the Departments of Internal Medicine (F.S., C.C.), Surgery (A.V.), Pharmacology (N.M.), and Biochemistry (A.B.), Catholic University, Rome, Italy; and Department of Internal Medicine, University of Tor Vergata, Rome, Italy (N.D.D., M.T.).

Patients with central obesity have impaired insulin-stimulated vasodilation and increased ET-1 (endothelin 1) vasoconstriction, which may contribute to insulin resistance and vascular damage. Apelin enhances insulin sensitivity and glucose disposal but also acts as a nitric oxide (NO)-dependent vasodilator and a counter-regulator of AT (angiotensin [Ang] II type 1) receptor-induced vasoconstriction. We, therefore, examined the effects of exogenous (Pyr)apelin on NO-mediated vasodilation and Ang II- or ET-1-dependent vasoconstrictor tone in obese patients. In the absence of hyperinsulinemia, forearm blood flow responses to graded doses of acetylcholine and sodium nitroprusside were not different during saline or apelin administration (both >0.05). During intra-arterial infusion of regular insulin, however, apelin enhanced the vasodilation induced by both acetylcholine and nitroprusside (both <0.05). Interestingly, the vasodilator effect of concurrent blockade of AT (telmisartan) and AT (PD 123,319) receptors was blunted by apelin (3±5% versus 32±9%; <0.05). Similarly, during apelin administration, blockade of ET receptors (BQ-123) resulted in lower vasodilator response than during saline (23±10% versus 65±12%; <0.05). NO synthase inhibition by L-NMMA (l--monometylarginine) during the concurrent blockade of either Ang II or ET receptors resulted in similar vasoconstriction in the absence or presence of apelin (>0.05). In conclusion, in patients with central obesity, apelin has favorable effects not only to improve insulin-stimulated endothelium-dependent and endothelium-independent vasodilator responses but also to blunt Ang II- and ET-1-dependent vasoconstriction by a mechanism not involving NO. Taken together, our results suggest that targeting the apelin system might favorably impact some hemodynamic abnormalities of insulin-resistant states like obesity.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.116.08916DOI Listing
May 2017

Vascular Effects of Obestatin in Lean and Obese Subjects.

Diabetes 2017 05 7;66(5):1214-1221. Epub 2017 Feb 7.

Department of Internal Medicine, University of Rome Tor Vergata, Rome, Italy.

Obese patients have impaired vasodilator reactivity and increased endothelin 1 (ET-1)-mediated vasoconstriction, two abnormalities contributing to vascular dysfunction. Obestatin, a product of the ghrelin gene, in addition to favorable effects on glucose and lipid metabolism, has shown nitric oxide (NO)-dependent vasodilator properties in experimental models. Given these premises, we compared the effects of exogenous obestatin on forearm flow in lean and obese subjects and assessed its influence on ET-1-dependent vasoconstrictor tone in obesity. In both lean and obese participants, infusion of escalating doses of obestatin resulted in a progressive increase in blood flow from baseline (both < 0.001). This vasodilation was predominantly mediated by enhanced NO activity, because -monomethyl-l-arginine markedly blunted the flow response to obestatin in both groups (both < 0.05 vs. saline). In obese subjects, antagonism of ET receptors by BQ-123 increased forearm flow during saline ( < 0.001) but did not induce additional vasodilation ( > 0.05) during obestatin. Circulating obestatin levels were not different between lean and obese participants ( = 0.41). Our findings indicate that obestatin causes NO-dependent vasodilation in the human circulation. This effect is preserved in obesity, where it is accompanied by reduced ET-1-mediated vasoconstriction. These latter observations make obestatin a promising target for vascular prevention in obesity and diabetes.
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http://dx.doi.org/10.2337/db16-1067DOI Listing
May 2017

Endothelial and Perivascular Adipose Tissue Abnormalities in Obesity-Related Vascular Dysfunction: Novel Targets for Treatment.

J Cardiovasc Pharmacol 2017 Jun;69(6):360-368

*Department of Internal Medicine, Catholic University, Rome, Italy; and †Department of Internal Medicine, University of Tor Vergata, Rome, Italy.

The heavy impact of obesity on the development and progression of cardiovascular disease has sparked sustained efforts to uncover the mechanisms linking excess adiposity to vascular dysfunction. In addition to its well-established role in maintaining vascular homeostasis, the endothelium has been increasingly recognized as a key player in modulating healthy adipose tissue expansion in response to excess calories by providing adipocyte precursors and driving angiogenesis. When this increased storage need is unmet, excessive deposition of fat occurs at ectopic locations, including perivascular adipose tissue (PVAT). PVAT is in intimate contact with the vessel wall, hence affecting vascular function and structure. In lean individuals, PVAT exerts anticontractile and anti-inflammatory activities to protect the vasculature. In obesity, instead, these beneficial properties are lost and PVAT releases inflammatory mediators, promotes oxidative stress, and contributes to vascular dysfunction. The underlying mechanisms elicited by these outside-in signals include resistance to the vasodilator actions of insulin and activation of endothelin (ET)-1-mediated vasoconstriction. A number of adipokines and gut hormones, which are important modulators of food intake, energy balance, glucose and lipid metabolism, insulin sensitivity, and inflammation, have also positive vascular actions. This feature makes them promising tools for targeting both the metabolic and cardiovascular complications of obesity, a view supported by recent large-scale clinical trials indicating that novel drugs for type 2 diabetes with cardiovascular potential may translate into clinically significant benefits. There is, therefore, real hope that unleashing the power of fat- and gut-derived substances might provide effective dual-action therapies for obesity and its complications.
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http://dx.doi.org/10.1097/FJC.0000000000000469DOI Listing
June 2017
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