the effects of GLP-1 on SIRT1 and on the related metabolic pathways in vascular endothelial cells: potential effects on vascular injury in diabetic patients

Background: Incretin therapy may have a potential protective role in the treatment of diabetes associated with the cardiovascular comorbidities. GLP-1 may have beneficial effects in the endothelium and in the cardiac tissue although the molecular mechanisms by which GLP-1 exerts these actions are still unknown. Recently, it has been demonstrated that SIRT1, a NAD’+ deacetylase protein, has a protective role on vascular damage in diabetes by reducing oxidative stress. In several cells and in animal models of diabetes SIRT1 gene expression is reduced. Therefore, SIRT1 may represent a new therapeutic target in the prevention of macrovascular complications of diabetes. Aim: To investigate the effects of GLP-1 on SIRT1 gene expression in human umbelical vein endotelial cells (HUVEC) grown at normal and high glucose. Furthermore, we explored the molecular pathways by which GLP-1 may regulate SIRT1 gene expression. Methods: HUVEC were cultured at 5.5 mM o 20 mM glucose in the presence/ absence of two GLP-1 peptides: GLP-1(7-37) and GLP-1(9-36)NH2. Gene expression of SIRT1 was assessed by RT-PCR real time. Akt, AMPK and ERK phosphorylation were measured by Western Blot. Results: SIRT1 gene expression was significantly reduced in HUVEC grown at 20mM in comparison to cells grown at 5.5 mM of glucose. The treatment of cells with GLP-1(7-37) or with GLP-1(9-36)NH2 increased SIRT1 gene expression at 20mM glucose but not at 5.5 mM glucose. Furthermore, GLP-1(7-37) e GLP-1(9-36)NH2 enhanced two different intracellular pathways: GLP-1(7-37) stimulated Akt while GLP-1(9-36)NH2 activated AMPK. Conclusions: SIRT1 is a new and promising therapeutic target for diabetes. The increase of SIRT1 expression by GLP-1 peptides opens new perspectives for the use of incretin therapy in the prevention of diabetic macrovascular complications. Furthermore, the evidence of different GLP-1-activated pathways allows us to hypothesize different mechanisms in the regulation of the expression of SIRT1Premesse: L'introduzione della terapia incretinica nella cura del diabete ha rivelato un potenziale ruolo protettivo di questi farmaci verso le comorlidità cardiovascolari. Il GLP-1 è dotato di effetti protettivi a livello endoteliale e cardiaco, ma i meccanismi molecolari attraverso i quali il GLP-1 esercita tali azioni sono solo in parte conosciuti. Recentemente, è stato dimostrato che SIRT1, una protein- deacetilasi NAD+dipendente, esercita un ruolo protettivo da danno vascolare nel diabete, attraverso la riduzione dello stress ossidativo cellulare. In diversi modelli cellulari e animali di diabete l'espressione genica di SIRT1 è ridotta. SIRT1, può dunque rappresentare un nuovo target terapeutico per la prevenzione delle complicanze macrovascolari nel diabete mellito. Scopo: Valutare gli effetti di GLP-1 sull'espressione genica di SIRT1, in cellule endoteliali in condizioni di normoglicemia e di iperglicemia. Identificare, inoltre, le vie metaboliche attivate dal GLP-1, nella regolazione di SIRT1. Metodi: Gli esperimenti sono stati eseguiti in vitro, in colture di cellule endoteliali (HUVEC). L'espressione genica di SIRT1 è stata misurata con RTPCR, in cellule HUVEC dopo trattamento con i peptidi di GLP-1, GLP-1(7-37) e GLP-1(9-36)NH2 in condizioni di normoglicemia (glucosio 5.5 mM) ed iperglicemia (glucosio 20mM). È stata successivamente valutata l'espressione proteica e l'attivazione delle vie Akt, AMPK ed ERK mediante western blot. Risultati: L'espressione genica di SIRT1 è ridotta nelle cellule endoteliali in condizioni di iperglicemia. Entrambi i peptidi di GLP-1 sono in grado di normalizzare l'espressione genica di SIRT1 in condizioni di iperglicemia. In condizioni normoglicemiche non vi è alcun effetto di GLP-1 sull'espressione genica di SIRT1. Inoltre si è visto che i due peptidi stimolano due vie metaboliche differenti: il peptide GLP-1(7-37) attiva la via Akt, mentre il GLP-1(9-36)NH2 attiva la via AMPK. Conclusioni: La normalizzazione dell'espressione genica di SIRT1 rappresenta un nuovo e promettente target terapeutico per il diabete mellito. La normalizzazione dell'espressione di SIRT1 da parte dei due peptidi GLP-1, apre nuove prospettive per l'impiego della terapia incretinica nella prevenzione delle complicanze macrovascolari nel diabete mellito. L'evidenza di due vie metaboliche differenti attivate dai due peptidi permette di ipotizzare dei meccanismi indipendenti da parte di GLP-1(7-37) e GLP-1(9-36)NH2 nella regolazione dell'espressione di SIRT1, aprendo la ricerca di nuovi bersagli molecolari per la terapia del diabete con GLP-

RGS2 expression and aldosterone: renin ratio modulate response to drug therapy in hypertensive patients

Objective RGS2 (regulators of G-protein signalling) is a negative regulator of G(alpha q) protein signalling, which mediates the action of several vasoconstrictors. Low RGS2 expression increases G-protein-coupled signalling in hypertensive patients. The aim of the present study was to correlate RGS2 expression in peripheral blood mononuclear cells (PBMs) with response to antihypertensive therapy in never-treated patients with essential hypertension. Methods and design RGS2 expression was measured by real-time quantitative RT-PCR in peripheral blood mononuclear cells (PBMs) from 102 essential hypertensives. The diagnosis of essential hypertension was based on all clinically required tests, including the captopril suppression test. Antihypertensive treatment was given in accordance to international guidelines. End-point of the study was systolic blood pressure (BP) less than 140mmHg and diastolic BP less than 90mmHg with three or less different antihypertensive agents, which identified responders to treatment. Resistant hypertension was defined as the failure to control systolic and/or diastolic BP despite at least three different classes of antihypertensive agents, including a diuretic. Results During follow-up, 85 (83%) patients reached the end point (responders). Resistant hypertensives (n=17, 17%) were older, had higher baseline BP, plasma aldosterone and aldosterone : renin ratio (ARR) and lower plasma renin activity than patients who reached the end point. RGS2 was negatively correlated to systolic BP at enrolment and significantly lower in PBMs from resistant hypertensives in comparison with patients that reached BP goal. According to logistic regression analysis, high RGS2 expression was predictor of reaching BP goal, whereas high ARR after captopril, age and systolic pressure at enrolment were predictor of resistant hypertension. Conclusion RGS2 expression affects the response to antihypertensive treatment. Reduced RGS2 expression contributes to resistance to antihypertensive agents through poor negative feedback on the effects of aldosterone and of other vasoactive agents. J Hypertens 28: 1104-1108 (C) 2010 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins

Obsessive-Compulsive and Post Traumatic Avoidance Symptoms Influence the Response to Antihypertensive Therapy: Relevance in Uncontrolled Hypertension

pharmaceutical

BLOOD PRESSURE CONTROL HAS DISTINCT EFFECTS ON EXECUTIVE FUNCTION, ATTENTION, MEMORY, AND MARKERS OF CEREBROVASCULAR DAMAGE. RELEVANCE FOR EVALUATING THE IMPACT OF ANTIHYPERTENSIVE TREATMENT ON COGNITIVE DOMAINS.

Hypertension causes cognitive impairment, involving mainly executive functions, but the effect of blood pressure (BP) control on the different cognitive domains is still debated. We correlated executive function, attention and memory with BP control and cerebrovascular damage in 60 undemented middle-aged hypertensives at baseline and after 6-year follow-up. At first evaluation, the patients with poor BP control had higher score of white matter lesions, reduced cerebrovascular reserve capacity and greater carotid intima-media thickness (IMT) than those with good BP control. Performance on executive tests correlated with IMT and with performance on attention tests, which was impaired by low diastolic BP. At long-term follow-up, performance in attention and executive tests improved in spite of the minor improvement of BP control, increased IMT and worse memory. Low diastolic BP has a negative effect on attention, which affects executive performance at first cross-sectional examination. This confounding effect has to be taken into consideration when planning studies on cognitive function. Longitudinal studies are required to unravel the effect of BP control on cognitive function, as only long-term antihypertensive treatment improves both attention and executive performanc

Diagnostic tools for the study of vascular cognitive dysfunction in hypertension and antihypertensive drug research

Arterial hypertension is one of the main risk factors for cerebrovascular diseases, and antihypertensive treatment has significantly reduced their associated mortality. However, morbidity has not been reduced to a similar extent and a still increasing number of patients suffers from recurring strokes and from the disabling consequences of cerebrovascular diseases and develops progressive cognitive impairment. It is still debated to what extent antihypertensive treatment may prevent the development of cognitive dysfunction, due to the lack of a focused approach to vascular cognitive impairment, to the lack of a systematic study of the early phases of dementia, and to the use of diagnostic tests that are not sensitive and specific for a slow onset clinical condition, such as dementia. The aim of the present expert consensus report is to enlist the diagnostic tools that are currently available to assess mild cognitive impairment (MCI) and early dementia and that are sensitive and specific enough to be used in observational, longitudinal, and interventional clinical research studies, aiming to investigate the impact of antihypertensive drugs on vascular dementia (VD)

Changes in surgicaL behaviOrs dUring the CoviD-19 pandemic. The SICE CLOUD19 Study

BACKGROUND: The spread of the SARS-CoV2 virus, which causes COVID-19 disease, profoundly impacted the surgical community. Recommendations have been published to manage patients needing surgery during the COVID-19 pandemic. This survey, under the aegis of the Italian Society of Endoscopic Surgery, aims to analyze how Italian surgeons have changed their practice during the pandemic.METHODS: The authors designed an online survey that was circulated for completion to the Italian departments of general surgery registered in the Italian Ministry of Health database in December 2020. Questions were divided into three sections: hospital organization, screening policies, and safety profile of the surgical operation. The investigation periods were divided into the Italian pandemic phases I (March-May 2020), II (June-September 2020), and III (October-December 2020).RESULTS: Of 447 invited departments, 226 answered the survey. Most hospitals were treating both COVID-19-positive and -negative patients. The reduction in effective beds dedicated to surgical activity was significant, affecting 59% of the responding units. 12.4% of the respondents in phase I, 2.6% in phase II, and 7.7% in phase III reported that their surgical unit had been closed. 51.4%, 23.5%, and 47.8% of the respondents had at least one colleague reassigned to non-surgical COVID-19 activities during the three phases. There has been a reduction in elective (>200 procedures: 2.1%, 20.6% and 9.9% in the three phases, respectively) and emergency (<20 procedures: 43.3%, 27.1%, 36.5% in the three phases, respectively) surgical activity. The use of laparoscopy also had a setback in phase I (25.8% performed less than 20% of elective procedures through laparoscopy). 60.6% of the respondents used a smoke evacuation device during laparoscopy in phase I, 61.6% in phase II, and 64.2% in phase III. Almost all responders (82.8% vs. 93.2% vs. 92.7%) in each analyzed period did not modify or reduce the use of high-energy devices.CONCLUSION: This survey offers three faithful snapshots of how the surgical community has reacted to the COVID-19 pandemic during its three phases. The significant reduction in surgical activity indicates that better health policies and more evidence-based guidelines are needed to make up for lost time and surgery not performed during the pandemic