Discovery and characterization of a new class of NAD+-independent SIRT1 activators.

The activity of sirtuin 1 (SIRT1, a member of the NAD+-dependent deacetylases family) decreases during aging as NAD+ levels naturally decline, thus increasing the risk of several age-associated diseases. Several sirtuin-activating compounds (STACs) have been developed to counteract the age-associated reduction in SIRT1 activity, and some of them are currently under development in clinical trials. STACs induce SIRT1 activation, either through allosteric activation of the enzyme in the presence of NAD+, or by increasing NAD+ levels by inhibiting its degradation or by supplying a key precursor in biosynthesis. In this study, we have identified (E)-2'-des-methyl sulindac analogues as a novel class of STACs that act also in the absence of NAD+, a peculiar behavior demonstrated through enzymatic and mass spectrometry experiments, both in vitro and in cell lines. The activation of the SIRT1 pathway was confirmed in vivo through gene expression and metabolomics analysis. Our data suggest that these compounds could serve as candidate leads for a novel therapeutic strategy aimed at addressing a key metabolic deficiency that may contribute to metabolic and age-associated diseases.

Colorectal cancer patient-derived organoids and cell lines harboring ATRX and/or DAXX mutations lack Alternative Lengthening of Telomeres (ALT).

Telomere maintenance is necessary to maintain cancer cell unlimited viability. However, the mechanisms maintaining telomere length in colorectal cancer (CRC) have not been extensively investigated. Telomere maintenance mechanisms (TMM) include the re-expression of telomerase or alternative lengthening of telomeres (ALT). ALT is genetically associated with somatic alterations in alpha-thalassemia/mental retardation X-linked (ATRX) and death domain-associated protein (DAXX) genes. Cells displaying ALT present distinctive features including C-circles made of telomeric DNA, long and heterogenous telomeric tracts, and telomeric DNA co-localized with promyelocytic leukemia (PML) bodies forming so-called ALT-associated PML bodies (APBs). Here, we identified mutations in ATRX and/or DAXX genes in an extensive collection of CRC samples including 119 patient-derived organoids (PDOs) and 232 established CRC cell lines. C-circles measured in CRC PDOs and cell lines showed low levels overall. We also observed that CRC PDOs and cell lines did not display a significant accumulation of APBs or long telomeres with no appreciable differences between wild-type and mutated ATRX/DAXX samples. Overall, our extensive analyses indicate that CRC is not prone to engage ALT, even when carrying genetic lesions in ATRX and/or DAXX, and support the notion that ATRX/DAXX genomic footprints are not reliable predictors of ALT.

TGS1 mediates 2,2,7-trimethyl guanosine capping of the human telomerase RNA to direct telomerase dependent telomere maintenance.

Pathways that direct the selection of the telomerase-dependent or recombination-based, alternative lengthening of telomere (ALT) maintenance pathway in cancer cells are poorly understood. Using human lung cancer cells and tumor organoids we show that formation of the 2,2,7-trimethylguanosine (TMG) cap structure at the human telomerase RNA 5' end by the Trimethylguanosine Synthase 1 (TGS1) is central for recruiting telomerase to telomeres and engaging Cajal bodies in telomere maintenance. TGS1 depletion or inhibition by the natural nucleoside sinefungin impairs telomerase recruitment to telomeres leading to Exonuclease 1 mediated generation of telomere 3' end protrusions that engage in RAD51-dependent, homology directed recombination and the activation of key features of the ALT pathway. This indicates a critical role for 2,2,7-TMG capping of the RNA component of human telomerase (hTR) in enforcing telomerase-dependent telomere maintenance to restrict the formation of telomeric substrates conductive to ALT. Our work introduces a targetable pathway of telomere maintenance that holds relevance for telomere-related diseases such as cancer and aging.

Cancer-derived EVs show tropism for tissues at early stage of neoplastic transformation.

From the past decade, extracellular vesicles (EVs) have attracted considerable attention as tools for the selective delivery of anti-neoplastic drugs to cancer tissues. Compared to other nanoparticles, EVs display interesting unique features including immune compatibility, low toxicity and the ability to encapsulate a large variety of small- and macro-molecules. However, in virtually all studies, investigations on EVs have been focused on fully transformed cancers: the possibility to apply EV technology also to early-stage tumors has never been explored. Methods: Herein, we studied the ability of cancer-derived EVs to recognize and deliver their cargo also to incipient cancers. To this purpose, EV biodistribution was studied in MMTV-NeuT genetically modified mice during early mammary transformation, in fully developed breast tumors and in the normal gland of wild type syngeneic mice. EVs were loaded with indocyanine green (ICG), a near-infrared (NIR) dye together with oncolytic viruses and i.v. injected in mice. The nanoparticle biodistribution was assayed by in vivo and ex vivo optical imaging (detecting the ICG) and semiquantitative real-time PCR (measuring the adenoviral genome) in different tissues. Results: Our results demonstrate the ability of cancer-derived EVs to recognize early-stage neoplastic tissues opening the possibility to selectively deliver theranostics also for tumor prevention. Conclusions: Taken together our study demonstrates the ability of EVs to recognize and deliver diagnostic and therapeutic agents not only to fully transformed tissues but also to early stage tumors. These findings pave the way for the synthesis of "universal" EVs-based formulation for targeted cancer therapy.

Inhibition of SIRT1 deacetylase and p53 activation uncouples the anti-inflammatory and chemopreventive actions of NSAIDs.

BACKGROUND: Nonsteroidal anti-inflammatory drugs (NSAIDs) have been proposed as chemopreventive agents for many tumours; however, the mechanism responsible for their anti-neoplastic activity remains elusive and the side effects due to cyclooxygenase (COX) inhibition prevent this clinical application. METHODS: Molecular biology, in silico, cellular and in vivo tools, including innovative in vivo imaging and classical biochemical assays, were applied to identify and characterise the COX-independent anti-cancer mechanism of NSAIDs. RESULTS: Here, we show that tumour-protective functions of NSAIDs and exisulind (a sulindac metabolite lacking anti-inflammatory activity) occur through a COX-independent mechanism. We demonstrate these NSAIDs counteract carcinogen-induced proliferation by inhibiting the sirtuin 1 (SIRT1) deacetylase activity, augmenting acetylation and activity of the tumour suppressor p53 and increasing the expression of the antiproliferative gene p21. These properties are shared by all NSAIDs except for ketoprofen lacking anti-cancer properties. The clinical interest of the mechanism identified is underlined by our finding that p53 is activated in mastectomy patients undergoing intraoperative ketorolac, a treatment associated with decreased relapse risk and increased survival. CONCLUSION: Our study, for the first-time, links NSAID chemopreventive activity with direct SIRT1 inhibition and activation of the p53/p21 anti-oncogenic pathway, suggesting a novel strategy for the design of tumour-protective drugs.

Resistant hypertension: an overview.

Despite the availability of anti-hypertensive medications with proven efficacy and good tolerability, many hypertensive patients have blood pressure (BP) levels not at the goals set by international societies. Some of these patients are either non-adherent to the prescribed drugs or not optimally treated. However, a proportion has resistant hypertension (RH) defined as office BP above goal despite the use of ≥3 antihypertensive medications at maximally tolerated doses (one ideally being a diuretic). Diagnosis of RH based upon office measurements, however, needs confirmation through 24-h BP monitoring to exclude "white coat" RH since cardiovascular events and mortality rates follow mean ambulatory BPs. Standardized combination therapy based upon angiotensin converting enzyme inhibitors or angiotensin receptor blockers, amlodipine or other dihydropiridine calcium channel blockers and thiazide or thiazide-like diuretics has been advocated to treat RH with spironolactone as preferred fourth add-on drug. Interventional procedures such as renal denervation have been devised to treat RH and tested with insofar not positive results in series of patients not responding to medical treatment. It is unclear whether RH constitutes a specific phenotype of EH or should rather be considered a more serious form of uncontrolled hypertension. Whatever the case, its presence associates with an increased cardio- and cerebrovascular risk and deserves, therefore, particular care.

Association between plasma gamma-glutamyltransferase fractions and metabolic syndrome among hypertensive patients.

Among the risk factors associated to metabolic syndrome (MetS), hypertension shows the highest prevalence in Italy. We investigated the relationship between the newly identified serum γ-glutamyltransferase (GGT) fractions, b- s- m- f-GGT, and risk factors associated to MetS in hypertensive patients. A total of ninety-five consecutive hypertensive patients were enrolled. GGT fractions were analysed by gel-filtration chromatography, and hepatic steatosis was evaluated by ultrasound. MetS was diagnosed in 36% of patients. Considering the whole group, b- and f-GGT showed the highest positive correlation with BMI, glucose, triglycerides and insulin, and the highest negative correlation with HDL cholesterol. While both serum triglycerides and insulin were independently associated with b-GGT levels, only triglycerides were independently associated with f-GGT. The values of b-GGT activity increased with steatosis grade (g0 = 1.19; g2 = 3.29; ratio g2/g0 = 2.75, p < 0.0001 linear trend). Patients with MetS showed higher levels of b-GGT, m-GGT and f-GGT [median (25th-75th) U/L: 3.19 (1.50-6.59); 0.55 (0.26-0.81); 10.3 (9.1-13.6); respectively] as compared to subjects presenting with one or two MetS criteria [1.75 (0.95-2.85), p < 0.001; 0.33 (0.19-0.60), p < 0.05; 8.8 (7.0-10.6), p < 0.001]. Our data point to a potential role for b- and f-GGT fractions in identifying MetS patients among hypertensive subjects, thus providing a minimally invasive blood-based tool for MetS diagnosis.

The laminA/NF-Y protein complex reveals an unknown transcriptional mechanism on cell proliferation.

Lamin A is a component of the nuclear matrix that also controls proliferation by largely unknown mechanisms. NF-Y is a ubiquitous protein involved in cell proliferation composed of three subunits (-YA -YB -YC) all required for the DNA binding and transactivation activity. To get clues on new NF-Y partner(s) we performed a mass spectrometry screening of proteins that co-precipitate with the regulatory subunit of the complex, NF-YA. By this screening we identified lamin A as a novel putative NF-Y interactor. Co-immunoprecipitation experiments and confocal analysis confirmed the interaction between the two endogenous proteins. Interestingly, this association occurs on euchromatin regions, too. ChIP experiments demonstrate lamin A enrichment in several promoter regions of cell cycle related genes in a NF-Y dependent manner. Gain and loss of function experiments reveal that lamin A counteracts NF-Y transcriptional activity. Taking advantage of a recently generated transgenic reporter mouse, called MITO-Luc, in which an NF-Y-dependent promoter controls luciferase expression, we demonstrate that lamin A counteracts NF-Y transcriptional activity not only in culture cells but also in living animals. Altogether, our data demonstrate the occurrence of lamin A/NF-Y interaction and suggest a possible role of this protein complex in regulation of NF-Y function in cell proliferation.

Bioluminescence imaging of estrogen receptor activity during breast cancer progression.

Estrogen receptors (ER) are known to play an important regulatory role in mammary gland development as well as in its neoplastic transformation. Although several studies highlighted the contribution of ER signaling in the breast transformation, little is known about the dynamics of ER state of activity during carcinogenesis due to the lack of appropriate models for measuring the extent of receptor signaling in time, in the same animal. To this aim, we have developed a reporter mouse model for the non-invasive in vivo imaging of ER activity: the ERE-Luc reporter mouse. ERE-Luc is a transgenic mouse generated with a firefly luciferase (Luc) reporter gene driven by a minimal promoter containing an estrogen responsive element (ERE). This model allows to measure receptor signaling in longitudinal studies by bioluminescence imaging (BLI). Here, we have induced sporadic mammary cancers by treating systemically ERE-Luc reporter mice with DMBA (9,10-dimethyl 1,2-benzanthracene) and measured receptor signaling by in vivo imaging in individual animals from early stage until a clinically palpable tumor appeared in the mouse breast. We showed that DMBA administration induces an increase of bioluminescence in the whole abdominal area 6 h after treatment, the signal rapidly disappears. Several weeks later, strong bioluminescence is observed in the area corresponding to the mammary glands. In vivo and ex vivo imaging analysis demonstrated that this bioluminescent signal is localized in the breast area undergoing neoplastic transformation. We conclude that this non-invasive assay is a novel relevant tool to identify the activation of the ER signaling prior the morphological detection of the neoplastic transformation.

Health care delivery in type 2 diabetes. A survey in an Italian primary care practice.

AIMS: Evidence-based guidelines provide targets and performance measures for the treatment of type 2 diabetic patients but a wide gap separates guidelines-driven recommendations from their clinical application, a phenomenon hindering the transfer of proven benefits to affected populations. METHODS: We analyzed the quality of diabetic care delivered by 8 general practitioners joint in a group practice attending 571 diabetic patients (5.6% of the total enlisted subjects) by assessing process (% of HbA1c, SBP and LDL-C determinations) and intermediate outcome (% of patients with HbA1c <7% vs >8%, systolic BP <130 mmHg vs >140 mmHg, LDL-cholesterol <100 mg/dL vs >130 mg/dL) indicators. RESULTS: HbA1c was at target in 49% of patients and >8% in 22%; SBP and LDL-C determination was available in about two-thirds of patients, only a minority at target for SBP and LDL-C. Antihyperglycemic and antihypertensive treatment was prescribed in most patients but only a third was on statins. During the post-evaluation phase, percentages of patients with HbA1c >8%, SBP < 130 mmHg and LDL-C < 100 mg/dL and the drug prescription pattern did not change. CONCLUSIONS: Several weaknesses affect primary care delivery to type 2 diabetic patients and efforts are needed to improve the management of this high-risk group.

Q192R Paraoxonase (PON)1 Polymorphism, Insulin Sensitivity, and Endothelial Function in Essential Hypertensive Men.

AIMS: Essential hypertension is characterized by increased reactive oxygen species (ROS) generation harmful for insulin sensitivity and nitric oxide (NO)-mediated vasomotor function, a noxious effect that paraoxonase (PON)1, an antioxidant circulating high-density lipoprotein (HDL)-bound esterase, may counteract. The PON1 gene contains several polymorphisms including a glutamine (Q) to arginine (R) transition at position 192 encoding circulating allozymes with higher antioxidant activity that might influence both parameters. METHODS: Q192R was determined by polymerase chain reaction in 72 never-treated, glucose-tolerant, uncomplicated essential hypertensive men. Insulin sensitivity was assessed by homeostasis model assessment (HOMA) and endothelial function by forearm vasodilation (strain-gage venous plethysmography) to intra-arterial acetylcholine (ACH) with sodium nitroprusside (NIP) as a NO-independent control. Additional evaluation variables included 24-hour blood pressure (BP), lipids, BMI, smoking status, and metabolic syndrome (MetS) by Adult Treatment Panel (ATP)-III criteria. R192 was considered as the rare allele, and its associations analyzed by dominant models (Q/Q vs. Q/R + R/R). RESULTS: Genotype frequencies were consistent with the Hardy-Weinberg equilibrium. HOMA was lower and insulin resistance (the upper fourth of HOMA values distribution) less prevalent in Q/R + R/R carriers in whom ACH-mediated vasodilatation was greater and endothelial dysfunction (the bottom fourth of ACH(AUC) values distribution) less frequent than in Q/Q homozygotes. Q192R polymorphism and MetS were unrelated parameters despite their common association with insulin resistance. 24-hour BP, BMI, lipids, and smoking habits were homogeneously distributed across genotypes. CONCLUSIONS: Q192R polymorphism associates differentially with insulin sensitivity and endothelial function in essential hypertensive men.

Lack of a relationship between circulating gamma-glutamyltransferase levels and carotid intima media thickness in hypertensive and diabetic patients.

BACKGROUND: By increasing the intracellular prooxidant burden, gamma-glutamyltransferase (GGT) may accelerate atherosclerotic vascular disease. That noxious influence may be reflected by circulating enzyme levels, a correlate of cardiovascular risk factors, and a predictor of incident events. To evaluate this hypothesis, we tested the association between circulating GGT and common carotid intima-media thickness (CIMT), a surrogate index of systemic atherosclerotic involvement, in a large and well-characterized group of patients at risk of cardiovascular disease (CVD). PATIENTS: This study analyzed 548 patients with hypertension and/or diabetes and a widely prevalent history of CVD. Subjects with known hepatic disease and abnormal GGT values were excluded. METHODS: CIMT (B-mode ultrasonography) values were the mean of four far-wall measurements at both common carotids. Metabolic syndrome (MetS) was diagnosed according to National Cholesterol Education Program-Adult Treatment Panel III criteria. Due to inherent sex-related differences in GGT levels, the data were analyzed separately in males and females in samples dichotomized by the median. RESULTS: The age-adjusted CIMT values did not differ by GGT levels in males or females. In contrast, the carotid wall was consistently thicker in patients with a history of CVD and MetS independent of age and concurrent GGT values. In both sexes, GGT was associated with key components of the MetS such as triglycerides, fasting plasma glucose, and body mass index. CONCLUSION: The data collected in this mixed group of hypertensive and/or diabetic patients with widely prevalent history of CVD do not support the concept of a direct pathophysiological link between GGT levels within reference limits and atherosclerotic involvement.

Right ventricular remodelling in systemic hypertension: a cardiac MRI study.

BACKGROUND: Consistent evidence shows an impact of systemic haemodynamic overload on the right ventricle, but its functional and structural consequences have received scarce attention for several reasons including the difficult application of conventional imaging techniques due to the complex shape and orientation of that cardiac chamber. AIMS: To evaluate whether mild to moderate, uncomplicated hypertension associates with abnormal right ventricular structure and function and how those changes relate to homologous changes in the left ventricle. Data were acquired by steady-state free-precession cardiac MRI, the state of the art tool for the morphological and functional evaluation of the right ventricle. MATERIALS AND METHODS: Twenty-five (12 women) uncomplicated, untreated, essential hypertensive patients were compared with 24 (13 women) sedentary normotensive controls of comparable age. Wall thickness, indexed ventricular mass, end-diastolic volumes, early peak filling rate, a correlate of diastolic relaxation, and ejection fraction were measured at both ventricles. Remodelling index, the ratio of ventricular mass to end-diastolic volume, was used as an index of concentricity. RESULTS: Right ventricular mass index, ventricular wall thickness and remodelling index were greater in hypertensive subjects and associated with reduced peak filling rate, a pattern consistent with concentric right ventricular remodelling. In the hypertensive group, positive, highly significant biventricular correlations existed between indexed mass, early peak filling rate and ejection fraction. CONCLUSIONS: Systemic hypertension associates with concentric right ventricular remodelling and impaired diastolic function, confirming that the unstressed ventricle is not immune to the effects of systemic hypertension. Structural and functional right ventricular adaptation to systemic hypertension tends to parallel the homologous modifications induced by systemic haemodynamic overload on the left ventricle.

Angiotensin II, tissue factor and the thrombotic paradox of hypertension.

Tissue factor (TF), the physiologic initiator of blood coagulation, may contribute to the increased risk of thrombotic complications that characterizes arterial hypertension, as suggested by hypertensive animal models showing evidence for TF activation, and clinical studies in hypertensive patients at higher cardiovascular risk with increased circulating levels of TF and thrombogenic microparticles. Angiotensin II stimulates TF expression both in vitro and in vivo, an effect abolished by ACE or angiotensin II receptor inhibition. Moreover, renin-angiotensin system blockers, including aliskiren, a direct renin inhibitor, are able to modulate TF expression in monocytes and vascular endothelial cells activated by inflammatory cytokines. This behavior is suggestive of anti-inflammatory and anti-thrombotic properties of renin-angiotensin system blockers, and is compatible with the possibility that blocking local renin-angiotensin system activation might downregulate TF, thus reducing the risk of ischemic complications in hypertensive patients.

Abnormal right ventricular mechanics in early systemic hypertension: a two-dimensional strain imaging study.

AIMS: To analyse the relationship between increasing systemic blood pressure (BP) and right ventricular (RV) function as assessed by two-dimensional strain imaging. METHODS AND RESULTS: Longitudinal peak strain and strain rate (SR) were sampled by speckle-tracking methodology at the RV free wall and interventricular septum (IVS) and RV and left ventricular (LV) structure and function were evaluated by conventional echo-Doppler sonography in 89 never-treated, non-obese subjects with office BP values varying from the optimal to mildly hypertensive range. Data were analysed by 24 h systolic BP (SBP) tertiles (cut-offs: 117 and 130 mmHg, n = 29, 30, and 30, respectively), thus partitioning subjects with optimal BP from those with high-normal and mildly increased values. RV peak systolic strain and early diastolic SR decreased in the mid-BP third without further changes in the upper tertile. IVS thickened gradedly by increasing systemic 24 h SBP; posterior wall remodelled to a lesser extent and poorly related to BP load and LV mass index did not change. RV and IVS systolic and diastolic strain indices associated inversely with increasing septal thickness. Conventional right and left indices of global ventricular function, left atrial size, and estimated systolic pulmonary pressure did not differ. CONCLUSION: Two-dimensional strain-assessed RV function is sensitive to increased systemic BP, even at levels below the conventional diagnostic limits for arterial hypertension. Subclinical RV systolic and diastolic abnormalities paralleled BP-driven septal remodelling, perhaps as a reflection of the crucial role played by IVS in RV function.

Right ventricular dysfunction in early systemic hypertension: a tissue Doppler imaging study in patients with high-normal and mildly increased arterial blood pressure.

PURPOSE: To analyze the relationship between increasing systemic blood pressure (BP) and right ventricular (RV) function. SUBJECTS AND METHODS: Ninety-eight never-treated, nonobese patients with BP values varying from the optimal to the mild hypertensive range. Peak early diastolic (Em) and systolic (Sm) velocities were recorded at the tricuspid and mitral annuli by tissue Doppler imaging (TDI); global RV and left ventricular (LV) structure and function by conventional echo-Doppler sonography; insulin sensitivity by homeostasis model assessment (HOMA) index. Data were analyzed by 24-h systolic BP (cut-offs 117 and 130 mmHg), thus partitioning an optimal BP from an intermediate high-normal and an upper mildly increased BP stratum. RESULTS: Em decreased in the mid-third and decelerated further in association with reduced Sm in the upper BP tertile; both correlated negatively to septal thickness and positively to homologous TDI-derived LV indices. RV and LV indices of global ventricular function, estimated pulmonary pressure, HOMA did not differ by systemic BP. CONCLUSION: RV diastolic and systolic function deteriorates in response to slightly increased systemic BP. The process paralleled homologous changes at the LV side and was driven by interventricular septum remodeling, perhaps as a reflection of its role in RV function and biventricular interdependence. Insulin sensitivity seemed to play no relevant role.

Early left ventricular mechanics abnormalities in prehypertension: a two-dimensional strain echocardiography study.

BACKGROUND: Prehypertension predicts established hypertension. In this study, the aim was to analyze left ventricular (LV) mechanics in borderline prehypertensive (pre-HT) and hypertensive (HT) subjects through two-dimensional (2D)-strain echocardiography and then evaluate possible relations between cardiac parameters and insulin metabolism (homeostasis model assessment of insulin resistance (HOMA(IR)). METHODS: Seventy-four consecutive newly diagnosed, untreated HT were divided, on the basis of their office blood pressure (BP) measurements, confirmed by ambulatory BP monitoring (ABPM), in 41 borderline pre-HT (ABPM: 122.5 +/- 6.7/76.2 +/- 5.2 mm Hg) and 33 never-treated mild HT (ABPM: 138.3 +/- 7.3/87.6 +/- 7.1 mm Hg). Thirty-three healthy normotensive (NT) controls (ABPM: 114.8 +/- 6.3/73.1 +/- 6.1 mm Hg) (P < 0.0001) were also studied (NT). All subjects performed 2D color Doppler and pulsed-wave tissue Doppler imaging (PW-TDI). RESULTS: Left ventricular mass (LVM) was significantly higher in pre-HT (39.2 +/- 8.7 g/m(2.7)) and in HT (43.6 +/- 8.5 g/m(2.7)) compared with NT (30.9 +/- 7.4 g/m(2.7)) (P < 0.0001). A mild LV diastolic dysfunction was found both with Doppler mitral flow velocity and PW-TDI at mitral annulus level analysis. Longitudinal 2D strain in pre-HT (-18.9% +/- 3.4) and in HT (-18.0% +/- 3.3) was significantly lower than in NT (-23.9% +/- 3.0) (P < 0.002). These LV abnormalities were associated with systolic ABPM, LVM, and HOMA(IR). CONCLUSIONS: Early abnormalities of LV longitudinal systolic deformation were found both in pre-HT and HT, together with a mild LV diastolic dysfunction. In both groups this early cardiac systolic and diastolic dysfunction is associated to insulin resistance, systolic pressure load, and cardiac remodeling.

Soluble CD40 ligand levels in essential hypertensive men: evidence of a possible role of insulin resistance.

BACKGROUND: Elevated levels of the proinflammatory cytokine soluble CD40 ligand (sCD40L) were reported in subjects with diabetes, impaired glucose tolerance, metabolic syndrome (MS), obesity, and insulin resistance. Metabolic abnormalities might also account for increased sCD40L in subjects with essential hypertension. METHODS: Several metabolic and vascular correlates of sCD40L levels have been investigated in 90 nondiabetic never-treated essential hypertensive men. RESULTS: Median sCD40L level was 8.7 ng/ml (interquartile range: 4.9-11.7). On the basis of sCD40L, subjects were divided by tertiles (thresholds at 6.6 and 11.0 ng/ml). The three groups did not differ for age, body mass index (BMI), smokers, blood pressure (BP), prevalence of nondippers, lipids and lipoproteins, renal function, and albuminuria. Carotid intima-media thickness (IMT: 0.79 +/- 0.22, 0.83 +/- 0.29, and 0.85 +/- 0.30 mm) and percentage of subjects with wall thickening (IMT >0.9 to <1.3 mm: 23, 27, and 27%, respectively) were superimposable in the three groups. No differences were observed in high-sensitivity C-reactive protein (hs-CRP) and no correlation emerged between sCD40L and hs-CRP. An increase through sCD40L tertiles emerged for basal insulin (11.2 +/- 5.6, 14.7 +/- 7.7, and 16.8 +/- 13.5 microU/ml, P = 0.10) and fasting glucose (95 +/- 11, 103 +/- 16, and 105 +/- 14 mg/dl, P = 0.028). Consistently, along with the increase in sCD40L, a worsening in insulin sensitivity was observed, which was expressed as homeostasis model assessment for insulin sensitivity (HOMA%S: 99 +/- 52, 77 +/- 43, and 72 +/- 35, P < 0.05), composite insulin sensitivity index (ISIcomp; Matsuda index: 5.11 +/- 2.65, 3.61 +/- 1.98, and 3.28 +/- 1.87, P = 0.025), or oral glucose insulin sensitivity (OGIS) index (OGIS: 421 +/- 67, 386 +/- 90, and 362 +/- 72, P = 0.004). CONCLUSIONS: In newly diagnosed hypertensive men, sCD40L levels are inversely related to insulin sensitivity, with no correlation with BP, other cardiovascular risk factors, or the degree of subclinical atherosclerosis.

The effect of angiotensin receptor blockers on C-reactive protein and other circulating inflammatory indices in man.

Anti-inflammatory properties may contribute to the pharmacological effects of angiotensin II receptor blockers (ARBs), a leading therapeutic class in the management of hypertension and related cardiovascular and renal diseases. That possibility, supported by consistent evidence from in-vitro and animal studies showing pro-inflammatory properties of angiotensin II, has been evaluated clinically by measuring the effect of ARBs on C-reactive protein and other circulating indices of inflammation (e-selectin, adhesion molecules, interleukin-6, tissue necrosis factor-alpha, monocyte chemoattractant protein-1) of potential clinical relevance, a body of evidence that this paper aims to review.