Protective effects of sirtuins in cardiovascular diseases: from bench to bedside

Sirtuins (Sirt1-Sirt7) comprise a family of nicotinamide adenine dinucleotide (NAD+)-dependent enzymes. While deacetylation reflects their main task, some of them have deacylase, adenosine diphosphate-ribosylase, demalonylase, glutarylase, and desuccinylase properties. Activated upon caloric restriction and exercise, they control critical cellular processes in the nucleus, cytoplasm, and mitochondria to maintain metabolic homeostasis, reduce cellular damage and dampen inflammation—all of which serve to protect against a variety of age-related diseases, including cardiovascular pathologies. This review focuses on the cardiovascular effects of Sirt1, Sirt3, Sirt6, and Sirt7. Most is known about Sirt1. This deacetylase protects from endothelial dysfunction, atherothrombosis, diet-induced obesity, type 2 diabetes, liver steatosis, and myocardial infarction. Sirt3 provides beneficial effects in the context of left ventricular hypertrophy, cardiomyopathy, oxidative stress, metabolic homeostasis, and dyslipidaemia. Sirt6 is implicated in ameliorating dyslipidaemia, cellular senescence, and left ventricular hypertrophy. Sirt7 plays a role in lipid metabolism and cardiomyopathies. Most of these data were derived from experimental findings in genetically modified mice, where NFκB, Pcsk9, low-density lipoprotein-receptor, PPARγ, superoxide dismutase 2, poly[adenosine diphosphate-ribose] polymerase 1, and endothelial nitric oxide synthase were identified among others as crucial molecular targets and/or partners of sirtuins. Of note, there is translational evidence for a role of sirtuins in patients with endothelial dysfunction, type 1 or type 2 diabetes and longevity. Given the availability of specific Sirt1 activators or pan-sirtuin activators that boost levels of the sirtuin cofactor NAD+, we anticipate that this field will move quickly from bench to bedsid

Cylindrical Micelles with "patchy" Coronas from the Crystallization-Driven Self-Assembly of ABC Triblock Terpolymers with a Crystallizable Central Polyferrocenyldimethylsilane Segment

Solution self-assembly of a series of linear ABC triblock terpolymers with a central crystallizable poly­(ferrocenyldimethylsilane) (PFS) core-forming “B” block and terminal polystyrene (PS) and poly­(methyl methacrylate) (PMMA) “A” and “C” blocks has been investigated. Three PS-<i>b</i>-PFS-<i>b</i>-PMMA triblock terpolymers with different block ratios (<b>1</b>, 3.6:1.0:4.7; <b>2</b>, 7.0:1.0:6.9; and <b>3</b>, 1.1:1.0:1.4) but with similar degrees of polymerization for the central PFS block were prepared through a combination of living anionic and atom-transfer radical polymerization techniques, together with azide/alkyne “click” chemistry. Cylindrical micelles with a crystalline PFS core were formed in solvents selective for the terminal PS and PMMA blocks. In ethyl acetate, a slightly more selective solvent for the PS block, cylinders with significant microphase separation within the corona in the dry state were observed on the basis of TEM analysis. The use of acetone, which is slightly more selective for the PMMA block than the PS block, led to more distinct microphase separation to generate a “patchy” coronal morphology. Living crystallization-driven self-assembly studies in acetone allowed the formation of uniform cylindrical micelles and block comicelles of controlled length with “patchy” coronal segments by seeded growth methods

Monodisperse Cylindrical Micelles and Block Comicelles of Controlled Length in Aqueous Media

Cylindrical block copolymer micelles have shown considerable promise in various fields of biomedical research. However, unlike spherical micelles and vesicles, control over their dimensions in biologically relevant solvents has posed a key challenge that potentially limits in depth studies and their optimization for applications. Here, we report the preparation of cylindrical micelles of length in the wide range of 70 nm to 1.10 μm in aqueous media with narrow length distributions (length polydispersities <1.10). In our approach, an amphiphilic linear-brush block copolymer, with high potential for functionalization, was synthesized based on poly­(ferrocenyldimethylsilane)-<i>b</i>-poly­(allyl glycidyl ether) (PFS-<i>b</i>-PAGE) decorated with triethylene glycol (TEG), abbreviated as PFS-<i>b</i>-(PEO-<i>g</i>-TEG). PFS-<i>b</i>-(PEO-<i>g</i>-TEG) cylindrical micelles of controlled length with low polydispersities were prepared in <i>N</i>,<i>N</i>-dimethylformamide using small seed initiators via living crystallization-driven self-assembly. Successful dispersion of these micelles into aqueous media was achieved by dialysis against deionized water. Furthermore, B–A–B amphiphilic triblock comicelles with PFS-<i>b</i>-poly­(2-vinylpyridine) (P2VP) as hydrophobic “B” blocks and hydrophilic PFS-<i>b</i>-(PEO-<i>g</i>-TEG) “A” segments were prepared and their hierarchical self-assembly in aqueous media studied. It was found that superstructures formed are dependent on the length of the hydrophobic blocks. Quaternization of P2VP was shown to cause the disassembly of the superstructures, resulting in the first examples of water-soluble cylindrical multiblock comicelles. We also demonstrate the ability of the triblock comicelles with quaternized terminal segments to complex DNA and, thus, to potentially function as gene vectors

Bibliometrics of systematic reviews : analysis of citation rates and journal impact factors

Background: Systematic reviews are important for informing clinical practice and health policy. The aim of this study was to examine the bibliometrics of systematic reviews and to determine the amount of variance in citations predicted by the journal impact factor (JIF) alone and combined with several other characteristics. Methods: We conducted a bibliometric analysis of 1,261 systematic reviews published in 2008 and the citations to them in the Scopus database from 2008 to June 2012. Potential predictors of the citation impact of the reviews were examined using descriptive, univariate and multiple regression analysis. Results: The mean number of citations per review over four years was 26.5 (SD +/-29.9) or 6.6 citations per review per year. The mean JIF of the journals in which the reviews were published was 4.3 (SD +/-4.2). We found that 17% of the reviews accounted for 50% of the total citations and 1.6% of the reviews were not cited. The number of authors was correlated with the number of citations (r = 0.215, P =5.16) received citations in the bottom quartile (eight or fewer), whereas 9% of reviews published in the lowest JIF quartile (<=2.06) received citations in the top quartile (34 or more). Six percent of reviews in journals with no JIF were also in the first quartile of citations. Conclusions: The JIF predicted over half of the variation in citations to the systematic reviews. However, the distribution of citations was markedly skewed. Some reviews in journals with low JIFs were well-cited and others in higher JIF journals received relatively few citations; hence the JIF did not accurately represent the number of citations to individual systematic reviews

Transformation and patterning of supermicelles using dynamic holographic assembly

Although the solution self-assembly of block copolymers has enabled the fabrication of a broad range of complex, functional nanostructures, their precise manipulation and patterning remain a key challenge. Here we demonstrate that spherical and linear supermicelles, supramolecular structures held together by non-covalent solvophobic and coordination interactions and formed by the hierarchical self-assembly of block copolymer micelle and block comicelle precursors, can be manipulated, transformed and patterned with mediation by dynamic holographic assembly (optical tweezers). This allows the creation of new and stable soft-matter superstructures far from equilibrium. For example, individual spherical supermicelles can be optically held in close proximity and photocrosslinked through controlled coronal chemistry to generate linear oligomeric arrays. The use of optical tweezers also enables the directed deposition and immobilization of supermicelles on surfaces, allowing the precise creation of arrays of soft-matter nano-objects with potentially diverse functionality and a range of applications

PFS-b-PNIPAM:A first step towards polymeric nanofibrillar hydrogels based on uniform fiber-like micelles

Amphiphilic crystalline-coil diblock copolymers polyferrocenyldimethylsilane-<i>block</i>-poly­(<i>N</i>-isopropylacrylamide) of two different block ratios (PFS₅₆-<i>b</i>-PNIPAM₁₉₀ and PFS₂₆-<i>b</i>-PNIPAM₅₂₀) were synthesized by a copper-catalyzed azide–alkyne coupling reaction. They exhibited pronounced differences in self-assembly in alcohol solvents. While PFS₅₆-<i>b</i>-PNIPAM₁₉₀ formed mixtures of spherical and rod-like micelles in ethanol and 2-propanol, PFS₂₆-<i>b</i>-PNIPAM₅₂₀ formed long fibers of uniform width in these solvents. We used a seeded growth protocol to grow rod-like PFS₂₆-<i>b</i>-PNIPAM₅₂₀ micelles of uniform lengths. There were two surprising features of this experiment: First, micelle growth was unusually slow and required a long aging time (40 days) for them to reach their final length. Second, the micelles were characterized by a low number of polymer chains per unit length as determined by multiangle light scattering. This result suggests a loose packing of PFS chains in the micelle core. In an attempt to prepare thermoresponsive nanofibrillar hydrogels from these micelles, we explored approaches to transfer them from 2-propanol to water. These attempts were accompanied by extensive fragmentation of the micelles. We believe the fragility of these micelles is related to the loosely packed nature of the PFS chains in the micelle core. Fragmentation may also be affected by the cononsolvency effect of 2-propanol-water mixtures on the PNIPAM corona of the micelles. We could show, however, that the micelle fragments in water retained their anticipated thermoresponsive behavior

Dietary α-linolenic acid diminishes experimental atherogenesis and restricts T cell-driven inflammation

Aims Epidemiological studies report an inverse association between plant-derived dietary α-linolenic acid (ALA) and cardiovascular events. However, little is known about the mechanism of this protection. We assessed the cellular and molecular mechanisms of dietary ALA (flaxseed) on atherosclerosis in a mouse model. Methods and results Eight-week-old male apolipoprotein E knockout (ApoE−/−) mice were fed a 0.21 % (w/w) cholesterol diet for 16 weeks containing either a high ALA [7.3 % (w/w); n = 10] or low ALA content [0.03 % (w/w); n = 10]. Bioavailability, chain elongation, and fatty acid metabolism were measured by gas chromatography of tissue lysates and urine. Plaques were assessed using immunohistochemistry. T cell proliferation was investigated in primary murine CD3-positive lymphocytes. T cell differentiation and activation was assessed by expression analyses of interferon-γ, interleukin-4, and tumour necrosis factor α (TNFα) using quantitative PCR and ELISA. Dietary ALA increased aortic tissue levels of ALA as well as of the n−3 long chain fatty acids (LC n−3 FA) eicosapentaenoic acid, docosapentaenoic acid, and docosahexaenoic acid. The high ALA diet reduced plaque area by 50% and decreased plaque T cell content as well as expression of vascular cell adhesion molecule-1 and TNFα. Both dietary ALA and direct ALA exposure restricted T cell proliferation, differentiation, and inflammatory activity. Dietary ALA shifted prostaglandin and isoprostane formation towards 3-series compounds, potentially contributing to the atheroprotective effects of ALA. Conclusion Dietary ALA diminishes experimental atherogenesis and restricts T cell-driven inflammation, thus providing the proof-of-principle that plant-derived ALA may provide a valuable alternative to marine LC n−3 F

From abstract to impact in cardiovascular research: factors predicting publication and citation

Aims Through a 4-year follow-up of the abstracts submitted to the European Society of Cardiology Congress in 2006, we aimed at identifying factors predicting high-quality research, appraising the quality of the peer review and editorial processes, and thereby revealing potential ways to improve future research, peer review, and editorial work. Methods and results All abstracts submitted in 2006 were assessed for acceptance, presentation format, and average reviewer rating. Accepted and rejected studies were followed for 4 years. Multivariate regression analyses of a representative selection of 10% of all abstracts (n= 1002) were performed to identify factors predicting acceptance, subsequent publication, and citation. A total of 10 020 abstracts were submitted, 3104 (31%) were accepted for poster, and 701 (7%) for oral presentation. At Congress level, basic research, a patient number ≥ 100, and prospective study design were identified as independent predictors of acceptance. These factors differed from those predicting full-text publication, which included academic affiliation. The single parameter predicting frequent citation was study design with randomized controlled trials reaching the highest citation rates. The publication rate of accepted studies was 38%, whereas only 24% of rejected studies were published. Among published studies, those accepted at the Congress received higher citation rates than rejected ones. Conclusions Research of high quality was determined by study design and largely identified at Congress level through blinded peer review. The scientometric follow-up revealed a marked disparity between predictors of full-text publication and those predicting citation or acceptance at the Congres

The Sirt1 activator SRT3025 provides atheroprotection in Apoe−/− mice by reducing hepatic Pcsk9 secretion and enhancing Ldlr expression

Aims The deacetylase sirtuin 1 (Sirt1) exerts beneficial effects on lipid metabolism, but its roles in plasma LDL-cholesterol regulation and atherosclerosis are controversial. Thus, we applied the pharmacological Sirt1 activator SRT3025 in a mouse model of atherosclerosis and in hepatocyte culture. Methods and results Apolipoprotein E-deficient (Apoe−/−) mice were fed a high-cholesterol diet (1.25% w/w) supplemented with SRT3025 (3.18 g kg−1 diet) for 12 weeks. In vitro, the drug activated wild-type Sirt1 protein, but not the activation-resistant Sirt1 mutant; in vivo, it increased deacetylation of hepatic p65 and skeletal muscle Foxo1. SRT3025 treatment decreased plasma levels of LDL-cholesterol and total cholesterol and reduced atherosclerosis. Drug treatment did not change mRNA expression of hepatic LDL receptor (Ldlr) and proprotein convertase subtilisin/kexin type 9 (Pcsk9), but increased their protein expression indicating post-translational effects. Consistent with hepatocyte Ldlr and Pcsk9 accumulation, we found reduced plasma levels of Pcsk9 after pharmacological Sirt1 activation. In vitro administration of SRT3025 to cultured AML12 hepatocytes attenuated Pcsk9 secretion and its binding to Ldlr, thereby reducing Pcsk9-mediated Ldlr degradation and increasing Ldlr expression and LDL uptake. Co-administration of exogenous Pcsk9 with SRT3025 blunted these effects. Sirt1 activation with SRT3025 in Ldlr−/− mice reduced neither plasma Pcsk9, nor LDL-cholesterol levels, nor atherosclerosis. Conclusion We identify reduction in Pcsk9 secretion as a novel effect of Sirt1 activity and uncover Ldlr as a prerequisite for Sirt1-mediated atheroprotection in mice. Pharmacological activation of Sirt1 appears promising to be tested in patients for its effects on plasma Pcsk9, LDL-cholesterol, and atherosclerosi