Chemerin connects fat to arterial contraction Watts, Stephanie W; Dorrance, Anne M; Penfold, Mark E ...
Arteriosclerosis, thrombosis, and vascular biology,
06/2013, Letnik:
33, Številka:
6
Journal Article
Recenzirano
Odprti dostop
Obesity and hypertension are comorbid in epidemic proportion, yet their biological connection is largely a mystery. The peptide chemerin is a candidate for connecting fat deposits around the blood ...vessel (perivascular adipose tissue) to arterial contraction. We presently tested the hypothesis that chemerin is expressed in perivascular adipose tissue and is vasoactive, supporting the existence of a chemerin axis in the vasculature.
Real-time polymerase chain reaction, immunohistochemistry, and Western analyses supported the synthesis and expression of chemerin in perivascular adipose tissue, whereas the primary chemerin receptor ChemR23 was expressed both in the tunica media and endothelial layer. The ChemR23 agonist chemerin-9 caused receptor, concentration-dependent contraction in the isolated rat thoracic aorta, superior mesenteric artery, and mesenteric resistance artery, and contraction was significantly amplified (more than 100%) when nitric oxide synthase was inhibited and the endothelial cell mechanically removed or tone was placed on the arteries. The novel ChemR23 antagonist CCX832 inhibited phenylephrine-induced and prostaglandin F2α-induced contraction (+perivascular adipose tissue), suggesting that endogenous chemerin contributes to contraction. Arteries from animals with dysfunctional endothelium (obese or hypertensive) demonstrated a pronounced contraction to chemerin-9. Finally, mesenteric arteries from obese humans demonstrate amplified contraction to chemerin-9.
These data support a new role for chemerin as an endogenous vasoconstrictor that operates through a receptor typically attributed to function only in immune cells.
Display omitted
Trimethylamine (TMA), formed by intestinal microbiota, and its Flavin-Monooxygenase 3 (FMO3) product Trimethylamine-N-Oxide (TMAO), are potential modulators of host cardiometabolic ...phenotypes. High circulating levels of TMAO are associated with increased risk for cardiovascular diseases. We hypothesized that TMA/TMAO could directly change the vascular tone. Perivascular adipose tissue (PVAT) helps to regulate vascular homeostasis and may also possess FMO3. Thoracic aorta with(+) or without(-) PVAT, also + or - the endothelium (E), of male Sprague Dawley rats were isolated for measurement of isometric tone in response to TMA/TMAO (1nM–0.5 M). Immunohistochemistry (IHC) studies were done to identify the presence of FMO3. TMA and TMAO elicited concentration-dependent arterial contraction. However, at a maximally achievable concentration (0.2 M), contraction stimulated by TMA was of a greater magnitude (141.5 ± 16% of maximum phenylephrine contraction) than that elicited by TMAO (19.1 ± 4.03%) with PVAT and endothelium intact. When PVAT was preserved, TMAO-induced contraction was extensively reduced the presence (19.1 ± 4.03%) versus absence of E (147.2 ± 20.5%), indicating that the endothelium plays a protective role against TMAO-induced contraction. FMO3 enzyme was present in aortic PVAT, but the FMO3 inhibitor methimazole did not affect contraction stimulated by TMA in aorta + PVAT. However, the l-type calcium channel blocker nifedipine reduced TMA-induced contraction by ∼50% compared to the vehicle. Though a high concentration of these compounds was needed to achieve contraction, the findings that TMA-induced contraction was independent of PVAT and E and mediated by nifedipine-sensitive calcium channels suggest metabolite-induced contraction may be physiologically important.
Objectives
To evaluate if commercially available metronidazole and metronidazole benzoate suspensions cause a reduction in food intake in healthy chinchillas and if the reduction in food intake is ...dose‐dependent.
Materials and Methods
Twelve chinchillas were used in a randomised, controlled, blinded, complete‐crossover study. All treatments were administered orally every 12 hours for 3 days. Metronidazole (125 mg/mL) was administered at 20 mg/kg and metronidazole benzoate (25 mg/mL) was administered at 20 and 10 mg/kg. Food intake was recorded daily. The washout period between treatments was at least 14 days.
Results
At 20 mg/kg PO q12h administration of both commercial suspensions resulted in a significant reduction of food intake. The greatest mean reduction in food intake occurred after 2 to 3 days of drug administration (metronidazole: −54 ± 25%; metronidazole benzoate: −44 ± 36%). After administration of metronidazole benzoate at 10 mg/kg PO q12h, the reduction in food intake was significantly less pronounced (−24 ± 36%), suggesting that negative effect of metronidazole on food intake in chinchillas is dose‐dependent. Variation in metronidazole‐induced food intake reduction differed widely between individual chinchillas.
Clinical Significance
The oral administration of commercial metronidazole and metronidazole benzoate suspensions results in a dose‐dependent clinically relevant reduction in food intake in chinchillas. Metronidazole should be used cautiously in this species and food intake should be monitored during treatment. Future studies are needed in order to determine if metronidazole at 10 mg/kg q12h is an effective therapeutic dosage in chinchillas.
A micro-scale cross-flow heat exchanger is constructed from a hollow nickel micro-lattice structure, which is fabricated by conformally electroplating nickel onto a sacrificial polymer micro-lattice ...formed from self-propagating photopolymer waveguides. The periodic unit cell of the hollow nickel micro-lattice structure tested here includes lattice members with a diameter <1mm and a nominal pore size <9mm. The heat transfer performance of the micro-lattice-based heat exchanger is analyzed in terms of thermal conductance per unit volume, which is equal to the value of overall heat transfer coefficient multiplied by surface area to volume ratio. Calculated values range from 0.84 to 1.58W/cm3K for Reynolds number ranges of between 3400±200 and 6500±500 for hot water flow inside the hollow lattice members and 85±6 and 240±20 for cold water flow around the lattice members. Based on a developed correlation, the experimental heat transfer data is used to predict the thermal performance of larger and smaller micro-lattice-based heat exchangers, as well as various micro-lattice feature dimensions that are tunable with the fabrication process (node-to-node spacing, inner diameter, etc.). The micro-lattice heat exchanger was tested under quasi-static compression and the results illustrate the multifunctional capability for load bearing and energy absorption applications. This work demonstrates a multifunctional heat exchanger with a fully-scalable fabrication process which is useful for size and weight constrained heat transfer applications, including those in the automotive and aerospace industries.
The sympathetic nervous system plays an important role in some forms of human hypertension as well as the Dahl salt-sensitive rat model of hypertension; however, the sympathetic targets involved ...remain unclear. To address this, we examined the role of the renal and splanchnic sympathetic nerves in Dahl hypertension by performing sham surgery (n=10) or targeted sympathetic ablation of the renal nerves (renal denervation, n=11), the splanchnic nerves (celiac ganglionectomy, n=11), or both renal and splanchnic nerves (n=11) in hypertensive Dahl rats. Mean arterial pressure increased from ≈120 mm Hg, while on a 0.1% sodium chloride diet, to ≈140 mm Hg after being fed a 4.0% sodium chloride diet for 3 weeks. At that point, rats underwent sham or targeted sympathetic ablation. Four weeks after treatment, mean arterial pressure was lower in renal denervated (150.4±10.4) and celiac ganglionectomized (147.0±6.1) rats compared with sham rats (165.0±3.7) and even lower in rats that underwent both ablations (128.4±6.6). There were no differences in heart rate or fluid balance between sham and renal denervated rats; however, rats that underwent either celiac ganglionectomy or both ablations exhibited marked tachycardia as well as sodium and water retention after treatment. These data suggest that targeted sympathetic ablation is an effective treatment for established hypertension in the Dahl rat and that the kidneys and the splanchnic vascular bed are both independently important targets of the sympathetic nervous system in this model.
This paper constitutes a review of the last (Otiran) glaciation in New Zealand, spanning marine isotope stages (MIS) 4-2. We highlight the nature of glaciation, which is characterised by exceptional ...sedimentation, relatively mild maritime climatic conditions and the widespread presence of water associated with proglacial settings. These conditions produce glacial systems characterised by extensive outwash fans and relatively small terminal moraines. Extensive recent geochronological work allows us to recognise at least eight glacial advances during the Otiran. These occurred at 65 ± 3.25ka, 47.5 ± 3 ka, 38.5 ± 2 ka, 31.5 ± 3 ka, 26.5 ± 2 ka, 20.5 ± 2 ka, 17 ± 2 ka and 13 ± 1 ka, which we term the Otira 1 to 8 advances, respectively. Though the analytical uncertainty ranges for some of these advances overlap, all are independently distinguished through moraine morphologic relationships and/or stratigraphic relationships in outcrop. Major advances appear to be associated with climate influences such as periods of Southern Hemisphere insolation minima (65ka, and 31.5 ka advances), the last glacial maximum cooling (LGM) (20.5 ka) and periods of Antarctic cooling (13ka). The timing of greatest glacial extent in the last glacial cycle is not simultaneous across New Zealand. The MIS 4 advance was the greatest in the southern South Island, while the MIS 3/2 advances (26.5 ka) were greatest in the central South Island. In the northern South Island and the North Island, MIS 4, MIS 3/2, and the last glacial maximum appear to be equivalent in extent. We attribute these spatio-temporal variations in the timing of maximum glaciation to precipitation changes related to a northward shift in the track of the westerlies.
•Temperate style of New Zealand glaciation is described.•Eight significant glacial events are recognised in the last (Otiran) Ice age.•Multiple glacial drivers are recognised.•Evidence for possible northward movement of surface westerly winds in late MIS 3 is summarised.
Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder caused by an abnormal expansion of CAG repeats. Although pathogenesis has been attributed to this polyglutamine ...expansion, the underlying mechanisms through which the huntingtin protein functions have yet to be elucidated. It has been suggested that postnatal reduction of mutant huntingtin through protein interference or conditional gene knockout could prove to be an effective therapy for patients suffering from HD. For allele-specific targeting, transcription activator-like effectors (TALE) were designed to target single-nucleotide polymorphisms (SNP) in the mutant allele and packaged into a vector backbone containing KRAB to promote transcriptional repression of the disease-associated allele. Additional TALEs were packaged into a vector backbone containing heterodimeric FokI and were designed to be used as nucleases (TALEN) to cause a CAG-collapse in the mutant allele. Human HD fibroblasts were treated with each TALE-SNP or TALEN. Allele-expression was measured using a SNP-genotyping assay and mutant protein aggregation was quantified with Western blots for anti-ubiquitin. The TALE-SNP and TALEN significantly reduced mutant allele expression (p < 0.05) when compared to control transfections while not affecting expression of the nondisease allele. This study demonstrates the potential of allele-specific gene modification using TALE proteins, and provides a foundation for targeted treatment for individuals suffering from Huntington's or other genetically linked diseases.
The 5-HT
7
receptor is the primary mediator of both the
acute
(<hours) and
chronic
(day-week) decreases in mean arterial pressure (MAP) during low dose 5-HT infusion in rats. Previous data show the ...hypotensive response during chronic 5-HT infusion is due to a decrease total peripheral resistance (TPR) and specifically splanchnic vascular resistance. We hypothesized that changes in vascular resistance in both the splanchnic and skeletal muscle vascular beds are critical to the cardiovascular effects mediated by the 5-HT
7
receptor. Systemic and regional hemodynamic data were collected in conscious and anesthetized male rats using radiotelemetry, vascular catheters and transit-time flowmetry. Reversible antagonism of the 5-HT
7
receptor was achieved with the selective antagonist SB269970 (33 μg/kg, iv). From the very beginning and throughout the duration (up to 5 days) of a low dose (25 μg/kg) infusion of 5-HT, TPR, and MAP were decreased while cardiac output (CO) was increased. In a separate group of rats, the contribution of the 5-HT
7
receptor to the regional hemodynamic response was tested during 5-HT-induced hypertension. The decrease in MAP after 24 h of 5-HT (saline 83 ± 3 vs. 5-HT 72 ± 3 mmHg) was associated with a significant decrease in skeletal muscle vascular resistance (saline 6 ± 0.2 vs. 5-HT 4 ± 0.4 mmHg/min/mL) while splanchnic vascular resistance was similar in 5-HT and saline-treated rats. When SB269970 was administered acutely, MAP and skeletal muscle vascular resistance rapidly increased, whereas splanchnic resistance was unaffected. Our work suggests the most prominent regional hemodynamic response to 5-HT
7
receptor activation paralleling the fall in MAP is a decrease in skeletal muscle vascular resistance.
PDF
