Reduced cardiac vagal control reflected in low heart rate variability (HRV) is associated with greater risks for cardiac morbidity and mortality. In two-stage meta-analyses of genome-wide association studies for three HRV traits in up to 53,174 individuals of European ancestry, we detect 17 genome-wide significant SNPs in eight loci. HRV SNPs tag non-synonymous SNPs (in NDUFA11 and KIAA1755), expression quantitative trait loci (eQTLs) (influencing GNG11, RGS6 and NEO1), or are located in genes preferentially expressed in the sinoatrial node (GNG11, RGS6 and HCN4). Genetic risk scores account for 0.9 to 2.6% of the HRV variance. Significant genetic correlation is found for HRV with heart rate (−0.74
Voltage-gated potassium (KV) channels represent an important dilator influence in the cerebral circulation, but the composition of these tetrameric ion channels remains unclear. The goals of the present study were to evaluate the contribution of KV1 family channels to the resting membrane potential and diameter of small rat cerebral arteries, and to identify the alpha-subunit composition of these channels using patch-clamp, molecular and immunological techniques. Initial studies indicated that 1 micromol l(-1) correolide (COR), a specific antagonist of KV1 channels, depolarized vascular smooth muscle cells (VSMCs) in pressurized (60 mmHg) cerebral arteries from -55 +/- 1 mV to -34 +/- 1 mV, and reduced the resting diameter from 152 +/- 15 microm to 103 +/- 20 microm. In patch clamped VSMCs from these arteries, COR-sensitive KV1 current accounted for 65 % of total outward KV current and was observed at physiological membrane potentials. RT-PCR identified mRNA encoding each of the six classical KV1 alpha-subunits, KV1.1-1.6, in rat cerebral arteries. However, only the KV1.2 and 1.5 proteins were detected by Western blot. The expression of these proteins in VSMCs was confirmed by immunocytochemistry and co-immunoprecipitation of KV1.2 and 1.5 from VSMC membranes suggested KV1.2/1.5 channel assembly. Subsequently, the pharmacological and voltage-sensitive properties of KV1 current in VSMCs were found to be consistent with a predominant expression of KV1.2/1.5 heterotetrameric channels. The findings of this study suggest that KV1.2/1.5 heterotetramers are preferentially expressed in rat cerebral VSMCs, and that these channels contribute to the resting membrane potential and diameter of rat small cerebral arteries.
Voltage-gated potassium (K V ) channels represent an important dilator influence in the cerebral circulation, but the composition of these tetrameric ion channels remains unclear. The goals of the present study were to evaluate the contribution of K V 1 family channels to the resting membrane potential and diameter of small rat cerebral arteries, and to identify the a-subunit composition of these channels using patch-clamp, molecular and immunological techniques. Initial studies indicated that 1 mmol l _1 correolide (COR), a specific antagonist of K V 1 channels, depolarized vascular smooth muscle cells (VSMCs) in pressurized (60 mmHg) cerebral arteries from _55 ± 1 mV to _34 ± 1 mV, and reduced the resting diameter from 152 ± 15 mm to 103 ± 20 mm. In patch clamped VSMCs from these arteries, COR-sensitive K V 1 current accounted for 65 % of total outward K V current and was observed at physiological membrane potentials. RT-PCR identified mRNA encoding each of the six classical K V 1 a-subunits, K V 1.1-1.6, in rat cerebral arteries. However, only the K V 1.2 and 1.5 proteins were detected by Western blot. The expression of these proteins in VSMCs was confirmed by immunocytochemistry and co-immunoprecipitation of K V 1.2 and 1.5 from VSMC membranes suggested K V 1.2/1.5 channel assembly. Subsequently, the pharmacological and voltage-sensitive properties of K V 1 current in VSMCs were found to be consistent with a predominant expression of K V 1.2/1.5 heterotetrameric channels. The findings of this study suggest that K V 1.2/1.5 heterotetramers are preferentially expressed in rat cerebral VSMCs, and that these channels contribute to the resting membrane potential and diameter of rat small cerebral arteries.
Amorphous silica nanoparticles (SiNPs) are being used in biomedical, pharmaceutical, and many other industrial applications entailing human exposure. However, their potential vascular and systemic pathophysiologic effects are not fully understood. Here, we investigated the acute (24 hours) systemic toxicity of intraperitoneally administered 50 nm and 500 nm SiNPs in mice (0.5 mg/kg). Both sizes of SiNPs induced a platelet proaggregatory effect in pial venules and increased plasma concentration of plasminogen activator inhibitor-1. Elevated plasma levels of von Willebrand factor and fibrinogen and a decrease in the number of circulating platelets were only seen following the administration of 50 nm SiNPs. The direct addition of SiNPs to untreated mouse blood significantly induced in vitro platelet aggregation in a dose-dependent fashion, and these effects were more pronounced with 50 nm SiNPs. Both sizes of SiNPs increased lactate dehydrogenase activity and interleukin 1β concentration. However, tumor necrosis factor α concentration was only increased after the administration of 50 nm SiNPs. Nevertheless, plasma markers of oxidative stress, including 8-isoprostane, thiobarbituric acid reactive substances, catalase, and glutathione S-transferase, were not affected by SiNPs. The in vitro exposure of human umbilical vein endothelial cells to SiNPs showed a reduced cellular viability, and more potency was seen with 50 nm SiNPs. Both sizes of SiNPs caused a decrease in endothelium-dependent relaxation of isolated small mesenteric arteries. We conclude that amorphous SiNPs cause systemic inflammation and coagulation events, and alter vascular reactivity. Overall, the effects observed with 50 nm SiNPs were more pronounced than those with 500 nm SiNPs. These findings provide new insight into the deleterious effect of amorphous SiNPs on vascular homeostasis.
The metabolic syndrome, as defined by the International Diabetes Federation, was investigated in five large, extended, highly consanguineous, healthy Omani Arab families of a total of 1277 individuals. Heritability (h2) of the phenotypic abnormalities that make up the syndrome and other related traits was estimated by variance decomposition method using SOLAR software. The overall prevalence of the syndrome was 23%. The prevalence of abnormalities making the syndrome in a descending order were: obligatory waist circumference, hypertension, raised fasting blood glucose, low serum high‐density lipoprotein (HDL), and raised serum triglycerides (TGs). Highly significant, but widely spread, h2 values were obtained for: height (0.68), weight (0.68), BMI (0.68), serum HDL (0.63), serum leptin (0.55), percentage body fat (0.53), total serum cholesterol (0.53), fasting serum insulin (0.51), homeostasis model assessment‐insulin resistance index (0.48), serum TG (0.43), waist circumference (0.40), diastolic blood pressure (0.38), and 2‐hour glucose level (0.17), whereas for the metabolic syndrome itself, h2 was 0.38. The wide spread of h2 results (0.07 to 0.68) indicates that some determinants, such as weight, BMI, and HDL level, are under significant genetic influence among the Omani Arabs. Other determinants such as insulin resistance, abdominal obesity, diastolic blood pressure, and TG levels seem to be more environmentally driven.
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