Insulin suppresses IKs (KCNQ1/KCNE1) currents,which require β-subunit KCNE1

Abnormal QT prolongation in diabetic patients has become a clinical problem because it increases the risk of lethal ventricular arrhythmia. In an animal model of type 1 diabetes mellitus, several ion currents, including the slowly activating delayed rectifier potassium current (I_Ks), are altered. The I_Ks channel is composed of KCNQ1 and KCNE1 subunits, whose genetic mutations are well known to cause long QT syndrome. Although insulin is known to affect many physiological and pathophysiological events in the heart, acute effects of insulin on cardiac ion channels are poorly understood at present. This study was designed to investigate direct electrophysiological effects of insulin on I_Ks (KCNQ1/KCNE1) currents. KCNQ1 and KCNE1 were co-expressed in Xenopus oocytes, and whole cell currents were measured by a two-microelectrode voltage-clamp method. Acute application of insulin suppressed the KCNQ1/KCNE1 currents and phosphorylated Akt and extracellular signal-regulated kinase (ERK), the two major downstream effectors, in a concentration-dependent manner. Wortmannin (10^?6 M), a phosphoinositide 3-kinase (PI3K) inhibitor, attenuated the suppression of the currents and phosphorylation of Akt by insulin, whereas U0126 (10^?5 M), a mitogen-activated protein kinase kinase (MEK) inhibitor, had no effect on insulin-induced suppression of the currents. In addition, insulin had little effect on KCNQ1 currents without KCNE1, which indicated an essential role of KCNE1 in the acute suppressive effects of insulin. Mutagenesis studies revealed amino acid residues 111–118 within the distal third C-terminus of KCNE1 as an important region. Insulin has direct electrophysiological effects on I_Ks currents, which may affect cardiac excitability.     

Trial using pig cells with the H–D antigen knocked down

Purpose

This report describes an attempt to reduce the expression level of Hanganutziu–Deicher (H–D) antigens by small interfering RNA (siRNA) for pig cytidine monophospho-N-acetylneuraminic acid hydroxylase (pCMAH).

Methods

A pig endothelial cell (PEC) line, and PEC and fibroblasts from an α1,3galactosyltransferase knockout (GalT-KO) piglet were used. Real-time PCR was used to evaluate the degradation of mRNA by siRNA. The H–D antigen was stained, and then the cells were incubated with human serum for the FACS analysis. The extent of lysis in human serum was next calculated using an LDH assay.

Results

Suppression of the mRNA of pCMAH by each siRNA was first determined. The mixture of siRNAs for pCMAH reduced the expressions of the H–D antigen on the PEC and fibroblasts to a considerable extent. The further reduction in the xenoantigenicity for human serum of the GalT-KO cells was then confirmed. In addition, the PEC line showed a significant downregulation in complement-dependent cytotoxicity by the siRNAs, thus indicating that the anti-H–D antigen in human serum is capable of causing lysis of the pig cells.

Conclusion

pCMAH silencing by siRNA reduced the expression of the H–D antigen and its antigenicity, thus confirming that the H–D antigen is one of the major non-Gal antigens in this situation.     

Influence of age and gender on trigeminal sensory function and magnetically evoked masseteric exteroceptive suppression reflex

ObjectiveThe present study explored the effect of age and gender on trigeminal sensory function and masseteric exteroceptive suppression (ES) reflex responses.MethodsYoung healthy men (n = 12) and women (n = 12) (age: 23.5 ± 3.0 years) and older healthy men (n = 12) and women (n = 12) (age: 58.5 ± 5.2 years) participated. Sensory function was assessed on the skin overlying the mental foramen using mechanical stimuli. Surface EMG was recorded from the left masseter muscle to assess ES reflex responses evoked by a magnetic stimulus applied to the skin above the left mental nerve.ResultsThe older group had significantly higher tactile detection thresholds. Early ES1 was present in all subjects. Onset latency of ES1 was significantly delayed in older subjects. ES2 was present in all young subjects, but only in 5 of the 12 men and 8 of the 12 women in the older group. Significant gender differences were found for sensory and pain thresholds to mechanical stimuli as well as for duration of ES.ConclusionsAgeing affects tactile detection thresholds, onset latency of ES1 responses, and appearance of ES2. The present results indicate that trigeminal sensory function and brainstem reflex responses differ between genders and age groups. These findings may have implications for assessment of craniofacial pain conditions.     

Increased prenatal blood manganese may induce gestational blood pressure

Objective: Pregnancy hypertension is the most common gestational complication and poses a critical risk for mother and fetus. Whether environmental factors may play an important role in disease occurrence is not fully determined. Methods: To investigate the effects of prenatal manganese (Mn) exposure on gestational blood pressure, 386 women were examined. Results: Early pregnancy blood Mn was significantly (p < 0.05) correlated with blood pressure through gestation. A significant association between odds of pre-hypertension with blood Mn was shown (OR:1.150, 95% CI:1.052–1.258). Conclusion: The current study results might suggest the blood Mn level during early stage of pregnancy as a potential risk factor for increasing the risk of gestational blood pressure.     

Correction to: Current management strategies for visceral artery aneurysms: an overview

The article Current management strategies for visceral artery aneurysms