TAP1 I333V gene polymorphism and type 1 diabetes mellitus: a meta-analysis of 2248 cases.

Transporter associated with antigen processing 1 (TAP1) I333V gene polymorphism has been suggested to be associated with type 1 diabetes mellitus (T1DM) susceptibility. However, the results from individual studies are inconsistent. To explore the association of TAP1 I333V gene polymorphisms with T1DM, a meta-analysis involving 2246 cases from 13 individual studies was conducted. The pooled odd ratios (ORs) and their corresponding 95% confidence intervals (95% CIs) were evaluated by a fixed-effect model. A significant relationship was observed between TAP1 I333V gene polymorphism and T1DM in allelic (OR: 1.35, 95% CI: 1.08-1.68, P = 0.007), dominant (OR: 1.462, 95% CI: 1.094-1.955, P = 0.010), homozygous (OR: 1.725, 95% CI: 1.082-2.752, P = 0.022), heterozygous (OR: 1.430, 95% CI: 1.048-1.951, P = 0.024) and additive (OR: 1.348, 95% CI: 1.084-1.676, P = 0.007) genetic models. No significant association between TAP1 I333V gene polymorphism and T1DM was detected in a recessive genetic model (OR: 1.384, 95% CI: 0.743-2.579, P = 0.306) in the entire population, especially among Caucasians. No significant association between them was found in an Asian or African population. TAP1 I333V gene polymorphism was significantly associated with increased T1DM risk. V allele carriers might be predisposed to T1DM susceptibility.

Adrenergic regulation of the rapid component of delayed rectifier K+ currents in guinea pig cardiomyocytes.

BACKGROUND: Guinea pig ventricular cardiomyocytes display the rapid component of the delayed rectifier potassium current (Ikr) that contributes to ventricular repolarization and promotes stress-induced arrhythmias. Adrenergic stimulation favors ventricular arrhythmogenesis but its effects on Ikr are poorly understood. METHODS: Adrenergic modulation of Ikr was studied in isolated guinea pig ventricular cardiomyocytes using whole-cell patch clamping. RESULTS: We found that the Ikr amplitude was reduced to 0.66±0.02 and 0.62±0.03 in response to 0.1 µM phenylephrine (PE), an α1AR agonist, and 10 µM isoproterenol (ISO), a ßAR agonist, respectively. The effect of PE can be blocked by the selective α1A-adrenoceptor antagonist 5-methylurapidil, but not by the α1B-adrenoceptor antagonist chloroethylclonidine or α1D-adrenoceptor antagonist BMY7378. Additionally, the effect of ISO can be blocked by the ß1-selective AR antagonist CGP-20712A, but not by the ß2-selective AR antagonist ICI-118551. Although PE and ISO was continuously added to cells, ISO did not decrease the current to a greater extent when cells were first given PE. In addition, PE's effect on Ikr was suppressed by ß1AR stimulation. CONCLUSIONS: Ikr can by regulated by both the α1 and ß ARs system, and that in addition to direct regulation by each receptor system, crosstalk may exist between the two systems.

[Heat shock protein 27 attenuated doxorubicin-induced myocardial damage by reducing cardiomyocyte apoptosis, mitochondria damage and protein carbonylation].

OBJECTIVE: Oxidative stress and apoptosis play a critical role in the pathogenesis of congestive heart failure (CHF) induced by doxorubicin (Dox) or ischemia/reperfusion. Heat shock protein 27 (Hsp27) could reduce oxidative stress induced apoptosis in various cell types in vitro and attenuate ischemia/reperfusion induced cardiac dysfunction in isolated perfused mouse heart. In this study, we investigated the impact of Hsp27 overexpression on oxidative stress and apoptosis in Dox-induced mice cardiac dysfunction model. METHODS: Both Hsp27 transgenic mice (TG) and wild type littermates (WT) received a single dosage of Dox (25 mg/kg IP) or saline. On day 3, histological examinations (Paraffin section and HE staining, mitochondria ultrastructure), in situ cardiomyocytes apoptosis assay (TUNEL, immunohistochemistry against alpha-actinin for cardiomyocytes, hoechst33342 for nuclei staining), protein oxidative damage assay (immunoblot against DNP) were performed on cardiac tissue samples. Pleural effusion and histological changes of heart and lung were examined in dead mice. RESULTS: (1) Significant pleural effusion, pulmonary congestion, alveoli collapse and extravasated red blood cells were observed in all died mice. (2) Pronounced cardiomyocyte damages and inhomogeneous HE staining were observed in almost all dead mice except for one TG mouse died at day 4 which showed homogeneous HE staining and only slightly cardiomyocyte damages. (3) Cardiac fibrosis was presented in WT mice but not in TG mice. (4) Dox-induced cardiomyocyte apoptosis and protein carbonylation were significantly attenuated in TG mice compared those in WT mice. (5) Severity of Dox-induced mitochondria damage including increased density, swollen cristae and loss of cristae definition was significantly reduced in TG mice compared to that in WT mice were seen in all the examined myocytes of the LV myocardium samples of Dox-treated mice. CONCLUSION: Hsp27 could attenuate Dox-induced myocardial damage by reducing cardiomyocyte apoptosis, mitochondria damage and protein carbonylation.

[Overexpression of heat shock protein 27 reduces mortality and attenuates cardiac dysfunction induced by doxorubicin in a transgenic mouse model].

OBJECTIVE: To observe the effects of heat shock protein 27 (Hsp27) overexpression on doxorubicin (Dox) induced mortality and cardiac dysfunction in a transgenic (TG) mouse model. METHODS: A linear DNA constituted of alpha-myosin heavy chain (alpha-MHC) promoter, human Hsp27cDNA and poly A was microinjected into fertilized eggs to generate transgenic mice and mice containing the transgene were identified by polymerase chain reaction and independent transgenic lines were established. Following successful transmission, tissues including heart, lung, liver, brain, skeleton muscle, spleen and kidney were screened by Western blot to confirm the cardiac specific expression of the transgene. TG and wild type littermates (WT) received a single dosage of Dox injection (25 mg/kg IP) or saline injection and observed for 5 days. Mice mortality was noticed and left ventricular (LV) hemodynamics were measured at day 5 in surviving mice. Cardiomyocyte apoptosis was evaluated by TUNEL assay at day 3 post Dox or saline injections in a separate group. RESULTS: Three independent transgenic lines were generated, and all of them expressed cardiac specific Hsp27. Five days mortality was significantly reduced in TG group than that in WT group post Dox (P < 0.01), Dox induced cardiac dysfunction and cardiomyocyte apoptosis were also significantly attenuated in TG mice compared to WT mice (P < 0.05). CONCLUSION: Overexpression of Hsp27 reduced mortality, attenuated left ventricular dysfunction and cardiomyocyte apoptosis induced by Dox in a transgenic mouse model.