Prevalence and Spectrum of TBX5 Mutation in Patients with Lone Atrial Fibrillation.

Atrial fibrillation (AF), the most common type of cardiac rhythm disturbance encountered in clinical practice, is associated with substantially increased morbidity and mortality. Aggregating evidence demonstrates that abnormal cardiovascular development is involved in the pathogenesis of AF. A recent study has revealed that the TBX5 gene, which encodes a T-box transcription factor key to cardiovascular development, was associated with AF and atypical Holt-Oram syndrome. However, the prevalence and spectrum of TBX5 mutation in patients with lone AF remain unclear. In this study, the coding regions and splicing junction sites of TBX5 were sequenced in 192 unrelated patients with lone AF and 300 unrelated ethnically-matched healthy individuals used as controls. The causative potential of the identified TBX5 variation was evaluated by MutationTaster and PolyPhen-2. The functional effect of the mutant TBX5 was assayed by using a dual-luciferase reporter assay system. As a result, a novel heterozygous TBX5 mutation, p.H170D, was identified in a patient, with a mutational prevalence of approximately 0.52%. This mutation, which was absent in the 300 control individuals, altered the amino acid completely conserved evolutionarily across species, and was predicted to be disease-causing. Functional deciphers showed that the mutant TBX5 was associated with significantly reduced transcriptional activity when compared with its wild-type counterpart. Furthermore, the mutation significantly decreased the synergistic activation between TBX5 and NKX2-5 or GATA4. The findings expand the mutational spectrum of TBX5 linked to AF and provide new evidence that dysfunctional TBX5 may contribute to lone AF.

Effects of GRK5 and ADRB1 polymorphisms influence on systolic heart failure.

BACKGROUND: G-protein receptor kinase 5 (GRK5) Gln41 > Leu and ß1-adrenergic receptor (ADRB1) Arg389 > Gly polymorphisms presented the different distribution of genotype frequencies between Caucasian American and African American, and produced the difference in ß-blocker treatment effect among them with systolic heart failure (SHF). OBJECTIVE: This study sought to identify the distributed characteristics of these variant genotypes in Chinese population, and influence of GRK5 and ADRB1 polymorphisms on SHF morbidity and ß-blocker treatment effect in patients with SHF. METHODS: This study was based on cross-sectional survey data. 1794 and 1718 subjects' ADRB1 and GRK5 gene sequencing (sanger method) data were achieved respectively. Blood samples collection, clinical laboratory detection, electrocardiogram and echocardiography examinations were performed. Medication usage was confirmed at in-hospital visits or the questionnaire by personal interview. RESULTS: GRK5 Leu41Leu genotype was not found in our Chinese population. In non-SHF population, allele frequencies of GRK5 Gln41 and Leu41 were 2782 (0.992) and 22 (0.008) (Hardy-Weinberg equilibrium test χ(2) = 0.088, P = 0.767), and allele frequencies of ADRB1 Arg389 and Gly389 were 2127 (0.715) and 849 (0.285) (χ(2) = 0.272, P = 0.602). In SHF patients, allele frequencies of Gln41 and Leu41 were 446 (0.991) and 4 (0.009) (χ(2) = 0.018, P = 0.893), and allele frequencies of Arg389 and Gly389 were 331 (0.726) and 125 (0.274) (χ(2) = 1.892, P = 0.169). Further in logistic regression model, these ADRB1 and GRK5 variants were not significantly independently associated with the risk of SHF morbidity. Those carrying genotype ADRB1 Gly389Gly did not reduce significantly the risk of SHF morbidity after ß-blocker therapy. CONCLUSIONS: GRK5 Leu41Leu genotype was not found in our Chinese population, neither ADRB1 nor GRK5 variants presented independently associated with the risk of SHF morbidity, most ADRB1 and GRK5 polymorphisms did decrease significantly the risk of SHF morbidity after ß-blocker therapy except for those carrying genotype ADRB1 Gly389Gly.

miR-487b mitigates chronic heart failure through inhibition of the IL-33/ST2 signaling pathway.

We investigated the effects of microRNA-587b (miR-487b) in a rat model of chronic heart failure (CHF). Wistar rats were assigned to 10 groups (n=8 per group). Expression of interleukin-33 (IL-33), somatostatin 2 (ST2), IL-6, and TNF-α was higher in the CHF group than the control group. In the CHF, negative control (NC) for si-IL-33, NC for miR-487b mimic, NC for miR-487b inhibitor, and miR-487b inhibitor + si IL-33 groups, as compared to the blank and sham groups: steroid binding protein (SBP), D binding protein (DBP), left ventricular systolic pressure (LVSP), ± dp/dtmax, and superoxide dismutase (SOD) were all lower; myocardial fibrosis, MDA, left ventricular end-diastolic pressure (LVEDP), myocardial apoptosis rate, IL-6, and TNF-α were all higher; levels of IL-33 and ST2 mRNA and protein were higher; and levels of miR-487b were lower. Levels of IL-33 and ST2 mRNA and protein were lower, and SBP, DBP, LVSP, ± dp/dtmax, and SOD were higher in the miR-487b mimic and si-IL-33 groups than the CHF group. Expression of miR-487b was increased in the miR-487b mimic group, and expression of IL-33 and ST2 were increased and expression of miR-487b was decreased in the miR-487b inhibitor group. MiR-487b reduces apoptosis, inflammatory responses, and fibrosis in CHF by suppressing IL-33 through inhibition the IL-33/ST2 signaling pathway.

Cardioprotective effect of notoginsenoside R1 in a rabbit lung remote ischemic postconditioning model via activation of the TGF-ß1/TAK1 signaling pathway.

Pharmacological postconditioning using cardioprotective agents is able to reduce myocardial infarct size. Notoginsenoside R1 (NG-R1), a phytoestrogen isolated from Panax notoginseng saponins (PNS), is considered to have anti-oxidative and anti-apoptotic properties. However, its cardioprotective properties and underlying mechanisms remain largely unknown. The aim of the present study was to determine the cardioprotective and anti-apoptotic effects of NG-R1 in an ischemia-reperfusion (IR)-induced myocardial injury rabbit model. A total of 45 Japanese big-ear rabbits were equally randomized to three groups: Control group, remote ischemic postconditioning (RIP) group and NG-R1 intervention group. At the endpoint of the experiment, the animals were sacrificed to remove myocardial tissues for the detection of transforming growth factor (TGF)-ß1-TGF-ß activated kinase 1 (TAK1) pathway-related proteins by immunohistochemistry and western blot analysis, the activities of caspase-3, -8 and -9 in myocardial cells by fluorometric assay, and the apoptosis of myocardial cells by terminal deoxynucleotidyl-transferase-mediated dUTP nick end labeling. Right and left lung tissues were stained with hematoxylin and eosin (H&E) to observe the severity of injury. NG-R1 treatment reduced the activity of superoxide dismutase, increased the content of malondialdehyde, reduced the activities of caspase-3, -8 and -9, and inhibited the apoptosis of myocardial cells in rabbits undergoing RIP. In addition, the expression of TGF-ß1-TAK1 signaling pathway-related proteins was downregulated following NG-R1 intervention. H&E staining of bilateral lung tissues showed that cell morphology was generally intact without significant alveolar congestion, and there was no significant difference among the three groups. These results indicate that NG-R1 protects the heart against IR injury, possibly by inhibiting the activation of the TGF-ß1-TAK1 signaling pathway and attenuating apoptotic stress in the myocardium.