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Activating transcription factor 1 (ATF1) may be involved in essential hypertension (EH) by induction of NADPH oxidase 1 (NOX1) and radical oxygen species (ROSs) production. Abnormal expression of ATF1 was found in EH in previous microarray analysis. Here we tested whether a single nucleotide polymorphism (SNP) located in the 3′-untranslated region (3′UTR) of ATF1 was associated with EH susceptibility by affecting microRNA (miRNA) binding. In silico analysis indicated that rs11169571 (T > C) was a candidate SNP to modulate miRNA: ATF1 mRNA complex, with the greatest changed energy for hsa-miR-1283, and the luciferase reporter analysis showed that miR-1283 inhibited the activity of the reporter vector carrying –T allele, but not the –C allele. In addition, inhibition of miR-1283 in HA-VSMCs enhanced the expression of ATF1 mRNA as well as the ROS levels. Further case-control study showed that rs11169571 was significantly associated with increased risk of EH. Finally, we observed an increased ATF1 protein level in peripheral blood of EH patients with CC carriers compared to TT carriers of rs11169571, with an intermediate ATF1 level in TC carriers. These results suggested that rs11169571 of ATF1 gene may be associated with EH, and the SNP-modified posttranscriptional gene regulation by miRNAs could be a potentially pathogenetic mechanism of EH. [ABSTRACT FROM AUTHOR]

Background: Cardiac fibrosis increases with age. Fibroblast activation plays an essential role in cardiac fibrosis. Histone modifications are involved in various chromatin-dependent processes. Attenuation of the histone H3 trimethylation on lysine 27 demethylase UTX by RNA interference or heterozygous mutation extends lifespan in worm. The objective of this study was to explore whether epigenetic silencing of UTX mitigates aging-associated cardiac fibrosis., Methods: Middle-aged mice (15 months old) were used and started to receive adeno-associated virus-scrambled-small hairpin RNA and adeno-associated virus-UTX-small hairpin RNA every 3 months from 15 months to 21 months, respectively. The mice were euthanized at 24 months of age (length of the study)., Results: Adeno-associated virus-UTX-small hairpin RNA delivery significantly attenu-ated aging-associated increase in blood pressure, especially in diastolic blood pressure, indicating silencing of UTX rescued aging-associated cardiac dysfunction. Aging-associated cardiac fibrosis is characterized by fibroblast activation and abundant extracellular matrix deposition, including collagen deposition and alpha smooth muscle actin activation. Silencing of UTX abolished collagen deposition and alpha smooth muscle actin activation, decreased serum transforming growth factor β, blocked cardiac fibro blast s-to- myofi brobl asts trans-differentiation by elevation of cardiac resident mature fibroblast markers, TCF21, and platelet-derived growth factor receptor alpha, which are important proteins for maintaining cardiac fibroblast physiological function. In the mechanistic study, adeno-associated virus-UTX-small hairpin RNA blocked transforming growth factor β-induced cardiac fibro blast s-to- myofi brobl asts trans-differentiation in isolated fibroblasts from 24-month-old mouse heart. The same results demonstrated as the in vivo study., Conclusions: Silencing of UTX attenuates aging-associated cardiac fibrosis via blocking cardiac fibroblasts-to-myofibroblasts transdifferentiation and consequently attenuates aging-associated cardiac dysfunction and cardiac fibrosis.

Acute exhaustive endurance exercise can differentially impact the right ventricle (RV) versus the left ventricle (LV). However, the hemodynamic basis for these differences and its impact on postexercise recovery remain unclear. Therefore, we assessed cardiac structure and function along with hemodynamic properties of mice subjected to single bouts (216 ± 8 min) of exhaustive swimming (ES). One-hour after ES, LVs displayed mild diastolic impairment compared with that in sedentary (SED) mice. Following dobutamine administration to assess functional reserve, diastolic and systolic function were slightly impaired. Twenty-four hours after ES, LV function was largely indistinguishable from that in SED. By contrast, 1-h post swim, RVs showed pronounced impairment of diastolic and systolic function with and without dobutamine, which persisted 24 h later. The degree of RV impairment correlated with the time-to-exhaustion. To identify hemodynamic factors mediating chamber-specific responses to ES, LV pressure was recorded during swimming. Swimming initiated immediate increases in heart rates (HRs), systolic pressure, dP/d t max and -dP/d t min , which remained stable for ∼45 min. LV end-diastolic pressures (LVEDP) increased to ≥45 mmHg during the first 10 min and subsequently declined. After 45 min, HR and -dP/d t min declined, which correlated with gradual elevations in LVEDP (to ∼45 mmHg) as mice approached exhaustion. All parameters rapidly normalized postexercise. Consistent with human studies, our findings demonstrate a disproportionate negative impact of acute exhaustive exercise on RVs that persisted for at least 24 h. We speculate that the differential effects of exhaustive exercise on the ventricles arise from a ∼2-fold greater hemodynamic load in the RV than in LV originating from profound elevations in LVEDPs as mice approach exhaustion. NEW & NOTEWORTHY Acute exhaustive exercise differentially impacts the right ventricle (RV) versus left ventricle (LV), yet the underlying hemodynamic basis remains unclear. Using pressure-volume analyses and pressure-telemetry implantation in mice, we confirmed a marked disproportionate and persistent negative impact of exhaustive exercise on the RV. These differences in responses of the ventricles to exhaustive exercise are of clinical relevance, reflecting ∼2-fold greater hemodynamic RV loads versus LVs arising from massive (∼45 mmHg) increases in LV end-diastolic pressures at exhaustion.

To compare the safetyand efficacy of warfarin treatment continuation and heparin-bridging therapy during cardiac rhythm device (CRD) implantation in patients chronically treated with anticoagulants.We performed a search and analysis of peer-reviewed studies Four randomized controlled trials (RCTs)were included in our analysis with 941 patients. The bleeding risk in patients continuing warfarin perioperatively was lower than those interrupting warfarin and using a heparin-bridge (RD -0.08, 95% CI -0.17 to 0.02, p< 0.05). There was no significant difference in ischaemic risk between two methods (RD 0, 95% CI -0.01 to 0.02, p=1.00). Hence, in patients undergoing long-term warfarin therapy, continuation of warfarin treatment is a safe and efficacious perioperative strategy for during CRD implantations, while interruption of warfarin with a heparin bridge may increase the bleeding risk in these patients.