Atherosclerosis is a common and deadly cardiovascular disease with extremely high prevalence. Areas of the vasculature exposed to oscillatory shear stress (OSS) or disturbed blood flow are particularly prone to the development of atherosclerotic lesions. In part, various mechanosensitive receptors on the surface of endothelial cells play a role in regulating the ability of the vasculature to cope with variations in blood flow patterns. However, the exact mechanisms behind flow-mediated endothelial responses remain poorly understood. Along with the development of highly specific receptor agonists, the class of G coupled-protein receptors has been receiving increasing attention as potential therapeutic targets. G coupled-protein receptor 81 (GPR81), also known as hydroxycarboxylic acid receptor 1 (HCA 1 ), is activated by lactate, its endogenous ligand. In the present study, we show for the first time that expression of GPR81 is significantly downregulated in response to OSS in endothelial cells and that activation of GPR81 using physiologically relevant doses of lactate can rescue OSS-induced reduced GPR81 expression. Importantly, our findings demonstrate that activation of GPR81 can exert valuable atheroprotective effects in endothelial cells exposed to OSS by reducing oxidative stress and significantly downregulating the expression of inflammatory cytokines including interleukin (IL)-6, IL-8, monocyte chemoattractant protein (MCP)-1, and high mobility group box 1 (HMGB1). We also show that activation of GPR81 can potentially prevent the attachment of monocytes to the endothelium by suppressing OSS-induced secretion of vascular cellular adhesion molecule (VCAM)-1 and endothelial-selectin (E-selectin). Finally, we show that activation of GPR81 can rescue OSS-induced reduced expression of the key atheroprotective transcription factor Kruppel-like factor 2 (KLF2), which is mediated through the extracellularregulated kinase 5 (ERK5) pathway. These findings demonstrate a potential Abbreviations: ECL, electrochemiluminescence; E-selectin, endothelial-selectin; ELISA, Enzyme-linked immunosorbent assay; ERK5, extracellularregulated kinase 5; FBS, fetal bovine serum; GPR81, G coupled-protein receptor 81; GPCRs, G protein-coupled receptors; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; HMGB1, high mobility group box 1; HSS, high shear stress; HUVECs, human umbilical vascular endothelial cells; HCA 1 , hydroxycarboxylic acid receptor 1; IL-6, interleukin; KLF2, Kruppel-like factor 2; MAPK, mitogen-activated protein kinase; MCP-1, monocyte chemoattractant protein; OSS, oscillatory shear stress; PAK1, p21-activated kinase 1; PVDF, polyvinylidene fluoride; ROS, reactive oxygen species; RT-PCR, reverse transcription PCR; SDS-PAGE, sodium dodecyl sulfate-polyacrylamide gel electrophoresis; VCAM-1, vascular cellular adhesion molecule.

Background: Perimembranous ventricular septal defect (pmVSD) is a common congenital heart disease. Transaxillary occluder device closure of the pmVSD has been proved effective and an alternative to surgical closure. The study aimed to evaluate the immediate operation outcomes and the early and midterm follow-up outcomes of transaxillary occluder device closure. Methods: From January 2014 to December 2017, we retrospectively analyzed the patients who underwent transaxillary device closure of the pmVSD. All patients underwent transthoracic echocardiography (TTE), chest x-ray, and electrocardiogram (ECG) before and after the procedure (before discharging). Follow-up evaluation was completed at the time of 3, 6, 12 months and yearly thereafter in outpatient setting with TTE and ECG. Results: A total of 428 patients (216 male, 212 female) underwent transaxillary occluder device closure of the pmVSD under the guidance of transesophageal echocardiography (TEE). The mean age at the operation time was 2.2 ± 1.5 year (range 0.5-16.2 year). The mean weight was 8.5 ± 4.1 kg (range 6-61 kg). The mean size of the occluder implanted in the operation was 5.3 ± 1.4 (range 4-8 mm), matching the mean defect size of 4.2 ± 1.1 (range 3-6 mm). The device closure operation was successfully achieved in 422 pmVSD patients (98.6%), and 6 patients failed in occluding and were converted to open surgery because of a great residual shunt and obvious device-related aortic regurgitation . Immediate complete closure was detected by postoperative TEE in all, but 3 patients had trivial residual shunting. Total early adverse events emerged in 47 patients (11.1%). New mild tricuspid and aortic regurgitation occurred in 17 and 3 patients and disappeared in follow-up. Abnormal atrioventricular conduction events emerged in 23 patients, including left anterior block, complete right bundle branch block (CRBBB), incomplete right bundle branch block (IRBBB), administrated with close follow-up. Pericardial effusion occurred in 2 other patients, managed with puncture drainage. During a median follow-up period of 26.8 months (range 6-48 months), no serious adverse event and later-on complete atrioventricular block were encountered. Conclusion: In our experience, transaxillary device closure was performed via right infra-axillary mini-incision (invisible) guided by TEE, with low incidence of postoperative adverse events, confirming that transaxillary device closure of the pmVSD under the guidance of TEE is an effective alternative to surgical closure in well-selected pmVSD patients.

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