Bestrophin3 Deficiency in Vascular Smooth Muscle Cells Activates MEKK2/3-MAPK Signaling to Trigger Spontaneous Aortic Dissection.

BACKGROUND: Aortic dissection (AD) is a fatal cardiovascular disorder without effective medications due to unclear pathogenic mechanisms. Bestrophin3 (Best3), the predominant isoform of bestrophin family in vessels, has emerged as critical for vascular pathological processes. However, the contribution of Best3 to vascular diseases remains elusive. METHODS: Smooth muscle cell-specific and endothelial cell-specific Best3 knockout mice (Best3SMKO and Best3ECKO, respectively) were engineered to investigate the role of Best3 in vascular pathophysiology. Functional studies, single-cell RNA sequencing, proteomics analysis, and coimmunoprecipitation coupled with mass spectrometry were performed to evaluate the function of Best3 in vessels. RESULTS: Best3 expression in aortas of human AD samples and mouse AD models was decreased. Best3SMKO but not Best3ECKO mice spontaneously developed AD with age, and the incidence reached 48% at 72 weeks of age. Reanalysis of single-cell transcriptome data revealed that reduction of fibromyocytes, a fibroblast-like smooth muscle cell cluster, was a typical feature of human ascending AD and aneurysm. Consistently, Best3 deficiency in smooth muscle cells decreased the number of fibromyocytes. Mechanistically, Best3 interacted with both MEKK2 and MEKK3, and this interaction inhibited phosphorylation of MEKK2 at serine153 and MEKK3 at serine61. Best3 deficiency induced phosphorylation-dependent inhibition of ubiquitination and protein turnover of MEKK2/3, thereby activating the downstream mitogen-activated protein kinase signaling cascade. Furthermore, restoration of Best3 or inhibition of MEKK2/3 prevented AD progression in angiotensin II-infused Best3SMKO and ApoE-/- mice. CONCLUSIONS: These findings unveil a critical role of Best3 in regulating smooth muscle cell phenotypic switch and aortic structural integrity through controlling MEKK2/3 degradation. Best3-MEKK2/3 signaling represents a novel therapeutic target for AD.

Astilbin Protects Against Carbon Tetrachloride-Induced Liver Fibrosis in Rats.

BACKGROUND: Hepatic fibrosis is an inflammatory liver disease, and there is no effective therapy at present. Astilbin is a bioactive ingredient found in many medicinal and food plants, with antioxidative, anti-inflammatory, and antitumor properties. OBJECTIVES: This study aimed to investigate the protective effect and related molecular mechanism of astilbin against carbon tetrachloride (CCl4)-induced liver fibrosis in rats. METHODS: Liver fibrosis was induced by injection of CCl4 in male Sprague-Dawley rats, and those rats were then treated with astilbin at different concentrations. Pathological changes, collagen production, inflammatory cytokine, and oxidative stress were evaluated to evaluate the effects of astilbin on CCl4-induced hepatic fibrosis. Real-time PCR and western blot were performed to detect the mRNA and protein expression of indicated genes. RESULTS: We discovered that CCl4 caused significant fibrosis damage in rat liver, and astilbin dose-dependently improved the liver functions and fibrosis degree. Astilbin treatment significantly decreased collagen production, inflammatory response, and oxidative stress in vivo. Mechanically, administration of astilbin obviously elevated the hepatic levels of Nrf2 and its downstream components, including NAD(P)H:quinone oxidoreductase 1 (Nqo1), heme oxygenase (HO-1), glutamate-cysteine ligase catalytic subunit, and glutamate cysteine ligase modifier. CONCLUSIONS: Taken together, these findings demonstrate that astilbin could protect against CCL4 induced-liver fibrosis in rats.

[Surgical management of pregnancy-associated acute Stanford type A aortic dissection: analysis of 5 cases].

OBJECTIVE: To explore the diagnosis and treatment of pregnancy-associated acute Stanford type A aortic dissection to improve the maternal and fetal outcomes. METHODS: We analyzed the perioperative data of 5 pregnant women with acute Stanford type A aortic dissection treated between June, 2009 and February, 2017. RESULTS: The median age of the women was 30 years (range, 22-34 years) with gestational weeks of 23-38 weeks upon diagnosis. All the 5 patients received surgical interventions. Three patients underwent caesarean delivery and hysterectomy, and the fetuses survived after the surgery; 2 patients chose to continue pregnancy following the surgery, among whom one died due to postoperative complications and the other underwent termination of pregnancy. During follow-up, the surviving patients showed no endoleak in the descending aorta stent and the distal dissection remained stable. CONCLUSION: The maternal and fetal outcomes of pregnancy-associated acute Stanford type A aortic dissection can be improved by multidisciplinary cooperation and optimization of the surgical approaches according to the time of pregnancy, fetal development and conditions of the aortic lesions.

A case report and literature review of barium sulphate aspiration during upper gastrointestinal examination.

RATIONALE: Even though barium sulphate aspiration during upper gastrointestinal examination is a well-known phenomenon, complication such as long-term lung injury and death may still occur. This may depend upon the concentration, amount, anatomy, or certain predisposing factors. PATIENT CONCERNS: A 47-year-old woman who had a barium swallow to screen for foreign body in esophagus. DIAGNOSES: Chest radiographs demonstrated massive barium sulphate depositions in her trachea and inferior lobe of right lung. INTERVENTIONS: A chest x-ray was done that revealed massive barium sulphate depositions in her trachea and lower lobe of right lung. As the patient did not have further complaints, she requested a transfer to West China Hospital of Sichuan University, the hospital being near her residence, for further treatment. She eventually recovered and was discharged after 1 week. OUTCOMES: There were 23 articles (22 English and 1 Chinese with 17 men and 11 women) included in the study. The risk factors of barium sulphate aspiration are dysphagia (10/28, 35.71%) followed by esophageal obstruction caused by tumor (5/28, 17.86%) and foreign body in esophagus (3/28, 10.71%). Infants (5/28, 17.86%) are also one of the high-risk population. Both the lungs were affected in most of the patients (21/28, 75%). Majority of the presentation in patients (21/28, 75%) were dyspnea, hypoxemia, acute respiratory distress syndrome (ARDS), or respiratory failure. Few patients (7/28, 25%) showed no symptoms or mild symptoms such as cough and fever. Barium sulphate aspiration can be life-threatening with a high risk of death (nearly 40%). LESSONS: When performing an upper gastrointestinal examination with barium sulphate, careful consideration of concentration and amount of barium sulphate and that of risk factors should be undertaken so as to avoid life-threatening aspiration.

[Protective effect of retrograde venous perfusion of cryogenic liquid via accessory hemiazygos vein and treated with resveratrol on spinal cord injury in swine].

OBJECTIVES: To observe the protective effect of retrograde venous perfusion of cryogenic liquid via accessory hemiazygos vein and treated with resveratrol on spinal cord injury and evaluate the expression changes of microtubule-associated protein 2 (MAP-2) after spinal cord ischemia reperfusion injury (SCII) in swine. METHODS: Eighteen swine were divided into 3 groups: group I/R (n = 6, operation group), group CL (n = 6, retrograde venous perfusion of cryogenic liquid), group CL+Res (n = 6, retrograde venous perfusion of cryogenic liquid and treated with resveratrol after ischemia). In the group I/R, the aorta was clamped for 60 minutes and then removed. In the group CL and CL+Res, 9 g/L cold (4 °C) saline solution (perfusion rate, 16.65 ml/min) was infused into the accessory hemiazygos vein during ischemia.In the group CL+Res, the swine were treated with resveratrol (10 mg/kg) after spinal cord ischemia. Arterial pressure, blood gas analysis and the spinal canal and nasopharyngeal temperature changes were monitored during the surgery. Nervous function were assessed at 6 hours, 1, 2 days, 1, 2, 4 weeks and MAP-2 expression were detected at 4 weeks after reperfusion by using Western blot analysis in spinal cord tissue. RESULTS: After operation 18 swine were all survival. Behavioral scores of all groups decreased until 1 week after reperfusion and increased as time went by. The scores of group CL and CL+Res were higher than group I/R (F = 8.612, 17.276 and 11.985, P = 0.035,0.011 and 0.023) at 6 hours, 1, 2 days, group CL+Res were higher than group CL(P = 0.021) at 1 days after surgery. After descending aortic cross clamping, the spinal canal and nasopharyngeal temperature were obviously decreased in all groups and dropped to the lowest at 60 minutes after ischemia and 20 minutes after reperfusion in group I/R and the other groups respectively(F = 23.187-55.029, P < 0.01).In group CL(0.54 ± 0.26) and CL+Res (0.66 ± 0.31), the MAP-2 expression were higher than group I/R(0.37 ± 0.18) (F = 9.381, P = 0.037) , and the level in group CL+Res was higher than in group CL (P = 0.021) . CONCLUSION: Retrograde venous perfusion of cryogenic liquid via accessory hemiazygos vein and treated with resveratrol can relieve the ischemia-induced spinal cord injury in swine.

Matrine inhibits disturbed flow-enhanced migration via downregulation of ERK1/2-MLCK signaling vascular smooth muscle cells.

BACKGROUND: To investigate the effects of matrine on the vascular smooth muscle cell (VSMC) migration modulated by disturbed flow and their underlying molecular mechanisms in vitro. METHODS: Isolated rat aortic VSMCs were grown to confluence on 20- × 80-mm fibronectin-coated glass cover slides, and then, denuded zones were made at the position calculated to be the oscillating flow-reattachment zone and also in the downstream laminar flow region. VSMCs were treated with different doses of matrine (0, 10, 20, 30, and 40 mg/L), or PD98059 (30 µM), ML-7 (10 µM) combined with matrine (40 mg/L) for 30 minutes before and during the experiments. Then, the wounded monolayers were kept under static conditions or were subjected to laminar or disturbed flow for 21 hours or 10 hours. The VSMC migration was assessed by microscopic images. The extracellular signal-regulated kinase 1/2 (ERK1/2) and myosin light chain kinase (MLCK) proteins were determined by Western blot. RESULTS: Disturbed flow significantly increased phosphorylation of ERK1/2. Selective inhibition of ERK1/2 phosphorylation by inhibitor PD98059 and matrine significantly suppressed VSMC migration under disturbed flow. Disturbed flow significantly enhanced phosphorylation of MLCK, whereas both matrine and PD98059 inhibited the phosphorylation of MLCK under disturbed flow. The complete inhibition of MLCK phosphorylation using the selective MLCK inhibitor ML-7 significantly inhibited VSMC migration under disturbed flow. CONCLUSION: Matrine inhibits VSMC migration under disturbed flow, in part, by downregulation of ERK1/2-MLCK signaling pathway.