Thioridazine protects against disturbed flow-induced atherosclerosis by inhibiting RhoA/YAP-mediated endothelial inflammation.

Atherosclerotic diseases remain the leading cause of adult mortality and impose heavy burdens on health systems globally. Our previous study found that disturbed flow enhanced YAP activity to provoke endothelial activation and atherosclerosis, and targeting YAP alleviated endothelial inflammation and atherogenesis. Therefore, we established a luciferase reporter assay-based drug screening platform to seek out new YAP inhibitors for anti-atherosclerotic treatment. By screening the FDA-approved drug library, we identified that an anti-psychotic drug thioridazine markedly suppressed YAP activity in human endothelial cells. Thioridazine inhibited disturbed flow-induced endothelial inflammatory response in vivo and in vitro. We verified that the anti-inflammatory effects of thioridazine were mediated by inhibition of YAP. Thioridazine regulated YAP activity via restraining RhoA. Moreover, administration of thioridazine attenuated partial carotid ligation- and western diet-induced atherosclerosis in two mouse models. Overall, this work opens up the possibility of repurposing thioridazine for intervention of atherosclerotic diseases. This study also shed light on the underlying mechanisms that thioridazine inhibited endothelial activation and atherogenesis via repression of RhoA-YAP axis. As a new YAP inhibitor, thioridazine might need further investigation and development for the treatment of atherosclerotic diseases in clinical practice.

Preoperative risk factors for haemodynamic instability during pheochromocytoma surgery in Chinese patients.

OBJECTIVE: Pheochromocytoma surgery carries a high risk of haemodynamic instability (HI). However, there are few studies investigating the risk factors for HI for pheochromocytoma surgery in a Chinese population. Therefore, our objective was to identify preoperative risk factors for HI during surgery in a Chinese population with pheochromocytoma. PATIENTS AND METHODS: In this retrospective study, 134 patients undergoing surgery for pheochromocytoma at a single university-affiliated hospital between November 2002 and July 2017 were enrolled. Demographics, comorbidities, preoperative medical preparation, operation details and perioperative haemodynamics of these patients were retrospectively collected and analysed. Multivariable logistic regression analysis was performed to identify the preoperative risk factors for intraoperative HI. RESULTS: 32.8% (44/134) patients suffered from intraoperative HI. According to the result of multivariate analysis, tumour diameter >50 mm (odds ratio [OR] 2.526; 95% confidence interval [CI] 1.163-5.485; P = .019), diabetes/prediabetes (OR 2.251; 95% CI 1.039-4.876; P = .040) and preoperative systolic blood pressure fluctuation >50 mm Hg (OR 3.163; 95% CI 1.051-9.522, P = .041) were independent predictors for intraoperative HI. The observed incidence of HI was 8.9%, 42.6%, 47.8% and 60% when zero, one, two or three risk factors were present, respectively. CONCLUSIONS: HI is common among Chinese patients undergoing surgery for pheochromocytoma. Our study identified three predictive factors for intraoperative HI: a large tumour diameter, diabetes/prediabetes and a great preoperative systolic blood pressure fluctuation. Furthermore, patients are more likely to suffer from HI when they have more predictive risk factors. Identification of these risk factors can help to improve perioperative management.

Outcomes of hybrid procedure for type B aortic dissection with an aberrant right subclavian artery.

OBJECTIVE: To report our single-center experience of the hybrid procedure for type B aortic dissection (TBAD) with an aberrant right subclavian artery (ARSA) and the early to midterm outcomes in these patients. METHODS: From December 2011 to February 2016, 16 patients (12 males; median age, 51 years; range, 40-66 years) underwent thoracic endovascular aortic repair and extraanatomic bypass hybrid procedure for TBAD with an ARSA in our center. Demographics, coexisting medical conditions, imaging features, operation details, and follow-up outcomes of these patients were collected retrospectively and analyzed. RESULTS: Duration from onset to hybrid procedure ranged from 5 to 57 days, with a median duration of 17 days. The median duration of stay in the intensive care unit and duration of in-hospital stay was 126 hours (range, 14-450 hours) and 21 days (range, 11-31 days), respectively. The overall technique success rate was 100%. No perioperative death, major stroke, or spinal cord ischemia was registered. Immediate type Ia endoleak was detected in three patients (18.8%) and immediate type II endoleak was detected in one patient (6.3%). One access-related complication occurred, which was a femoral artery pseudoaneurysm requiring compression bandage. Brachial plexus injury was observed in two patients (12.5%) with weakness of the upper extremity. The median follow-up was 33 months (range, 11-59 months). During follow-up, a retrograde type A aortic dissection was found in one patient (6.3%) 3 months after procedure. The occlusion of left common carotid artery to left subclavian artery bypasses were confirmed by computed tomography angiography in two patients (12.5%). They were left untreated for no symptoms. Reintervention was required in one patient (6.3%) for persistent type II endoleak by using Amplatzer plugs to seal the origin of the ARSA 20 months after the operation. There was no recorded death or stroke during the study period. CONCLUSIONS: Our limited experience demonstrates that a hybrid procedure is a viable and relatively safe treatment strategy for patients with TBAD and an ARSA. A larger series of cases with a longer follow-up is needed to substantiate these results.

Targeting the tyrosine kinase Src in endothelium attenuates inflammation and atherogenesis induced by disturbed flow.

BACKGROUND AND PURPOSE: Previous studies have shown that Src can regulate inflammation and tumour progression. However, the mechanisms by which Src regulates the inflammatory response of vascular endothelium and atherogenesis are currently poorly understood. This study aimed to investigate the role of Src in endothelial inflammation and atherogenesis, as well as the underlying mechanisms. EXPERIMENTAL APPROACH: Real-time quantitative PCR was used to measure the mRNA levels of inflammatory genes. The phosphorylation and localization of proteins were examined using western blotting and immunofluorescence, respectively. The level of p-Src Y416 in mouse endothelium was directly determined using en face staining. Endothelial-specific knockdown of Src was achieved by tail vein injection of AAV-sgSrc in ApoE-/-; Cas9LSL/LSL; Cdh5-cre mice. Atherosclerosis was induced by partial ligation of the carotid artery. KEY RESULTS: Oscillatory shear stress (OSS) promotes the phosphorylation of Src at Y416 in endothelial cells, and Piezo1 is required for this regulatory process. Overexpression of constitutively active Src promotes endothelial inflammation, as well as phosphorylation of Stat3 (at Y705) and its nuclear translocation. Endothelial inflammation induced by OSS was abolished by the Src inhibitor dasatinib or si-Src. Dasatinib, when administered orally, reduced endothelial inflammation and plaque formation in ApoE-/- mice induced by partial carotid artery ligation. Additionally, plaque formation was decreased in the ligated left carotid artery of mice with endothelial-specific Src knockdown. CONCLUSION AND IMPLICATIONS: Disturbed flow promotes endothelial inflammation and atherogenesis through the Piezo1-Src-Stat3 pathway. Therefore, inhibiting Src in endothelial cells could be a promising therapeutic strategy to treat atherogenesis.

Curaxin CBL0137 inhibits endothelial inflammation and atherogenesis via suppression of the Src-YAP signalling axis.

BACKGROUND AND PURPOSE: Atherosclerotic vascular disease is the leading cause of mortality and morbidity worldwide. Our previous study uncovered that endothelium-specific knockdown of YAP suppresses atherogenesis, suggesting that YAP is a promising therapeutic target against atherosclerotic vascular disease. We established a drug screening platform, which aimed to identify new YAP inhibitors for anti-atherosclerotic treatment. EXPERIMENTAL APPROACH: Drug screening was performed by a luciferase reporter gene assay. RNA sequencing was performed to acquire the transcriptomic profile of CBL0137-treated endothelial cells. We assessed and validated the inhibitory effect of CBL0137 on YAP activity and inflammatory response in HUVECs and HAECs. We evaluated the vasoprotective effect of CBL0137 in vivo against plaque formation in ApoE-/- mice, using both disturbed flow-induced and chronic western diet-induced atherosclerotic models. KEY RESULTS: We identified CBL0137 as a novel YAP inhibitor from an FDA drug library. CBL0137 inhibited YAP activity by restraining its phosphorylation at Y357. CBL0137 inhibited YAP activity to repress endothelial inflammation. Mechanistically, CBL0137 suppressed YAP phosphorylation at Y357 via the tyrosine-protein kinase Src. Furthermore, administration of CBL0137 ameliorated endothelial inflammation and the atherogenesis induced by disturbed flow and consumption of an atherogenic diet in ApoE-/- mice. CONCLUSION AND IMPLICATIONS: To our knowledge, this is the first study to identify CBL0137 as a novel YAP inhibitor. We have demonstrated that pharmacologically targeting YAP by CBL0137 inhibits atherogenesis. The present results suggest that CBL0137 holds promise as a new drug for the treatment of atherosclerotic vascular disease.

Perivascular adipose tissue: Fine-tuner of vascular redox status and inflammation.

Perivascular adipose tissue (PVAT) refers to the aggregate of adipose tissue surrounding the vasculature, exhibiting the phenotypes of white, beige and brown adipocytes. PVAT has emerged as an active modulator of vascular homeostasis and pathogenesis of cardiovascular diseases in addition to its structural role to provide mechanical support to blood vessels. More specifically, PVAT is closely involved in the regulation of reactive oxygen species (ROS) homeostasis and inflammation along the vascular tree, through the tight interaction between PVAT and cellular components of the vascular wall. Furthermore, the phenotype-genotype of PVAT at different regions of vasculature varies corresponding to different cardiovascular risks. During ageing and obesity, the cellular proportions and signaling pathways of PVAT vary in favor of cardiovascular pathogenesis by promoting ROS generation and inflammation. Physiological means and drugs that alter PVAT mass, components and signaling may provide new therapeutic insights in the treatment of cardiovascular diseases. In this review, we aim to provide an updated understanding towards PVAT in the context of redox regulation, and to highlight the therapeutic potential of targeting PVAT against cardiovascular complications.

Shear Stress and Metabolic Disorders-Two Sides of the Same Plaque.

Significance: Shear stress and metabolic disorder are the two sides of the same atherosclerotic coin. Atherosclerotic lesions are prone to develop at branches and curvatures of arteries, which are exposed to oscillatory and low shear stress exerted by blood flow. Meanwhile, metabolic disorders are pivotal contributors to the formation and advancement of atherosclerotic plaques. Recent Advances: Accumulated evidence has provided insight into the impact and mechanisms of biomechanical forces and metabolic disorder on atherogenesis, in association with mechanotransduction, epigenetic regulation, and so on. Moreover, recent studies have shed light on the cross talk between the two drivers of atherosclerosis. Critical Issues: There are extensive cross talk and interactions between shear stress and metabolic disorder during the pathogenesis of atherosclerosis. The communications may amplify the proatherogenic effects through increasing oxidative stress and inflammation. Nonetheless, the precise mechanisms underlying such interactions remain to be fully elucidated as the cross talk network is considerably complex. Future Directions: A better understanding of the cross talk network may confer benefits for a more comprehensive clinical management of atherosclerosis. Critical mediators of the cross talk may serve as promising therapeutic targets for atherosclerotic vascular diseases, as they can inhibit effects from both sides of the plaque. Hence, further in-depth investigations with advanced omics approaches are required to develop novel and effective therapeutic strategies against atherosclerosis. Antioxid. Redox Signal. 37, 820-841.

Outcomes Of Chimney Technique For Aortic Arch Diseases: A Single-Center Experience With 226 Cases.

PURPOSE: The goal of present study is to document our single-center experience with chimney technique for aortic arch diseases. PATIENTS AND METHODS: From August 2012 to October 2017, 226 patients (mean age 54±12 years; 197 men) with aortic arch diseases underwent thoracic endovascular aortic repair combined with chimney stents. The aortic stent-grafts were deployed in zone 0 (n=22), zone 1 (n=13), or zone 2 (n=191). RESULTS: The technical success rate was 84% (189/226) and immediate type Ia endoleak (ELIa) happened in 37 (16%) patients. The 30-day mortality and morbidity rates were 2% (4/226) and 4% (8/226), respectively. Major adverse events include four major strokes, three spinal cord ischemia and one aortic rupture in the early-term. The clinical and imaging follow-up rates were 98% (218/222) and 78% (173/222), respectively. The average lengths of clinical and imaging follow-up were 22±16 months and 20±15 months, respectively. Chimney stent obstructions in left subclavian arteries were recorded in six (3%) patients. During follow-up, five patients died (2%) and two major strokes occurred (1%). One patient (0.5%) underwent reintervention. CONCLUSION: The current study documented that the chimney technique is effective and safe for treating aortic arch diseases in different aortic zones. Cautions are needed to assess the permanency of chimney stent and to reduce the immediate ELIa rate.

Surgical resection of adrenocortical carcinoma with invasion into the inferior vena cava: a case report and literature review.

Adrenocortical carcinoma (ACC) is a malignant endocrine tumor. Moreover, ACC with invasion into the inferior vena cava is rare. Early diagnosis and treatment are crucial for such cases. Radical surgical resection is the key therapeutic option in ACC.