The Role of Inflammasome in Abdominal Aortic Aneurysm and Its Potential Drugs.

Abdominal aortic aneurysm (AAA) has been recognized as a serious chronic inflammatory degenerative aortic disease in recent years. At present, there is no other effective intervention except surgical treatment for AAA. With the aging of the human population, its incidence is increasing year by year, posing a serious threat to human health. Modern studies suggest that vascular chronic inflammatory response is the core process in AAA occurrence and development. Inflammasome, a multiprotein complex located in the cytoplasm, mediates the expression of various inflammatory cytokines like interleukin (IL)-1ß and IL-18, and thus plays a pivotal role in inflammation regulation. Therefore, inflammasome may exert a crucial influence on the progression of AAA. This article reviews some mechanism studies to investigate the role of inflammasome in AAA and then summarizes several potential drugs targeting inflammasome for the treatment of AAA, aiming to provide new ideas for the clinical prevention and treatment of AAA beyond surgical methods.

Dapagliflozin alleviates high glucose-induced injury of endothelial cells via inducing autophagy.

Hyperglycaemia is a key factor in the progression of diabetes complications. Dapagliflozin (DAPA), a new type of hypoglycaemic agent, has been shown to play an important role in anti-apoptotic, anti-inflammatory and antioxidant activities. Previous studies have demonstrated an endothelial protective effect of DAPA, but the underlying mechanism was still unclear. Autophagy is a homeostatic cellular mechanism that circulates unfolded proteins and damaged organelles through lysosomal dependent degradation. In this study, we aimed to investigate whether DAPA plays a protective role against high glucose (HG)-induced endothelial injury through regulating autophagy. The results showed that DAPA treatment resulted in increased cell viability. Additionally, DAPA treatment decreased interleukin (IL)-1ß, IL-6, and tumour necrosis factor-α levels in endothelial cells subjected to HG conditions. We observed that HG inhibited autophagy, and DAPA increased the autophagy level by inhibiting the protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signalling pathway. Chloroquine reversed all of these beneficial effects as an autophagy inhibitor. In summary, the endothelial protective effect of DAPA in HG can be attributed in part to its role in activating of autophagy via the AKT/mTOR signalling pathway. Therefore, suggesting that the activation of autophagy by DAPA may be a novel target for the treatment of HG-induced endothelial cell injury.

Design a dual-response two-photon fluorescent probe for simultaneous imaging of mitochondrial viscosity and peroxynitrite in a thrombosis model.

BACKGROUND: Venous thromboembolism is a sudden cardiovascular disease that can lead to death, and its pathologic development is closely related to vascular viscosity and inflammation. However, direct evidence from in vivo is really scarce. The key limitation is that the combined probes cannot detect multiple markers simultaneously, which may lead to unreliable results. Therefore, to develop a single probe that can simultaneously monitor the variations of viscosity in the vascular microenvironment as well as inflammation level during venous thrombosis. RESULTS: A dual-responsive two-photon fluorescent probe, Cou-ONOO, was designed and synthesized. Cou-ONOO provides a visualization tool for monitoring the viscosity of the vascular as well as the inflammatory marker ONOO‾ during thromboembolism via dual-channel simultaneous imaging. As a single probe that can recognize dual targets, Cou-ONOO effectively avoids the problems from unreliable results caused by complex synthesis and differences in intracellular localization, diffusion, and metabolism of different dyes as using combinatorial probes. Using Cou-ONOO, simultaneous imaging the variations of viscosity and ONOO‾at the cellular and tissue levels was successfully performed. In addition, Cou-ONOO also successfully visualized and tracked the viscosity of the vascular microenvironment and ONOO‾ during venous embolism in mice. SIGNIFICANCE: Experimental results show that both viscosity and inflammation are abnormally overexpressed in the microenvironment at the thrombus site during venous thrombosis. An intuitive visualization tool to elucidate the variations of viscosity as well as inflammation level in the vascular microenvironment during thrombosis was provided, which will facilitate a better clinical understanding of the pathological process of thrombosis.

Association of cardiometabolic multimorbidity and adherence to a healthy lifestyle with incident dementia: a large prospective cohort study.

BACKGROUND: The co-occurrence of cardiometabolic diseases (CMDs) is increasingly prevalent and has been associated with an additive risk of dementia in older adults, but the extent to which this risk can be offset by a healthy lifestyle is unknown. We aimed to examine the associations of cardiometabolic multimorbidity and lifestyle with incident dementia and related brain structural changes. METHODS: This prospective study extracted health and lifestyle data from 171 538 UK Biobank participants aged 60 years or older without dementia at baseline between 2006 and 2010 and followed up until July 2021, as well as brain structural data in a nested imaging subsample of 11 972 participants. Cardiometabolic multimorbidity was defined as the presence of two or more CMDs among type 2 diabetes, coronary heart disease, stroke, and hypertension. Lifestyle patterns were determined based on 7 modifiable lifestyle factors including smoking, alcohol consumption, physical activity, diet, sleep duration, sedentary behavior, and social contact. RESULTS: Over a median follow-up of 12.3 years, 4479 (2.6%) participants developed dementia. The presence of CMDs was dose-dependently associated with an increased risk of dementia. Compared with participants with no CMDs and a favourable lifestyle, those with ≥ 3 CMDs and an unfavourable lifestyle had a five times greater risk of developing dementia (HR 5.33, 95% CI 4.26-6.66). A significant interaction was found between CMD status and lifestyle (Pinteraction=0.001). The absolute difference in incidence rates of dementia per 1000 person years comparing favourable versus unfavourable lifestyle was - 0.65 (95% CI - 1.02 to - 0.27) among participants with no CMDs and - 5.64 (- 8.11 to - 3.17) among participants with ≥ 3 CMDs, corresponding to a HR of 0.71 (0.58-0.88) and 0.42 (0.28-0.63), respectively. In the imaging subsample, a favourable lifestyle was associated with larger total brain, grey matter, and hippocampus volumes across CMD status. CONCLUSION: Our findings suggest that adherence to a healthy lifestyle might substantially attenuate dementia risk and adverse brain structural changes associated with cardiometabolic multimorbidity.

Perspective of SGLT2i in the Treatment of Abdominal Aortic Aneurysms.

ABSTRACT: The incidence of abdominal aortic aneurysm (AAA) in the elderly is increasing year by year with high mortality. Current treatment is mainly through surgery or endovascular intervention, which is not sufficient to reduce future risk. Therefore, we still need to find an effective conservative measure as an adjunct therapy or early intervention to prevent AAA progression. Traditional therapeutic agents, such as ß-receptor blockers, calcium channel blockers, and statins, have been shown to have limited effects on the growth of AAA. Recently, sodium-glucose cotransport proteins inhibitors (SGLT2is), a new class hypoglycemic drug, have shown outstanding beneficiary effects on cardiovascular diseases by plasma volume reduction, vascular tone regulation, and various unidentified mechanisms. It has been demonstrated that SGLT2i is abundantly expressed in the aorta, and some studies also showed promising results of SGLT2i in treating animal AAA models. This article aims to summarize the recent progress of AAA studies and look forward to the application of SGLT2i in AAA treatment for early intervention or adjunct therapy after surgical repair or stent graft.

Case Report: Simultaneous Ascending Aortic Dissection and Pulmonary Artery Dissection Combined by Aortopulmonary Fistula After Aortic Valve Replacement.

Aortopulmonary fistula with/without pulmonary artery dissection is an extremely rare and fatal complication of acute aortic dissection and is often discovered postmortem. We present a case with a simultaneous ascending aortic dissection and pulmonary artery dissection combined by aortopulmonary fistula after aortic valve surgery. However, the patient died of postoperative complications after surgery. Herein, the anatomical basis for this rare entity and its outcome is explored with an emphasis.

Thoracic Endovascular Aortic Repair for Retrograde Type A Aortic Intramural Hematoma.

Objectives: To evaluate the effects of thoracic endovascular aortic repair (TEVAR) in descending aorta for retrograde type A aortic intramural hematoma (re-TAIMH). Methods: From January 2013 to September 2019, 65 consecutive patients diagnosed with re-TAIMH and treated by TEVAR were enrolled in this retrospective cohort study, of whom 44 patients presented with entry tear in descending aorta (Group A) and 21 with penetrating atherosclerotic ulcer (Group B). The clinical data, including baseline characteristics, adverse events, aortic remolding, and overall survival were reviewed. Results: The mean age of all the patients was 52.0 ± 8.3 years, and 54 (83.1%) patients were men. The mean maximal ascending aortic diameter (MAAD) was 43.1 ± 5.4 mm, and the mean maximal ascending aortic hematoma thickness (MAAHT) was 9.6 ± 4.7 mm. TEVAR was performed under general anesthesia in 53 (81.5%) patients, while 12 (18.5%) patients were treated under local anesthesia. There were two deaths during hospitalization (one with rupture and another with multiple organ dysfunction syndrome), and overall survival at 1, 4, and 7 years for all 65 patients was 93.8, 92.0, and 87.4%, respectively. The MAAD and MAATH decreased significantly after TEVAR (p < 0.05) in the two groups, so did the mean descending aortic diameter at the pulmonary bifurcation level. Type I endoleak, dialysis, progression to type A aortic dissection, and enlargement in MAAHT and MAAD were more common complications, which occurred in four, three, two, and two patients, respectively. Conclusion: Patients with retrograde TAIMH treated by TEVAR had a favorable prognosis including late survival and aortic remolding. However, some post-intervention complications were not negligible.

Exosomal long non-coding RNA LIPCAR derived from oxLDL-treated THP-1 cells regulates the proliferation of human umbilical vein endothelial cells and human vascular smooth muscle cells.

BACKGROUND: It has been reported that long non-coding RNA (lncRNA) LIPCAR is involved in the progression of atherosclerosis. However, the mechanism underlying the effects of LIPCAR on regulating the occurrence and development of atherosclerosis remains unclear. METHODS: Reverse transcription-quantitative PCR was performed to detect the levels of LIPCAR in the plasma of patients with atherosclerosis and in THP-1 macrophages. THP-1 cells were stimulated with oxidized low-density lipoprotein (ox-LDL) to induce foam cell formation. Furthermore, Transwell assay was carried out to evaluate the migration ability of vascular smooth muscle cells (VSMCs). RESULTS: The expression of LIPCAR in the plasma of patients with atherosclerosis was significantly higher compared with that in healthy subjects, while LIPCAR knockdown notably reversed ox-LDL-induced THP-1 cell apoptosis. In addition, LIPCAR was upregulated in exosomes derived from THP-1 cells treated with ox-LDL (THP-1/ox-LDL Exo). Furthermore, THP-1/ox-LDL Exo significantly increased the expression levels of CDK2 and proliferative cell nuclear antigen in human VSMCs, while these effects were reversed following LIPCAR silencing. CONCLUSION: The results of the present study suggested that exosomal lncRNA LIPCAR derived from ox-LDL modified THP-1 cells could promote the progression of atherosclerosis. Therefore, LIPCAR may be considered as a novel biomarker for the development of new strategies to treat atherosclerosis.

What Influences the Patients with Left Atrial Myxoma: From Embolism to Postoperative Atrial Fibrillation.

BACKGROUND: Preoperative embolism and postoperative atrial fibrillation (POAF) are two important factors associated with impaired health conditions and increased economic burden in patients with left atrial (LA) myxoma. The aim of this study was to analyze embolic events, identify predictors of POAF, and evaluate the risk of late-term survival in patients with LA myxoma. METHODS: From December 2009 to December 2019, 177 consecutive patients with LA myxoma who met the selection criteria were included in the retrospective analysis. Multivariate logistic regression analysis was performed to identify predictors of POAF. Propensity score matching was used for confounder control, and Cox proportional hazards models were used to evaluate the risk of late-term mortality. RESULTS: The study population comprised of 125 patients in non-POAF group and 52 patients in POAF group. Preoperative embolism was present in 27.1% of the all cases. By multivariate analysis, age, NYHA functional class III, LA diameter, and cross-clamp time were identified as independent predictors of in-hospital POAF. The overall survival at 1, 5, and 10 years for the 177 patients was 98.9%, 93.7%, and 84.4%, respectively. There was no statistical difference in late-term survival between the two groups in the Cox proportion-adjusted survival curve. After propensity score 1:1 matching, patients with POAF had a longer postoperative hospital stay and Kaplan-Meier survival curve also showed no statistical difference between the two groups. CONCLUSIONS: Patients with LA myxoma after surgical treatment had a favorable prognosis. In-hospital POAF was not independently associated with late-term mortality in patients with LA myxoma.

Endovascular repair of type A aortic intramural hematoma accompanied by aberrant right subclavian artery and Kommerell's diverticulum: a case report.

BACKGROUND: The lesions of aberrant right subclavian artery, Kommerell's diverticulum and type A aortic intramural hematoma are rare, and we usually treat them with open surgery. In some cases patients have increased risk to undergo surgery, the experiences of endovascular or medical treatment are limited. CASE PRESENTATION: Here we reported a case of a 53-year-old man with these three entities present with chest and back ache and attempted a novel approach, thoracic endovascular aortic repair, in the absence of surgical treatment. The patient lived over 5 years and this case provides initial experience and lesson about the endovascular and medical management of the uncommon and dangerous disease- type A aortic intramural hematoma with aortic congenital malformation. CONCLUSION: Thoracic endovascular aortic repair with medical treatment may be a potential alternative approach for type A aortic intramural hematoma.

Molecular mechanism underlying anti-inflammatory activities of lirioresinol B dimethyl ether through suppression of NF-κB and MAPK signaling in in vitro and in vivo models.

The aim of the present study is to explore the anti-inflammatory mechanism of lirioresinol B dimethyl ether via inhibition of multiple signaling pathways in both in vitro and in vivo pharmacological models. To determine the anti-inflammatory activity of the lirioresinol B dimethyl ether, RAW 264.7 macrophages challenged with lipopolysaccharide (LPS) were treated with various concentrations of lirioresinol B dimethyl ether (5, 15, 25, and 50 µM). The results indicated that pretreatment with lirioresinol B dimethyl ether significantly suppressed nuclear factor kappa B (NF-κB) activation, nitric oxide (NO) production, the protein expressions of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). Lirioresinol B dimethyl ether inhibited LPS-induced activation of production of pro-inflammatory cytokines as well as prostaglandin E2 (PGE2) release. The results obtained by electrophoretic mobility shift assay (EMSA) demonstrated a concentration dependent reduction of the LPS-stimulated activation of NF-κB and activator protein-1 (AP-1) by lirioresinol B dimethyl ether in in vitro and in vivo models. Moreover, lirioresinol B dimethyl ether also reduced the expression of toll-like receptor (TLR)-4 protein and myeloid differentiation primary response gene 88 (MyD88) as well as promoted the degradation of IκBα. Lirioresinol B dimethyl ether also significantly down-regulated the phosphorylation of Jun N-terminal kinase (JNK), p-38 and extracellular signal-regulated kinase (ERK). Furthermore, the results of acute and chronic inflammation demonstrated that lirioresinol B dimethyl ether (10 and 50 mg per kg) reduced paw edema and mechanical hyperalgesia in carrageenan- and Complete Freund's Adjuvant (CFA)-induced in vivo mouse models, respectively. Hence, the current results indicate that lirioresinol B dimethyl ether either act by inhibiting pro-inflammatory mediators through down-regulation of mitogen activated protein kinases (MAPKs) signaling pathways and reduction of NF-κB activation.