The S-Nitrosylation of Septin2 (SNO-Septin2) axis: A novel potential therapeutic target for treating aneurysms and dissection.

Aortic aneurysm and aortic dissection (AAD) are severe life-threatening cardiovascular disorders for which no approved pharmaceutical therapies are currently available. Protein S-nitrosylation (SNO) is a typical redox-dependent posttranslational modification whose role in AAD has yet to be described. Recently, Zhang et al. revealed for the first time that SNO modification of macrophage cytoskeletal protein septin2 promotes vascular inflammation and extracellular matrix degradation in aortic aneurysm. Mechanically, the TIAM1-RAC1(T lymphoma invasion and metastasis-inducing protein 1-Ras-related C3 botulinum toxin substrate 1) axis participates in the progression of AAD induced with S-nitrosylated septin2. More importantly, developing R-ketorolac and NSC23766 compounds that specifically target the TIAM1-RAC1 pathway may be new a potential strategy for alleviating AAD.

Biomimetic-Structured Cobalt Nanocatalyst Suppresses Aortic Dissection Progression by Catalytic Antioxidation.

As one of the most lethal cardiovascular diseases, aortic dissection (AD) is initiated by overexpression of reactive oxygen species (ROS) in the aorta that damages the vascular structure and finally leads to massive hemorrhage and sudden death. Current drugs used in clinics for AD treatment fail to efficiently scavenge ROS to a large extent, presenting undesirable therapeutic effect. In this work, a nanocatalytic antioxidation concept has been proposed to elevate the therapeutic efficacy of AD by constructing a cobalt nanocatalyst with a biomimetic structure that can scavenge pathological ROS in an efficient and sustainable manner. Theoretical calculations demonstrate that the antioxidation reaction is catalyzed by the redox transition between hydroxocobalt(III) and oxo-hydroxocobalt(V) accompanied by inner-sphere proton-coupled two-electron transfer, forming a nonassociated activation catalytic cycle. The efficient antioxidation action of the biomimetic nanocatalyst in the AD region effectively alleviates oxidative stress, which further modulates the aortic inflammatory microenvironment by promoting phenotype transition of macrophages. Consequently, vascular smooth muscle cells are also protected from inflammation in the meantime, suppressing AD progression. This study provides a nanocatalytic antioxidation approach for the efficient treatment of AD and other cardiovascular diseases.

Asiatic acid alleviates vascular remodeling in BAPN-induced aortic dissection through inhibiting NF-κB p65/CX3CL1 signaling.

Inflammation assumes a pivotal role in the aortic remodeling of aortic dissection (AD). Asiatic acid (AA), a triterpene compound, is recognized for its strong anti-inflammatory properties. Yet, its effects on ß-aminopropionitrile (BAPN)-triggered AD have not been clearly established. The objective is to determine whether AA attenuates adverse aortic remodeling in BAPN-induced AD and clarify potential molecular mechanisms. In vitro studies, RAW264.7 cells pretreated with AA were challenged with lipopolysaccharide (LPS), and then the vascular smooth muscle cells (VSMCs)-macrophage coculture system was established to explore intercellular interactions. To induce AD, male C57BL/6J mice at three weeks of age were administered BAPN at a dosage of 1 g/kg/d for four weeks. To decipher the mechanism underlying the effects of AA, RNA sequencing analysis was conducted, with subsequent validation of these pathways through cellular experiments. AA exhibited significant suppression of M1 macrophage polarization. In the cell coculture system, AA facilitated the transformation of VSMCs into a contractile phenotype. In the mouse model of AD, AA strikingly prevented the BAPN-induced increases in inflammation cell infiltration and extracellular matrix degradation. Mechanistically, RNA sequencing analysis revealed a substantial upregulation of CX3CL1 expression in BAPN group but downregulation in AA-treated group. Additionally, it was observed that the upregulation of CX3CL1 negated the beneficial impact of AA on the polarization of macrophages and the phenotypic transformation of VSMCs. Crucially, our findings revealed that AA is capable of downregulating CX3CL1 expression, accomplishing this by obstructing the nuclear translocation of NF-κB p65. The findings indicate that AA holds promise as a prospective treatment for adverse aortic remodeling by suppressing the activity of NF-κB p65/CX3CL1 signaling pathway.

Efficacy and Safety of Sacubitril/Valsartan in Chronic Type B Aortic Dissection Combined With Mild Hypertension.

BACKGROUND: Optimal antihypertensive medication for chronic type B aortic dissection (AD) remains undecided. This study compared the efficacy and safety of sacubitril/valsartan with valsartan to determine suitable antihypertensive drug combinations. METHODS: In this single-center, open-label, randomized, controlled trial, patients with chronic Stanford type B AD and mild hypertension were randomized to receive sacubitril/valsartan 100/200 mg or valsartan 80/160 mg. The primary endpoint was the reduction in mean sitting systolic blood pressure (msSBP) at week 8 in patients with sacubitril/valsartan vs. valsartan. Key secondary endpoints included changes in (i) mean sitting diastolic blood pressure (msDBP); (ii) pulse pressure (PP); and (iii) mean ambulatory blood pressure (BP) for 24-hour, daytime, and nighttime. Safety assessments included adverse events (AEs) and serious AEs. This trial was registered with the Chinese Clinical Trial Registry, identifier: ChiCTR2300073399. RESULTS: A total of 315 patients completed the study. Sacubitril/valsartan provided a significantly greater reduction in msSBP than valsartan at week 8 (between-treatment difference: -5.1 mm Hg [95% confidence interval -5.8 to -4.5], P < 0.001). Reductions in msSBP, msDBP, and PP as well as the mean ambulatory BP for 24-hour, daytime, and nighttime, were significantly greater in sacubitril/valsartan compared with valsartan (all P < 0.001). No excessive episodes of AEs occurred in the sacubitril/valsartan group. CONCLUSIONS: Sacubitril/valsartan and valsartan reduced BP compared with baseline values. However, sacubitril/valsartan improved BP control to a greater extent than valsartan. It may offer a new treatment option for patients with mild hypertension and chronic type B AD.

Safety and efficacy of ketorolac in improving the prognosis of acute type A aortic dissection patients: a protocol of a randomized, double-blinded, and placebo-controlled study.

BACKGROUND: Acute type A aortic dissection (aTAAD) is a critical and life-threatening condition. Previous research has demonstrated that the use of ketorolac not only reduces the progression, incidence, and severity of aortic aneurysms in animal models, but also decreases postoperative mortality and complications in patients undergoing open abdominal aortic aneurysm replacement. However, there is a lack of studies investigating the efficacy of ketorolac in treating aTAAD in humans. Therefore, we conducted a study to evaluate the safety and efficacy of ketorolac in patients with aTAAD. Our hypothesis was that ketorolac treatment for aTAAD patients would meet safety indicators and effectively improve patient prognosis. METHODS/DESIGN: This study is a single-center, randomized, double-blinded, and placebo-controlled study. A total of 120 patients with aTAAD will be recruited and will be randomized into the ketorolac group and placebo group with a ratio of 1:1. Ketorolac tromethamine 60 mg per 2 ml will be intramuscularly injected within 2 h before surgery, followed by intramuscular injections of 30 mg per 1 ml BID. on the first and second postoperative days in the Ketorolac group, while 0.9% saline will be administered at the same dose, dosage form, and time in the placebo group. This study aims to evaluate the safety and efficacy of ketorolac in improving the prognosis of aTAAD. The primary endpoint is the composite endpoint event concerning drug-related adverse events. Secondary endpoints include drug-related adverse events, laboratory examination of blood, diagnostic imaging tests, clinical biomarkers, etc. DISCUSSION: This study has been approved by the Medical Ethics Committee of Affiliated Nanjing Drum Tower Hospital, Nanjing University Medical College (approval number: 2023-197-02). This study is designed to evaluate the safety and efficacy of ketorolac in patients with aTAAD. All participating patients will sign an informed consent form, and the trial results will be published in international peer-reviewed journals. TRIAL REGISTRATION: The Chinese Clinical Trial Registry ( http://www.chictr.org.cn ) ChiCTR2300074394. Registered on 4 October 2023.

Histone deacetylase 9-mediated phenotypic transformation of vascular smooth muscle cells is a potential target for treating aortic aneurysm/dissection.

Aortic aneurysm/dissection (AAD) is a serious cardiovascular condition characterized by rapid onset and high mortality rates. Currently, no effective drug treatment options are known for AAD. AAD pathogenesis is associated with the phenotypic transformation and abnormal proliferation of vascular smooth muscle cells (VSMCs). However, endogenous factors that contribute to AAD progression remain unclear. We aimed to investigate the role of histone deacetylase 9 (HDAC9) in AAD pathogenesis. HDAC9 expression was considerably increased in human thoracic aortic dissection specimens. Using RNA-sequencing (RNA-seq) and chromatin immunoprecipitation, we demonstrated that HDAC9 transcriptionally inhibited the expression of superoxide dismutase 2 and insulin-like growth factor-binding protein-3, which are critically involved in various signaling pathways. Furthermore, HDAC9 triggered the transformation of VSMCs from a systolic to synthetic phenotype, increasing their proliferation and migration abilities and suppressing their apoptosis. Consistent with these results, in vivo experiments revealed that TMP195, a pharmacological inhibitor of HDAC9, suppressed the formation of the ß-aminopropionitrile-induced AAD phenotype in mice. Our findings indicate that HDAC9 may be a novel endogenous risk factor that promotes the onset of AAD by mediating the phenotypic transformation of VSMCs. Therefore, HDAC9 may serve as a potential therapeutic target for drug-based AAD treatment. Furthermore, TMP195 holds potential as a therapeutic agent for AAD treatment.

Liraglutide attenuates angiotensin II-induced aortic dissection and aortic aneurysm via inhibiting M1 macrophage polarization in APOE -/- mice.

BACKGROUND: Aortic Aneurysm and Dissection (AAD) are severe cardiovascular conditions with potentially lethal consequences such as aortic rupture. Existing studies suggest that liraglutide, a long-acting glucagon-like peptide receptor (GLP-1R) agonist, offers protective benefits across various cardiovascular diseases. However, the efficacy of liraglutide in mitigating AAD development is yet to be definitively elucidated. METHODS: Ang II (Angiotension II) infusion of APOE-/- mouse model with intraperitoneal injection of liraglutide (200 µg/kg) to study the role of GLP-1R in AAD formation. Bone Marrow Derived Macrophages (BMDM) and Raw264.7 were incubated with LPS, liraglutide, exendin 9-39 or LY294002 alone or in combination. SMC phenotype switching was examined in a macrophage and vascular smooth muscle cell (VSMC) co-culture system. An array of analytical methods, including Western Blot, Immunofluorescence Staining, Enzyme-LinkedImmunosorbent Assay, Real-Time Quantitative Polymerase Chain Reaction, RNA-seq, and so on were employed. RESULTS: Our investigation revealed a significant increase in M1 macrophage polarization and GLP-1R expression in aortas of AD patients and Ang II-induced AAD APOE-/- mice. Administering liraglutide in APOE-/- mice notably reduced Ang II-induced AAD incidence and mortality. It was found that liraglutide inhibits M1 macrophage polarization primarily via GLP-1R activation, and subsequently modulates vascular smooth muscle cell phenotypic switching was the primary mechanism. RNA-Seq and subsequent KEGG enrichment analysis identified CXCL3, regulated by the PI3K/AKT signaling pathway, as a key element in liraglutide's modulation of M1 macrophage polarization. CONCLUSION: Our study found liraglutide exhibits protective effects against AAD by modulating M1 macrophage polarization, suppressing CXCL3 expression through the PI3K/AKT signaling pathway. This makes it a promising therapeutic target for AAD, offering a new avenue in AAD management.

Untargeted metabolomics identifies indole-3-propionic acid to relieve Ang II-induced endothelial dysfunction in aortic dissection.

Indole-3-propionic acid (IPA), a gut microbiota-derived metabolite of tryptophan, has been proven to fulfill an essential function in cardiovascular disease (CVD) and nerve regeneration disease. However, the role of IPA in aortic dissection (AD) has not been revealed. We aimed to investigate the role of IPA in the pathogenesis of AD and the underlying mechanisms of IPA in endothelial dysfunction. Untargeted metabolomics has been employed to screen the plasma metabolic profile of AD patients in comparison with healthy individuals. Network pharmacology provides insights into the potential molecular mechanisms underlying IPA. 3-aminopropionitrile fumarate (BAPN) and angiotensin II (Ang II) were administered to induce AD in mice, while human umbilical vein endothelial cells (HUVECs) were employed for in vitro validation of the signaling pathways predicted by network pharmacology. A total of 224 potentially differential plasma metabolites were identified in the AD patients, with 110 up-regulated metabolites and 114 down-regulated metabolites. IPA was the most significantly decreased metabolite involved in tryptophan metabolism. Bcl2, caspase3, and AKT1 were predicted as the target genes of IPA by network pharmacology and molecular docking. IPA suppressed Ang II-induced apoptosis, intracellular ROS generation, inflammation, and endothelial tight junction (TJ) loss. Animal experiments demonstrated that administration of IPA alleviated the occurrence and severity of AD in mice. Taken together, we identified a previously unexplored association between tryptophan metabolite IPA and AD, providing a novel perspective on the underlying mechanism through which IPA mitigates endothelial dysfunction to protect against AD.

Costunolide mitigates inflammation and promotes extracellualr matrix integrity of thoracic aortic dissection by inhibiting NF-κB signaling.

BACKGROUND: Thoracic aortic dissection (TAD) is one of the most fatal cardiovascular diseases. One of its important pathological characteristics is the local inflammatory response. Many studies have found that Macrophage polarization plays an extremely critical role in the inflammatory progression and tissue remodeling of TAD. Costunolide (CTD) has an improving effect on oxidative stress and inflammation in the body. However, whether it can promote the integrity of extracellular matrix in Aortic dissection and its mechanism are still unclear. METHODS: The male C57BL/6J mice were used to construct an animal model of TAD with ß-aminopropionitrile (BAPN) (100 mg/kg/day, lasting for 28 days), and then CTD (10 mg/kg or 100 mg/kg) was injected intraperitoneally for 28 days to check the survival rate, TAD incidence, aortic morphology and other indicators of the mice. Using hematoxylin-eosin (HE), Masson, Elastin van Gieson (EVG) staining, immunofluorescence (IF), and immunohistochemical staining, the study aimed to determine the therapeutic effects of CTD on an animal model with BAPN-induced TAD. To enhance the examination of the regulatory mechanism of CTD, we conducted transcriptome sequencing on arterial tissues of mice in both the BAPN group and the BAPN + CTD100 group. Next, ANG II were used to construct TAD model in vascular smooth muscle cells (VMSCs). The effects of CTD on the proliferation, migration, invasion, and apoptosis of ANG II-induced cells are to be detected. The expression of MMP2, MMP9, P65, and p-P65 in each group will be examined using Western blot. Finally, the overexpression of IκB kinaseß (IKKß) will be established in VMSCs cells to further explore the protective function of CTD. RESULTS: The result showed that CTD significantly inhibited BAPN induced mortality and TAD incidence in the animal model, improved aortic vascular morphology, promoted the integrity of extracellular matrix in TAD, reduced tissue inflammation, reduced the accumulation of M1 macrophage, promoted M2 macrophage polarization, and reduced the expression of NF-κB pathway related proteins. Mechanistically, CTD significantly weakened the proliferation, migration, invasion, and apoptosis. p-P65 protein expression of TAD cells were induced by ANG II and IKK-ß. CONCLUSION: CTD has the potential to alleviate inflammation, VSMC apoptosis, MMP2/9 levels, and enhance extracellular matrix integrity in TAD by inhibiting the NF-κB signaling pathway.

The role of anatomic shape features in the prognosis of uncomplicated type B aortic dissection initially treated with optimal medical therapy.

OBJECTIVE: Currently, the long-term outcomes of uncomplicated type B aortic dissection (TBAD) patients managed with optimal medical therapy (OMT) remain poor. Aortic expansion is a major factor that determines patient long-term survival. The objective of this study was to investigate the association between anatomic shape features and (i) OMT outcome; (ii) aortic growth rate for TBAD patients initially treated with OMT. METHODS: 108 CT images of TBAD in the acute and chronic phases were collected from 46 patients who were initially treated with OMT. Statistical shape models (SSM) of TBAD were constructed to extract shape features from the earliest initial CT scans of each patient by using principal component analysis (PCA) and partial least square (PLS) regression. Additionally, conventional shape features (e.g., aortic diameter) were quantified from the earliest CT scans as a baseline for comparison. We identified conventional and SSM features that were significant in separating OMT "success" and failure patients. Moreover, the aortic growth rate was predicted by SSM and conventional features using linear and nonlinear regression with cross-validations. RESULTS: Size-related SSM and conventional features (mean aortic diameter: p=0.0484, centerline length: p=0.0112, PCA score c1: p=0.0192, and PLS scores t1: p=0.0004, t2: p=0.0274) were significantly different between OMT success and failure groups, but these features were incapable of predicting the aortic growth rate. SSM shape features showed superior results in growth rate prediction compared to conventional features. Using multiple linear regression, the conventional, PCA, and PLS shape features resulted in root mean square errors (RMSE) of 1.23, 0.85, and 0.84 mm/year, respectively, in leave-one-out cross-validations. Nonlinear support vector regression (SVR) led to improved RMSE of 0.99, 0.54, and 0.43 mm/year, for the conventional, PCA, and PLS features, respectively. CONCLUSION: Size-related shape features of the earliest scan were correlated with OMT failure but led to large errors in the prediction of the aortic growth rate. SSM features in combination with nonlinear regression could be a promising avenue to predict the aortic growth rate.

Cannabidiol protects against acute aortic dissection by inhibiting macrophage infiltration and PMAIP1-induced vascular smooth muscle cell apoptosis.

Acute aortic dissection (AAD) progresses rapidly and is associated with high mortality; therefore, there remains an urgent need for pharmacological agents that can protect against AAD. Herein, we examined the therapeutic effects of cannabidiol (CBD) in AAD by establishing a suitable mouse model. In addition, we performed human AAD single-cell RNA sequencing and mouse AAD bulk RNA sequencing to elucidate the potential underlying mechanism of CBD. Pathological assays and in vitro studies were performed to verify the results of the bioinformatic analysis and explore the pharmacological function of CBD. In a ß-aminopropionitrile (BAPN)-induced AAD mouse model, CBD reduced AAD-associated morbidity and mortality, alleviated abnormal enlargement of the ascending aorta and aortic arch, and suppressed macrophage infiltration and vascular smooth muscle cell (VSMC) apoptosis. Bioinformatic analysis revealed that the pro-apoptotic gene PMAIP1 was highly expressed in human and mouse AAD samples, and CBD could inhibit Pmaip1 expression in AAD mice. Using human aortic VSMCs (HAVSMCs) co-cultured with M1 macrophages, we revealed that CBD alleviated HAVSMCs mitochondrial-dependent apoptosis by suppressing the BAPN-induced overexpression of PMAIP1 in M1 macrophages. PMAIP1 potentially mediates HAVSMCs apoptosis by regulating Bax and Bcl2 expression. Accordingly, CBD reduced AAD-associated morbidity and mortality and mitigated the progression of AAD in a mouse model. The CBD-induced effects were potentially mediated by suppressing macrophage infiltration and PMAIP1 (primarily expressed in macrophages)-induced VSMC apoptosis. Our findings offer novel insights into M1 macrophages and HAVSMCs interaction during AAD progression, highlighting the potential of CBD as a therapeutic candidate for AAD treatment.

A proteome-wide screen identifies the calcium binding proteins, S100A8/S100A9, as clinically relevant therapeutic targets in aortic dissection.

Aortic dissection (AD) is a fatal cardiovascular disease with limited pharmacotherapies. To discover novel therapeutic targets for AD, the present study was conducted on ascending aorta samples from AD patients versus those from control subjects using proteomic analysis. Integrated proteomic data analysis identified S100 calcium-binding proteins A8 and A9 (S100A8/A9) as new therapeutic targets for AD. As assessed by ELISA, the circulating levels of S100A8/A9 were elevated in AD patients. In addition, we validated the upregulation of S100A8/A9 in a mouse model of AD. In vitro and in vivo studies substantiated that S100A8/A9, as danger-associated molecular pattern molecules, promotes the smooth muscle cells phenotypic switch by inhibiting serum response factor (SRF) activity but elevating NF-κB dependent inflammatory response. Depletion of S100A8/A9 attenuates the occurrence and development of AD. As a proof of concept, we tested the safety and efficacy of pharmacological inhibition of S100A8/A9 by ABR-25757 (paquinimod) in a mouse model of AD. We observed that ABR-25757 ameliorated the incidence of rupture and improved elastin morphology associated with AD. Further single-cell RNA sequencing disclosed that the phenotypic switch of vascular smooth muscle cells (VSMCs) and inflammatory response pathways were responsible for ABR-25757-mediated protection against AD. Thus, this study reveals the regulatory mechanism of S100A8/A9 in AD and offers a potential therapeutic avenue to treat AD by targeting S100A8/A9.

Effect of TEVAR Combined with Drugs and Drug Therapy Alone on the Efficacy and Safety of Stable Standford B Aortic Dissection.

Objective: Stanford type B aortic dissection is a condition in which the intima of the aorta tears, and TEVAR is an interventional treatment to manage this dissection through intimal repair. To evaluate the medium-term clinical efficacy of endovascular repair (TEVAR) for Aortic dissection and drug Conservative management for Stanford B Aortic dissection aneurysms and further explore whether the former is superior to drug Conservative management in the medium-term efficacy. Methods: The clinical data of 70 patients with stable Standford type B Aortic dissection admitted to our hospital from March 2016 to March 2020 were retrospectively analyzed. They were divided into the treatment group (n = 47) and the control group (n = 23). The control group patients were treated solely with medication, while the treatment group patients were treated with TEVAR on the basis of the control group patients. The treatment efficacy and safety of the two groups of patients were compared and analyzed. All patients will be followed up once a month for 12 months after discharge and every 2 months thereafter (for a total of 3 years). Results: The findings highlight the need to carefully weigh the benefits and harms in the treatment of Stanford type B aortic dissection, especially when considering TEVAR surgery. Future research should focus on reducing postoperative complications to optimize treatment strategies and improve overall patient outcomes.TEVAR surgery significantly reduces hospital mortality, but is also associated with significantly increased postoperative complications, emphasizing the complexity of treatment decisions. This finding provides critical information about weighing the risks and survival benefits of surgery, helping medical teams and patients make informed treatment choices. The hospital mortality rate of patients in the treatment group was 12.77%, while the hospital mortality rate of patients in the control group was 21.74%. The difference between the two groups was statistically significant (P < .05). The incidence of postoperative complications in the treatment group was 23.40%, while the control group did not experience any major complications. The difference between the two groups was statistically significant (P < .05). The mortality rate of patients in the treatment group within 30 days of discharge was 0%, while the mortality rate of patients in the control group within 30 days of discharge was 11.11%. The difference between the two groups was statistically significant (P < .05). The Kaplan Meier curve showed that the survival rates at 3 years of the control and treatment groups were 56.52% and 95.12%, respectively. The log-rank test showed a statistical difference between the two groups. Univariate and multivariate regression analysis showed that postoperative neurological complications (HR = 32.41; P = .00) and preoperative Aortic valve regurgitation (HR = 3.91; P = .00) were risk factors for medium-term death. Conclusion: The TEVAR combination drug is a safe and effective treatment for stable Stanford B Aortic dissection. It can reduce mortality. Compared with drug treatment, it has obvious advantages in medium-term treatment effects. Early rising for high-risk patients can make them have better long-term outcomes. Limitations of the study include its retrospective nature and the use of data from only a single medical center, which may limit the external generalizability of the results.

Epigenomics in aortic dissection: From mechanism to therapeutics.

Aortic dissection (AD) has an unfavorable prognosis. It requires early diagnosis, appropriate treatment strategies, and suspicion to recognize symptoms; thus, it is commonly described as an acute aortic emergency. The clinical manifestations of painless AD are complex and variable. However, there is no effective treatment to prevent the progression of AD. Therefore, study of the molecular targets and mechanisms of AD to enable prevention or early intervention is particularly important. Although multiple gene mutations have been proposed as linked to AD development, evidence that multiple epigenetic elements are strongly associated is steadily increasing. These epigenetic processes include DNA methylation, N6-methyladenosine, histone modification, non-histone posttranslational modification, and non-coding RNAs (ncRNAs). Among these processes, resveratrol targeting Sirtuin 1 (SIRT1), 5-azacytidine (5azaC) targeting DNA methyltransferase (DNMT), and vitamin C targeting ten-eleven translocation 2 (Tet2) showed unique advantages in improving AD and vascular dysfunction. Finally, we explored potential epigenetic drugs and diagnostic methods for AD, which might provide options for the future.

piRNA-823 is a novel potential therapeutic target in aortic dissection.

Aortic dissection (AD) presents a medical challenge for clinicians. Here, to determine the role of a novel small non-coding piRNA-823 (piR-823) in AD, murine and human aorta from patients with AD were used. A high expression levels of piR-823 were found in patients with AD. Using performed loss- and gain-of-function assays in vitro and in vivo, we explore the regulatory effect of piR-823 on vascular smooth muscle cells (VSMCs) and AD. piR-823 obviously facilitates the proliferation, migration, and phenotypic transformation of VSMCs with or without nicotine treatment. piR-823 directly binds and suppresses histone deacetylase 1 (HDAC1) expression, and regulates the acetylation of histone 3 (H3) via H3K9ac and H3K27ac, eventually, VSMC functions and AD. To consolidate our findings, AD murine model was performed, and we observed that piR-823 antagomir strongly inhibited the pathogenesis of AD through regulating vascular remodeling. Thus, our study finds a potential target for the prevention and treatment strategy for nicotine-induced AD.

Senkyunolide I ameliorates thoracic aortic aneurysm and dissection in mice via inhibiting the oxidative stress and apoptosis of endothelial cells.

BACKGROUND: Thoracic aortic aneurysm and aortic dissection (TAAD) is one of the most fatal cardiovascular diseases. Senkyunolide I (SEI) is a component of traditional Chinese medicine with remarkable anti-inflammatory properties and exhibits remarkable protective effects, but its impact on TAAD remains unclear. Our study aimed to explore the role of SEI in a murine model of TAAD and further explore the immunopharmacological mechanism. METHODS AND MATERIALS: The in vivo model were assessed using echocardiography, gross anatomy, and tissue staining. Western blot and immunofluorescence were performed to evaluate the effects of SEI in vivo and in vitro. A SEI solution injection containing 1 % dimethyl sulfoxide (DMSO) was administered intraperitoneally to the TAAD model group, while a normal saline injection comprising 1 % DMSO was administered to the sham group. RESULTS: SEI prevented TAAD formation induced by BAPN/Ang II and reduced the TAAD incidence in mice. SEI treatment significantly inhibited the degradation of collagen and elastin fibers in the extracellular matrix. Furthermore, it reduced the expression of inflammatory factors in the aortic intima. Western blot analysis revealed that SEI-treated mice showed a significant decrease in apoptosis-related protein levels in the aorta compared with the TAAD group. PI3K, Akt, and mTOR in the SEI treatment group were significantly lower than in the model group. SEI could also attenuate H2O2-induced Human umbilical vein endothelial cells (HUVECs) damage and reverse the decline in migrant cells. The apoptosis of HUVECs was considerably reduced by the SEI treatment. CONCLUSIONS: Conclusively, SEI may alleviate the progression of TAAD by suppressing the PI3K/Akt/NF-κB signaling pathway. The SEI's ability to inhibit inflammation and oxidative stress opens the way to restore the function of endothelial cells and vascular homeostasis, and thus to provide novel and promising options for the treatment of TAAD patients.

Does intensive blood pressure control benefit type B aortic dissection patients who undergoing surgical repair?

OBJECTIVES: The aim of this research is to determine the optimum blood pressure (BP) control goal for hypertensive type B aortic dissection (TBAD) patients undergoing surgery. METHODS: Between January 2019 and April 2021, 259 hypertensive TBAD patients undergoing surgery were included in the research. 98 patients received intensive BP control with a target of systolic BP (SBP) < 120 mmHg, and 161 received standard BP control targeting SBP between 120 and 140 mmHg. Clinical data from two groups were compared. RESULTS: Patients who received intensive BP control experienced a significantly higher incidence of acute kidney injury (AKI) postoperatively (21/98, 21.4% vs 14/161, 8.7%, p = 0.004). The intensive group took more anti-hypertensive drugs per day compared with the standard group (1.9 vs 1.5, p < 0.001). Triple-drug combination treatment was more frequent in the intensive group (38.8% vs 14.3%, p < 0.001), as were angiotensin-converting-enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB; 67.3% vs 44.7%, p 0.001), and thiazide-like diuretic (44.9% vs 18.0%, p < 0.001). CONCLUSIONS: Intensive BP control treatment increases the incidence of AKI and raises the utilization of the anti-hypertensive drug, but did not reduce the operative mortality and late mortality in TBAD patients undergoing surgical repair.

Pharmacological treatment in patients with aortic dissection.

OBJECTIVES: To describe medical management in aortic dissection (AD) and to analyse the possible associations between antihypertensive, antithrombotic, anticoagulant and statin agents, respectively, and long-term survival. METHODS: From Swedish medical registers, all patients diagnosed with AD in 2006-2015 were identified. Filled prescriptions prior to admission and within 1 year from discharge in patients discharged and alive at 30 days were registered. Associations between pharmacological treatment and long-term survival were analysed using Cox proportional hazards models. RESULTS: Of 3951 patients hospitalised with acute AD, 3046 (77%) were discharged and alive at 30 days. In hospitalised patients, mean age was 66 years (SD 13), and 36% (n=1098) were women. Within 1 year from discharge, 96% (n=2939) had at least one antihypertensive drug. Beta blocker was the most commonly used drug type (90%, n=2741). Statin treatment (47%, n=1418) was associated with higher long-term survival; HR 0.74 (95% CI 0.63 to 0.87, p<0.001). The positive association between statins and long-term survival remained, in subgroup analysis, in medically managed patients (HR 0.72 (95% CI 0.60 to 0.86, p<0.001)), but not in patients undergoing surgical repair (HR 0.82 (95% CI 0.58 to 1.14, p=0.230)). Beta blockers were associated with favourable long-term survival in surgically managed patients (HR 0.58 (95% CI 0.35 to 0.97, p=0.038)) but not in medically managed patients (HR 0.93 (95% CI 0.72 to 1.12, p=0.057)). Neither antiplatelet therapy nor anticoagulants were associated with long-term survival. CONCLUSIONS: Statin treatment was associated with favourable long-term outcome in medically managed AD patients, whereas treatment with beta blocker was associated with higher survival only in surgically managed AD patients. Statin use as well as optimal antihypertensive therapy in the chronic stage of the disease need to be further analysed, preferably in randomised controlled trials.