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Sporadic aortic aneurysm and dissections (AADs) are common vascular diseases that carry a high mortality rate. ADAMTS-4 (a disintegrin-like and metalloproteinase with thrombospondin motifs-4) is a secreted proteinase involved in inflammation and matrix degradation. We previously showed ADAMTS-4 levels were increased in human sporadic descending thoracic AAD (TAAD) samples. Here, we provide evidence that ADAMTS-4 contributes to aortic destruction and sporadic AAD development. In a mouse model of sporadic AAD induced by a high-fat diet and angiotensin II infusion, ADAMTS-4 deficiency ( Adamts-4−/− ) significantly reduced challenge-induced aortic diameter enlargement, aneurysm formation, dissection and aortic rupture. Aortas in Adamts-4−/− mice showed reduced elastic fibre destruction, versican degradation, macrophage infiltration, and apoptosis. Interestingly, ADAMTS-4 was directly involved in smooth muscle cell (SMC) apoptosis. Under stress, ADAMTS-4 translocated to the nucleus in SMCs, especially in apoptotic SMCs. ADAMTS-4 directly cleaved and degraded poly ADP ribose polymerase-1 (a key molecule in DNA repair and cell survival), leading to SMC apoptosis. Finally, we showed significant ADAMTS-4 expression in aortic tissues from patients with sporadic ascending TAAD, particularly in SMCs. Our findings indicate that ADAMTS-4 induces SMC apoptosis, degrades versican, promotes inflammatory cell infiltration, and thus contributes to sporadic AAD development.

The COVID-19 pandemic exposed racism as a public health crisis embedded in structural processes. Editors of surgical research journals pledged their commitment to improve structure and process through increasing diversity in the peer review and editorial process; however, little benchmarking data are available. A survey of editorial board members from high impact surgical research journals captured self-identified demographics. Analysis of manuscript submissions from 2016 to 2020 compared acceptance for diversity, equity, and inclusion (DEI)-focused manuscripts to overall rates. 25.6% of respondents were female, 2.9% Black, and 3.3% Hispanic. There was variation in the diversity among journals and in the proportion of DEI submissions they attract, but no clear correlation between DEI acceptance rates and board diversity. Diversity among board members reflects underrepresentation of minorities seen among surgeons nationally. Recruitment and retention of younger individuals, representing more diverse backgrounds, may be a strategy for change. DEI publication rates may benefit from calls for increasing DEI scholarship more so than changes to the peer review process. •Assessment of diversity among editorial boards of surgical research journals and analysis of over 41,810 manuscripts.•Respondents: 25.6% female, 2.9% Black/African American, 3.3% Hispanic/Latinx; increasing diversity in younger board members.•28% of respondents self-identified as underrepresented-in-medicine.•Acceptance rates for DEI-related manuscripts exceeded non-DEI manuscripts at all journals.•No clear association between diversity of editorial boards and acceptance rates for DEI.

Thoracic aortopathy is influenced by angiotensin II (AngII) and exhibits regional heterogeneity with the ascending aorta being particularly susceptible. In this region, smooth muscle cells (SMCs) and selected fibroblasts originate from the second heart field (SHF) and cardiac neural crest (CNC). While our previous study revealed a critical role of SHF-derived cells in AngII-mediated aortopathy, the contribution of CNC-derived cells remains unclear. To investigate lineage-specific responses to AngII, Mef2c-Cre R26RmT/mG mice were infused with AngII. Ascending aortas were harvested at baseline or after 3 days of infusion, representing the prepathological phase. Cells were sorted based on their embryonic origins and single-cell RNA sequencing was performed. Transcriptomic analysis revealed significant changes in both SHF- and nSHF-derived SMCs following short-term AngII infusion, although differences between the origins were modest. Similarly, fibroblast transcriptomes exhibited notable changes, yet lineage-specific differences remained modest, except for a newly identified fibroblast subpopulation where extracellular matrix-related genes such as Eln and Col3a1 were downregulated in SHF-derived fibroblasts compared to nSHF-derived fibroblasts. These findings suggest that while fibroblasts in the new subcluster exhibit lineage-specific extracellular matrix-related differences, overall transcriptomic variations between SHF- and nSHF-derived cells in response to AngII remain modest during the prepathological phase of AngII-induced thoracic aortopathy.

Activation of the AMPK-FOXO3 Pathway Reduces Fatty Acid–Induced Increase in Intracellular Reactive Oxygen Species by Upregulating Thioredoxin Xiao-Nan Li 1 , 2 , 3 , Jun Song 1 , 2 , 3 , Lin Zhang 1 , 2 , Scott A. LeMaire 1 , 2 , Xiaoyang Hou 1 , 2 , 3 , Cheng Zhang 1 , 2 , 3 , Joseph S. Coselli 1 , 2 , Li Chen 3 , Xing Li Wang 1 , 2 , Yun Zhang 3 and Ying H. Shen 1 , 2 1 Division of Cardiothoracic Surgery, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas; 2 Texas Heart Institute at St. Luke's Episcopal Hospital, Houston, Texas; 3 Qilu Hospital, Shandong University, Jinan, Shandong, China. Corresponding authors: Yun Zhang, zhangyun{at}sdu.edu.cn , and Ying H. Shen, hyshen{at}bcm.edu . X.-N.L. and J.S. contributed equally to this study. Abstract OBJECTIVE Oxidative stress induced by free fatty acids contributes to the development of cardiovascular diseases in patients with metabolic syndrome. Reducing oxidative stress may attenuate these pathogenic processes. Activation of AMP-activated protein kinase (AMPK) has been reported to reduce intracellular reactive oxygen species (ROS) levels. The thioredoxin (Trx) system is a major antioxidant system. In this study, we investigated the mechanisms involved in the AMPK-mediated regulation of Trx expression and the reduction of intracellular ROS levels. RESEARCH DESIGN AND METHODS We observed that activation of AMPK by 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) significantly reduced ROS levels induced by palmitic acid in human aortic endothelial cells. Activation of AMPK increased expression of the antioxidant Trx, which mediated the ROS reduction. RT-PCR showed that AMPK regulated Trx at the transcriptional level. RESULTS Forkhead transcription factor 3 (FOXO3) was identified as the target transcription factor involved in the upregulation of Trx expression. FOXO3 bound to the Trx promoter, recruited the histone acetylase p300 to the Trx promoter, and formed a transcription activator complex, which was enhanced by AICAR treatment. AMPK activated FOXO3 by promoting its nuclear translocation. We further showed that AICAR injection increased the expression of Trx and decreased ROS production in the aortic wall of ApoE−/− mice fed a high-fat diet. CONCLUSIONS These results suggest that activation of the AMPK-FOXO3 pathway reduces ROS levels by inducing Trx expression. Thus, the AMPK-FOXO3-Trx axis may be an important defense mechanism against excessive ROS production induced by metabolic stress and could be a therapeutic target in treating cardiovascular diseases in metabolic syndrome. Footnotes The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Received October 31, 2008. Accepted June 28, 2009. © 2009 by the American Diabetes Association.

Endothelial cells (ECs) are vital for blood vessel integrity and have roles in maintaining normal vascular function, healing after injury, and vascular dysfunction. Extensive phenotypic heterogeneity has been observed among ECs of different types of blood vessels in the normal and diseased vascular wall. Although ECs with different phenotypes can share common functions, each has unique features that may dictate a fine-tuned role in vascular health and disease. Recent studies performed with single-cell technology have generated powerful information that has significantly improved our understanding of EC biology. Here, we summarize a variety of EC types, states, and phenotypes recently identified by using new, increasingly precise techniques in transcriptome analysis.

Dianna Milewicz and colleagues report a genome-wide association study of sporadic thoracic aortic aneurysm and dissection. They identify an associated locus on 15q21 spanning the FBN1 gene. Although thoracic aortic aneurysms and dissections (TAAD) can be inherited as a single-gene disorder, the genetic predisposition in the majority of affected people is poorly understood. In a multistage genome-wide association study (GWAS), we compared 765 individuals who had sporadic TAAD (STAAD) with 874 controls and identified common SNPs at a 15q21.1 locus that were associated with STAAD, with odds ratios of 1.6–1.8 that achieved genome-wide significance. We followed up 107 SNPs associated with STAAD with P < 1 × 10 −5 in the region, in two separate STAAD cohorts. The associated SNPs fall into a large region of linkage disequilibrium encompassing FBN1 , which encodes fibrillin-1. FBN1 mutations cause Marfan syndrome, whose major cardiovascular complication is TAAD. This study shows that common genetic variants at 15q21.1 that probably act via FBN1 are associated with STAAD, suggesting a common pathogenesis of aortic disease in Marfan syndrome and STAAD.

Chromosomal deletions or reciprocal duplications of the 16p13.1 region have been implicated in a variety of neuropsychiatric disorders such as autism, schizophrenia, epilepsies, and attention-deficit hyperactivity disorder (ADHD). In this study, we investigated the association of recurrent genomic copy number variants (CNVs) with thoracic aortic aneurysms and dissections (TAAD). By using SNP arrays to screen and comparative genomic hybridization microarrays to validate, we identified 16p13.1 duplications in 8 out of 765 patients of European descent with adult-onset TAAD compared with 4 of 4,569 controls matched for ethnicity (P = 5.0 × 10⁻⁵, OR = 12.2). The findings were replicated in an independent cohort of 467 patients of European descent with TAAD (P = 0.005, OR = 14.7). Patients with 16p13.1 duplications were more likely to harbor a second rare CNV (P = 0.012) and to present with aortic dissections (P = 0.010) than patients without duplications. Duplications of 16p13.1 were identified in 2 of 130 patients with familial TAAD, but the duplications did not segregate with TAAD in the families. MYH11, a gene known to predispose to TAAD, lies in the duplicated region of 16p13.1, and increased MYH11 expression was found in aortic tissues from TAAD patients with 16p13.1 duplications compared with control aortas. These data suggest chromosome 16p13.1 duplications confer a risk for TAAD in addition to the established risk for neuropsychiatric disorders. It also indicates that recurrent CNVs may predispose to disorders involving more than one organ system, an observation critical to the understanding of the role of recurrent CNVs in human disease and a finding that may be common to other recurrent CNVs involving multiple genes.

“Academic surgeon” describes a member of a medical school department of surgery, but this term does not fully define the important role of such physician-scientists in advancing surgical science through translational research and innovation. The curriculum vitae and self-descriptive vignettes of the records of achievement of seven surgeons possessing documented records of academic leadership, innovation, and dissemination of knowledge were reviewed. Out analysis yielded seven attributes of the archetypal academic surgeon: 1) identifies complex clinical problems ignored or thought unsolvable by others, 2) becomes an expert, 3) innovates to advance treatment, 4) observes outcomes to further improve and innovate, 5) disseminates knowledge and expertise, 6) asks important questions to further improve care, and 7) trains the next generation of surgeons and scientists. Although alternative pathways to innovation and academic contribution also exist, the academic surgeon typically devotes years of careful observation, analysis, and iterative investigation to identify and solve challenging or unexplored clinical problems, ideally leverages resources available in academic medical centers to support these endeavors.

Free Fatty Acids Inhibit Insulin Signaling–Stimulated Endothelial Nitric Oxide Synthase Activation Through Upregulating PTEN or Inhibiting Akt Kinase Xing Li Wang , Lin Zhang , Keith Youker , Ming-Xiang Zhang , Jian Wang , Scott A. LeMaire , Joseph S. Coselli and Ying H. Shen From the Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas Address correspondence and reprint requests to Dr. Ying. H. Shen MS NAB 2010, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030. E-mail: hyshen{at}bcm.edu ; or Dr. Xing Li Wang, MS NAB 2010, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030. E-mail: xlwang{at}bcm.edu Abstract In metabolic syndrome, a systemic deregulation of the insulin pathway leads to a combined deregulation of insulin-regulated metabolism and cardiovascular functions. Free fatty acids (FFAs), which are increased in metabolic syndrome, inhibit insulin signaling and induce metabolic insulin resistance. This study was designed to examine FFAs’ effects on vascular insulin signaling and endothelial nitric oxide (NO) synthase (eNOS) activation in endothelial cells. We showed that FFAs inhibited insulin signaling and eNOS activation through different mechanisms. While linoleic acid inhibited Akt-mediated eNOS phosphorylation, palmitic acid appeared to affect the upstream signaling. Upregulation of PTEN (phosphatase and tensin homolog deleted on chromosome 10) activity and transcription by palmitic acid mediated the inhibitory effects on insulin signaling. We further found that activated stress signaling p38, but not Jun NH 2 -terminal kinase, was involved in PTEN upregulation. The p38 target transcriptional factor activating transcription factor (ATF)-2 bound to the PTEN promoter, which was increased by palmitic acid treatment. In summary, both palmitic acid and linoleic acid exert inhibitory effect on insulin signaling and eNOS activation in endothelial cells. Palmitic acid inhibits insulin signaling by promoting PTEN activity and its transcription through p38 and its downstream transcription factor ATF-2. Our findings suggest that FFA-mediated inhibition of vascular insulin signaling and eNOS activation may contribute to cardiovascular diseases in metabolic syndrome. ATF, activating transcription factor CREBP, cAMP-responsive element–binding protein EBM, endothelial cell basic medium eNOS, endothelial nitric oxide synthase FFA, free fatty acid HAEC, human aortic endothelial cell JNK, Jun NH2-terminal kinase PDK, phosphoinositide-dependent kinase PI, phosphatidylinositol PIP3, phosphatidylinositol-3.4,5-triphosphate Footnotes The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Accepted May 22, 2006. Received December 5, 2005. DIABETES

Thoracic aortic dissection (TAD) is the progressive separation of the layers of the thoracic aortic wall; this condition is strongly related to excessive dilatation of the aorta and is associated with very high mortality. The authors of this article present an in-depth review of the incidence, demographic distribution, and factors associated with TAD and related thoracic aortic syndromes, as well as a discussion of the challenges involved in assessing the epidemiology of these conditions. Thoracic aortic dissection (TAD) is estimated to occur at a rate of 3–4 cases per 100,000 persons per year and is associated with a high mortality. Reported rates are probably underestimates of the true incidence of TAD because of difficulties in diagnosis. The incidence of TAD appears to have been increasing over time. TAD is most common in men and older individuals. Aortic dilatation is a well-established risk factor for TAD but is not a prerequisite; most ascending aortic dissections occur when aortic diameter is <5.5 cm. Although atherosclerosis and typical cardiovascular risk factors, such as hypertension and smoking, are associated with TAD, evidence supporting their direct causal role is lacking. Notably, diabetes mellitus is remarkably uncommon in patients with TAD. Other risk factors for TAD include inflammatory diseases, iatrogenic aortic injury, and drug use. Congenital cardiovascular defects, such as bicuspid aortic valve, and certain genetic syndromes, such as Marfan syndrome, are the genetic factors most commonly associated with TAD. Specific nonsyndromic genetic mutations in families and single nucleotide polymorphisms have also been identified as possible risk factors for TAD. Key Points The incidence of thoracic aortic dissection is probably underestimated (3–4 cases per 100,000 persons per year) and seems to be increasing, in part because of improvements in diagnostic imaging Thoracic aortic dissection is a major cause of mortality in the general population, with rupture being the most common cause of death Although aortic dilatation is a well-established risk factor for thoracic aortic dissection, most ascending aortic dissections occur when aortic diameter is <5.5 cm Male sex and older age are risk factors for thoracic aortic dissection Although atherosclerosis and typical cardiovascular risk factors are associated with thoracic aortic dissection, evidence supporting their direct causal role is lacking, and diabetes is remarkably uncommon in these patients Congenital cardiovascular defects, such as bicuspid aortic valve, and genetic syndromes, such as Marfan syndrome, are the genetic factors most commonly associated with thoracic aortic dissection