Citations

Background: Spontaneous coronary artery dissection (SCAD) is an uncommon idiopathic disorder predominantly affecting young, otherwise healthy women. Rare familial cases reveal a genetic predisposition to disease. The aim of this study was to identify a novel susceptibility gene for SCAD. Methods: Whole-exome sequencing was performed in a family comprised of 3 affected individuals and filtered to identify rare, predicted deleterious, segregating variants. Immunohistochemical staining was used to evaluate protein expression of the identified candidate gene. The prevalence and spectrum of rare (<0.1%) variants within binding domains was determined by next-generation sequencing or denaturing high-performance liquid chromatography in a sporadic SCAD cohort of 675 unrelated individuals. Results: We identified a rare heterozygous missense variant within a highly conserved β-integrin–binding domain of TLN1 segregating with familial SCAD. TLN1 encodes talin 1—a large cytoplasmic protein of the integrin adhesion complex that links the actin cytoskeleton and extracellular matrix. Consistent with high mRNA expression in arterial tissues, robust immunohistochemical staining of talin 1 was demonstrated in coronary arteries. Nine additional rare heterozygous missense variants in TLN1 were identified in 10 sporadic cases. Incomplete penetrance, suggesting genetic or environmental modifiers of this episodic disorder, was evident in the familial case and 5 individuals with sporadic SCAD from whom parental DNA was available. Conclusions: Our findings reveal TLN1 as a disease-associated gene in familial and sporadic SCAD and, together with abnormal vascular phenotypes reported in animal models of talin 1 disruption, implicate impaired structural integrity of the coronary artery cytoskeleton in SCAD susceptibility.

The possible association between the membrane-associated guanylate kinase with inverted domain structure-1 (MAGI1) and inflammation has been suggested, but the molecular mechanisms underlying this link, especially during atherogenesis, remain unclear. In endothelial cells (ECs) exposed to disturbed flow (d-flow), p90 ribosomal S6 kinase (p90RSK) bound to MAGI1, causing MAGI1-S741 phosphorylation and sentrin/SUMO-specific protease 2 T368 phosphorylation-mediated MAGI1-K931 deSUMOylation. MAGI1-S741 phosphorylation upregulated EC activation via activating Rap1. MAGI1-K931 deSUMOylation induced both nuclear translocation of p90RSK-MAGI1 and ATF-6-MAGI1 complexes, which accelerated EC activation and apoptosis, respectively. Microarray screening revealed key roles for MAGI1 in the endoplasmic reticulum (ER) stress response. In this context, MAGI1 associated with activating transcription factor 6 (ATF-6). MAGI1 expression was upregulated in ECs and macrophages found in atherosclerotic-prone regions of mouse aortas as well as in the colonic epithelia and ECs of patients with inflammatory bowel disease. Further, reduced MAGI1 expression in Magi1 –/+ mice inhibited d-flow–induced atherogenesis. In sum, EC activation and ER stress–mediated apoptosis are regulated in concert by two different types of MAGI1 posttranslational modifications, elucidating attractive drug targets for chronic inflammatory disease, particularly atherosclerosis.

Background: Abdominal fat elevates while lower-body (LB) fat diminishes cardiovascular risk. However, molecular mechanisms differentiating the two fat depots are not completely understood. MicroRNA (miRNA) are important regulators of gene expression with widespread effects on several proteins. Objective: To explore miRNA differences between the two fat depots using unbiased next-generation sequencing (NGS) approach. Methods: Total RNA isolated from paired subcutaneous (sc) fat tissue obtained from abdomen (ABD) and LB (femoral) region of 12 healthy subjects (7 male; age: 27 ± 5 years; BMI: 23.5 ± 3.2 kg/m 2 ) was used to quantify miRNA expression. Body fat distribution was determined using dual-energy X-ray absorptiometry and abdominal computed tomography scans. RNA was prepped using the NEBNext small RNA library prep kit and sequenced using Illumina HiSeq 2000. Raw sequence data were processed using CAP-miRSeq pipeline. miRNA expression between the two depots was evaluated using EdgeR. Relationship between miRNA and regional fat depots were examined using Spearman’s correlation. Adjusted or unadjusted P value <0.05 was considered significant. Results: Using NGS, 383 ± 55 known miRNA with ≥5 raw reads were detected in the study samples. Principal component analysis including all miRNAs showed no any clear separation between ABD or LB fat tissue. However, 37 miRNAs were found to have altered expression in the two depots. miR-196a-5p (log2FC=1.138, p<0.001), miR-146b-5p ( log2FC=1.388, p<0.001), miR-1287 ( log2FC=1.059, p<0.001), miR-1247-5p (1.002, p<0.001), and miR-346 (log2FC =-1.240, p=0.002) were among the top five differentially expressed miRNA in ABD Vs. LB fat. Interestingly, ABD fat tissue expression of miR196a-5p (rho=-0.58, p=0.047) and miR146b-5p (rho=0.76, p=0.004) correlated with visceral fat while miR146b-5p (rho=0.66, p=0.02) and miR1287 (rho=0.79, p=0.002) correlated with ABD sc fat. Conclusions: Several miRNAs are differentially expressed between ABD and LB fat tissue which may partly contribute to depot specific alterations in adipose tissue function and consequent cardiometabolic risk. Furthermore, the associations between miRNA and regional fat depots suggest a functional role of these miRNA in fat distribution.

Background: Interest in facial masculinization surgery is expected to increase as gender-affirming surgery becomes more widely accepted and available. The purpose of this study is to summarize the current literature describing operative techniques in facial masculinization surgery and provide an algorithmic approach to treating this patient population. Methods: PubMed, EMBASE, and Medline databases were queried for literature on operative techniques and outcomes of facial masculinization surgery in transgender and cisgender patients, published through July 2018. Data on patient demographics, follow-up, operative techniques, complications, and outcomes were collected. Results: Fifteen of the 24 identified studies met inclusion criteria. Two studies discussed the outcomes of 7 subjects (6 trans-male and 1 cis-male) who underwent facial masculinization procedures. No objective outcomes were reported in either study; however, subjects were generally satisfied and there were no complications. The remaining studies reviewed operative techniques utilized in the cisgender population. Conclusion: A summary of considerations for each facial anatomic subunit and respective operative techniques for facial masculinization is presented. Current facial masculinization procedures in cisgender patients may be considered in the transgender patient population with favorable outcomes. However, further research is needed on techniques and objective outcome measures of facial masculinization procedures in the transgender population.