Background:The la ribonucleoprotein domain family member 6, LARP6, regulates collagen type 1 mRNA translation. Results: IGF-1 increases LARP6 expression, resulting in increased LARP6-collagen type 1 mRNA complex and collagen synthesis in smooth muscle. Conclusion: IGF-1 enhances collagen fibrillogenesis via induction of LARP6. Significance: This report uncovers a critical mechanism whereby IGF-1 induces a more stable plaque phenotype in atherosclerosis.

We have shown previously that insulin like-growth factor I (IGF-1) suppressed atherosclerosis in Apoe−/− mice and activated endothelial nitric oxide (NO) synthase. To determine whether IGF-1-induced atheroprotection depends on NO, IGF-1- or saline-infused mice were treated with L-NAME, the pan-NO synthase inhibitor or with D-NAME (control). IGF-1 reduced atherosclerosis in both the D-NAME and L-NAME groups suggesting that IGF-1’s anti-atherogenic effect was NO-independent. IGF-1 increased plaque smooth muscle cells, suppressed cell apoptosis and downregulated lipoprotein lipase and these effects were also NO-independent. On the contrary, IGF-1 decreased oxidative stress and suppressed TNF-α levels and these effects were blocked by L-NAME. Thus IGF-1’s anti-oxidant effect is dependent on its ability to increase NO but is distinct from its anti-atherosclerotic effect which is NO-independent.

Mutations in the COMP, COL9A1, COL9A2, COL9A3, MATN3, and SLC26A2 genes cause approximately 70% of multiple epiphyseal dysplasia (MED) cases. The genetic changes involved in the etiology of the remaining cases are still unknown, suggesting that other genes contribute to MED development. Our goal was to identify a mutation causing an autosomal dominant form of MED in a large multigenerational family. Initially, we excluded all genes known to be associated with autosomal dominant MED by using microsatellite and SNP markers. Follow-up with wholeexome sequencing analysis revealed a mutation c.2032G>A (p.Gly678Arg) in the COL2A1 gene (NCBI Reference Sequence: NM_001844.4), which co-segregated with the disease phenotype in this family, manifested by severe hip dysplasia and osteoarthritis. One of the affected family members had a double-layered patella, which is frequently seen in patients with autosomal recessive MED caused by DTDST mutations and sporadically in the dominant form of MED caused by COL9A2 defect. K E Y W O R D Sdouble-layered patella, multiple epiphyseal dysplasia, novel mutation in COL2A1

Objectives This study sought to determine if metoprolol succinate ER (MET), and nebivolol (NEB), a β1-AR with increased bioavailability of nitric oxide (NO), would have differing effects on plasma asymmetric dimethylarginine concentration in hypertensives. Background It was hypothesized that NEB, a β1-AR antagonist and β3-AR agonist with NO- releasing properties and MET, only a β1-AR antagonist, would have different effects on plasma ADMA concentration. Methods Forty-one hypertensive subjects randomly received either 50 mg of MET (n = 19) or 5 mg of NEB (n = 22) for 4 weeks followed by 100 mg MET and 10 mg NEB for 4 weeks. ADMA and IGF-1 were measured by ELISA kit; endothelial progenitor cells were estimated using fluorescein-labeled monoclonal antibody to KDR and CD133 receptors; arterial augmentation index was measured by radial tonometry. Results Baseline systolic/diastolic blood pressure was 155.1 ± 18.7/85.3 ± 12.5 mm Hg for MET subjects and 157.6 ± 20.7/87.1 ± 14.0 mm Hg for NEB subjects. Baseline ADMA was 0.32 ± 0.123 μmol/L in the MET group and 0.4035 ± 0.1378 in the NEB group. ADMA increased 44.78% and 72% in the MET group at weeks 4 and 8 (p < 0.05 for both), respectively, without increase in the NEB group. At week 8 augmentation index was increased in the MET group (p<0.05). IGF-1 and EPC were unchanged by treatment. Conclusions Plasma ADMA and augmentation index are increased in a dose-dependent fashion by MET but not with NEB.

Since the advent of endovascular aortic repair (EVAR) nearly three decades ago, there has been a paradigm shift in the treatment of the abdominal aortic aneurysm (AAA) to favor EVAR due to its reduced operative mortality, less invasive nature, and faster recovery times. However, more recently there has been an accumulation of data from large meta-analyses and randomized clinical trials revealing that EVAR has no survival benefit after approximately 2 years and is associated with substantially higher rates of reintervention and aneurysm rupture in the long term. These findings call into question the durability of EVAR compared with open aortic repair and emphasize the need for surgeons to remain competent with open aortic surgery in the modern era. This article will provide comprehensive review of a large body of literature comparing endovascular repair to open aortic surgery for the management of AAAs, and it will offer an overview of the open surgical repair technique for AAAs.

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Background: Legionellosis in the setting of preexisting endovascular prosthetic graft may represent a Coxiella burnetii infection as antibody cross-reactivity exists. Methods:We present a 63-year-old man status-post endovascular aneurysm repair (EVAR) with a history of ankylosing spondylitis, COPD, asthma, CAD with myocardial infarction, HTN, and HLD who presented with clinical symptoms of legionellosis. This was confirmed with a positive urine antigen test.Results: He completed a 21-day course of azithromycin for Legionella.His leukocytosis and liver function tests normalized, but he had continued lethargy and a persistently elevated erythrocyte sedimentation rate and Creactive protein. Imaging showed a radiographically infected EVAR graft (placed 10 months prior). The EVAR was explanted and the operating room cultures grew C. burnetii. Prolonged hydroxychloroquine and doxycycline therapy were required for vascular manifestations of Coxiella as azithromycin provides inappropriate coverage.Conclusions: Persistent constitutional symptoms in the setting of an EVAR require expanded investigation, especially in the setting of legionellosis.

In arterial remodeling, smooth muscle cell (SMC) loss of contractile phenotype and increased proliferation may result in vessel stenosis or a greater propensity for aneurysm formation and rupture. Here, we show that insulin-like growth factor-1 (IGF-1) induces contractile phenotype of human aortic SMCs in culture, and we investigate the signal transduction mechanisms responsible using Western blot. IGF-1 induced a dose-dependent increase in protein expression of the contractile marker alpha-actin (αSMA) (2.4-fold-increase, 18hr serum-free vs. 100ng/mL IGF-1, p<0.001), without affecting ACTA2 mRNA levels (real time RT-PCR, 4-18 hrs, p=NS). Moreover, IGF-1 upregulation of αSMA expression was not blocked by actinomycin D but was inhibited by cycloheximide (p<0.01), thereby demonstrating posttranscriptional and translation-dependent regulation by IGF-1, respectively. Furthermore, IGF-1-induced αSMA expression was not blocked with PD98059 or rapamycin (50 or 100 nM), but was completely inhibited with LY294002 (p<0.001), 500 nM rapamycin (p<0.01), and Torin 1, thereby indicating that the ability of IGF-1 to induce SMC differentiation was independent of Erk1/2 and mTORC1, but dependent on PI3K- and mTORC2-signaling. A prolyl-hydroxylase-inhibitor (EDHB) or a function-blocking antibody against the α2β1 integrin (BHA2.1) had no effect on IGF-1-upregulation of αSMA expression. However, both EDHB and BHA2.1 significantly attenuated IGF-1-induced expression of the proliferation marker PCNA, thereby suggesting that collagen and the α2β1 integrin promote IGF-1-induced proliferation. Conversely, a blocking antibody against the α5β1 integrin (JBS5) did not block IGF-1-induced PCNA expression but completely inhibited IGF-1 induction of αSMA expression (p<0.01) and abolished IGF-1-induced phosphorylation of a master regulator of cap-dependent protein translation, eukaryotic initiation factor-4E (eIF4E) (p<0.001). Therefore, we concluded that IGF-1 induced αSMA expression via a PI3K/mTORC2/eIF4E translational mechanism that is dependent on the α5β1 integrin. Overall, these findings provide evidence that the α5β1 and α2β1 integrins mediate IGF-1-signaling to govern IGF-1-induced translational regulation of SMC phenotype.