Matricellular protein CCN3 mitigates abdominal aortic aneurysm

Abdominal aortic aneurysm (AAA) is a major cause of morbidity and mortality; however, the mechanisms that are involved in disease initiation and progression are incompletely understood. Extracellular matrix proteins play an integral role in modulating vascular homeostasis in health and disease. Here, we determined that the expression of the matricellular protein CCN3 is strongly reduced in rodent AAA models, including angiotensin II-induced AAA and elastase perfusion-stimulated AAA. CCN3 levels were also reduced in human AAA biopsies compared with those in controls. In murine models of induced AAA, germline deletion of Ccn3 resulted in severe phenotypes characterized by elastin fragmentation, vessel dilation, vascular inflammation, dissection, heightened ROS generation, and smooth muscle cell loss. Conversely, overexpression of CCN3 mitigated both elastase- and angiotensin II-induced AAA formation in mice. BM transplantation experiments suggested that the AAA phenotype of CCN3-deficient mice is intrinsic to the vasculature, as AAA was not exacerbated in WT animals that received CCN3-deficient BM and WT BM did not reduce AAA severity in CCN3-deficient mice. Genetic and pharmacological approaches implicated the ERK1/2 pathway as a critical regulator of CCN3-dependent AAA development. Together, these results demonstrate that CCN3 is a nodal regulator in AAA biology and identify CCN3 as a potential therapeutic target for vascular disease

Glucocorticoids promote structural and functional maturation of foetal cardiomyocytes: a role for PGC-1α

Glucocorticoid levels rise dramatically in late gestation to mature foetal organs in readiness for postnatal life. Immature heart function may compromise survival. Cardiomyocyte glucocorticoid receptor (GR) is required for the structural and functional maturation of the foetal heart in vivo, yet the molecular mechanisms are largely unknown. Here we asked if GR activation in foetal cardiomyocytes in vitro elicits similar maturational changes. We show that physiologically relevant glucocorticoid levels improve contractility of primary-mouse-foetal cardiomyocytes, promote Z-disc assembly and the appearance of mature myofibrils, and increase mitochondrial activity. Genes induced in vitro mimic those induced in vivo and include PGC-1α, a critical regulator of cardiac mitochondrial capacity. SiRNA-mediated abrogation of the glucocorticoid induction of PGC-1α in vitro abolished the effect of glucocorticoid on myofibril structure and mitochondrial oxygen consumption. Using RNA sequencing we identified a number of transcriptional regulators, including PGC-1α, induced as primary targets of GR in foetal cardiomyocytes. These data demonstrate that PGC-1α is a key mediator of glucocorticoid-induced maturation of foetal cardiomyocyte structure and identify other candidate transcriptional regulators that may play critical roles in the transition of the foetal to neonatal heart

Efficacy of bortezomib therapy for extramedullary relapse of myeloma after autologous and non-myeloablative allogeneic transplantation.

We report the successful use of bortezomib to treat a patient with multiple myeloma (MM) who had extramedullary relapse (paraspinal and thoracic masses and multiple cranial nerve palsy) after autologous and non-myeloablative allogeneic hematopoietic stem cell transplantation (HSCT)

Acute visual loss and chorioretinal infarctionafter photodynamic therapy combined withintravitreal triamcinolone

.Abstract PURPOSE: To report acute visual loss associated with dynamic vascular changes after photodynamic therapy (PDT) combined with intravitreal triamcinolone (IVTA) for the treatment of occult choroidal neovascularization (CNV). METHODS: An 86-year-old woman complained of visual loss in her left eye. Angiographic examination showed a serous pigment epithelium detachment complicated by CNV. She underwent combined treatment with IVTA (4 mg) followed by standard verteporfin PDT administered after a 5-day interval. RESULTS: The patient developed vision loss 1 day after PDT. Ophthalmoscopic examination disclosed an acute serous neurosensory retinal detachment. Fluorescein angiography showed a large area of early hypofluorescence in correspondence to and extending beyond the photodynamic spot. Neurosensory retinal vessels involvement with dilation of the retinal arterioles and capillary nonperfusion were also revealed. Indocyanine green angiography showed choroidal infarction within the collateral choroid included in the area of light exposure, with associated nonperfusion of medium and large choroidal vessels being revealed. Five days after PDT, spontaneous severe bleeding with breakthrough into the vitreous occurred, in addition to an RPE tear. CONCLUSIONS: Acute loss of vision associated with vascular changes in retinal and choroidal circulation represents an uncommon but serious complication following combined PDT and IVTA. These risks should be carefully considered in combination therapies

Localization and expression of CHST6 and keratan sulfate proteoglycans in the human cornea.

Macular corneal dystrophy (MCD; OMIM 217800) is a rare autosomal recessive inherited disorder causedby mutations in the carbohydrate sulfotransferase 6 (CHST6) and characterised by the presence ofunsulfated keratan sulfate proteoglycans (KSPGs) forming abnormal deposits that eventually lead to visualimpairment. The aim of this study is to understand in which corneal cells CHST6 and KSPGs are expressedand exert their activity. Expression and localization of CHST6, keratan sulfate (KS) and proteins of theKSPGs, such as mimecan and lumican, were assessed both in human cornea sections and in culturedprimary keratinocytes (n¼3) and keratocytes (n¼4). Immunohistochemistry, semiquantitative RT-PCR, insitu RNA hybridization and HPLC analysis of glycosaminoglycans were used as read-outs. In human corneasKS was predominantly found in the stroma, but absent, or barely detectable, in the corneal epithelium.A similar pattern of distribution was found in the epidermis, with KS mainly localised in the derma. Asexpected, in the cornea CHST6 (the gene encoding the enzyme which transfers sulfate residues ontoKSPGs) was found expressed in the suprabasal, but not basal, layers of the epithelium, in the stroma and inthe endothelium. Analyses of KS by means of HPLC showed that in vitro cultured stromal keratocytesexpress and secrete more KS than keratinocytes, thus mirroring results observed in vivo. Similarlyexpression of the CHST6 gene and of KS proteoglycans such as mimecan, lumican is limited to stromalkeratocytes. Unlike keratocytes, corneal keratinocytes do not synthesize mimecan or lumican, and expressvery little, if none, CHST6. Any drug/gene therapy or surgical intervention aimed at curing this rare geneticdisorder must therefore involve and target stromal keratocytes. If coupled to the accuracy of HPLC-based assay that we developed to determine the amount of KS in serum, our findings could lead to more targetedtherapeutic treatments of the ocular features in MCD patients