Heat shock protein 90 is downregulated in calcific aortic disease

Peer reviewe

Heat shock protein 90 is downregulated in calcific aortic valve disease

Abstract Background Calcific aortic valve disease (CAVD) is an atheroinflammatory process; finally it leads to progressive calcification of the valve. There is no effective pharmacological treatment for CAVD and many of the underlying molecular mechanisms remain unknown. We conducted a proteomic study to reveal novel factors associated with CAVD. Methods We compared aortic valves from patients undergoing valvular replacement surgery due to non-calcified aortic insufficiency (control group, n = 5) to a stenotic group (n = 7) using two-dimensional difference gel electrophoresis (2D-DIGE). Protein spots were identified with mass spectrometry. Western blot and immunohistochemistry were used to validate the results in a separate patient cohort and Ingenuity Pathway Analysis (IPA) was exploited to predict the regulatory network of CAVD. Results We detected an upregulation of complement 9 (C9), serum amyloid P-component (APCS) and transgelin as well as downregulation of heat shock protein (HSP90), protein disulfide isomerase A3 (PDIA3), annexin A2 (ANXA2) and galectin-1 in patients with aortic valve stenosis. The decreased protein expression of HSP90 was confirmed with Western blot. Conclusions We describe here a novel data set of proteomic changes associated with CAVD, including downregulation of the pro-inflammatory cytosolic protein, HSP90

Research priorities for freshwater mussel conservation assessment

Freshwater mussels are declining globally, and effective conservation requires prioritizing research and actions to identify and mitigate threats impacting mussel species. Conservation priorities vary widely, ranging from preventing imminent extinction to maintaining abundant populations. Here, we develop a portfolio of priority research topics for freshwater mussel conservation assessment. To address these topics, we group research priorities into two categories: intrinsic or extrinsic factors. Intrinsic factors are indicators of organismal or population status, while extrinsic factors encompass environmental variables and threats. An understanding of intrinsic factors is useful in monitoring, and of extrinsic factors are important to understand ongoing and potential impacts on conservation status. This dual approach can guide conservation status assessments prior to the establishment of priority species and implementation of conservation management actions.NF-R was supported by a post-doctoral fellowship (Xunta de Galicia Plan I2C 2017-2020, 09.40.561B.444.0) from the government of the autonomous community of Galicia. BY was supported by the Ministry of Science and Higher Education (no. 0409-2016-0022). DLS was supported by the G. E. Hutchinson Chair at the Cary Institute of Ecosystem Studies. AO was supported by the Russian Foundation for Basic Research (no. 17-44-290016). SV was funded by European Investment Funds by FEDER/COMPETE/POCI- Operacional Competitiveness and Internacionalization Programme, under Project POCI-01-0145-FEDER-006958 and National Funds by FCT-Portuguese Foundation for Science and Technology, under the project UID/AGR/04033/2013. NF-R is very grateful to the University of Oklahoma Biological Survey for providing space to work in the U.S. and especially to Vaughn Lab members. Authors are very grateful to Akimasa Hattori, Allan K. Smith, Andrew Roberts, Daniel Graf, David Stagliano, David T. Zanatta, Dirk Van Damme, Ekaterina Konopleva, Emilie Blevins, Ethan Nedeau, Frankie Thielen, Gregory Cope, Heinrich Vicentini, Hugh Jones, Htilya Sereflisan, Ilya Vikhrev, John Pfeiffer, Karen Mock, Mary Seddon, Katharina Stockl, Katarzyna Zajac, Kengo Ito, Marie Capoulade, Marko Kangas, Michael Lange, Mike Davis, Pirkko-Liisa Luhta, Sarina Jepsen, Somsak Panha, Stephen McMurray, G. Thomas Watters, Wendell R. Haag, and Yoko Inui for their valuable contribution in the initial selection and description of extrinsic and intrinsic factors. We also wish to thank Dr. Amanda Bates, Chase Smith, and two anonymous reviewers for comments on earlier drafts of this manuscript. Any use of trade, firm, or product names is for descriptive purposes only and does not imply endorsement by the U.S. Government

Vitamin D Deficiency in Children with a Chronic Illness-Seasonal and Age-Related Variations in Serum 25-hydroxy Vitamin D Concentrations

Peer reviewe

Mapping the cellular mechanisms regulating atrial natriuretic peptide secretion

Abstract Atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) are cardiac hormones, which are involved in the regulation of blood pressure and fluid homeostasis. The major determinant for ANP and BNP release are atrial and ventricular wall stretch, but also some vasoactive factors such as endothelin-1 (ET-1) can enhance cardiac hormone secretion. The mechanical stretch rapidly activates multiple signal transduction pathways in cardiac cells, but the cellular mechanisms mediating stretch-induced ANP secretion are still unknown. The aim of the present study was to examine the cellular mechanisms of autocrine/paracrine factors and stretch-induced ANP secretion. Genistein, a potent protein tyrosine kinase (PTK) inhibitor, rapidly increased cardiac contractile force and ANP secretion in perfused rat heart. This effect of genistein may be unrelated to the inhibition of PTKs since this stimulation was blocked by a L-type calcium channel antagonist and Ca2+/calmodulin-dependent protein kinase II inhibitor. Pregnancy hormone relaxin increased heart rate and ANP secretion in perfused spontaneously beating heart, suggesting that relaxin may have a role in modulating cardiac function. Cellular mechanisms of atrial wall stretch-induced ANP secretion were also studied. This enhanced secretion was blocked by sarcoplasmic reticulum Ca2+-ATPase inhibitor thapsigargin and PTK inhibitor lavendustin A, indicating that thapsigargin sensitive Ca2+ pools and activation of PTK orPTK cascade have an important role in the regulation of stretch-secretion coupling. In addition, protein phosphatase inhibitor okadaic acid accelerated stretch-induced ANP secretion, suggesting that precise balance of protein kinase and phosphatase activity plays a role in mechanical stretch-induced ANP secretion. Finally interactions of endothelial factors regulating ANP exocytosis were studied. The potent nitric oxide synthase inhibitor L-NAME increased basal and atrial wall stretch-induced ANP secretion in the presence of ET-1, suggesting that nitric oxide may tonically inhibit ANP secretion

The effects of grazing history, soil properties and stand structure on the communities of saprotrophic fungi in wood-pastures

Wood-pastures are threatened anthropogenic biotopes that provide habitat for an extensive group of species. Here we studied the effect of management, grazing intensity, time since abandonment, historical land-use intensity, soil properties and stand conditions on communities of saprotrophic fungi in wood-pastures in Central Finland. We found that the proportion of broadleaved trees and soil pH are the major drivers in the communities of saprotrophic fungi in these boreal wood-pastures. In addition, tree species richness, soil moisture, historical land-use intensity and time since abandonment affected the communities of saprotrophic fungi. Current management or grazing intensity did not have a clear effect on saprotrophic fungal species richness, although dung-inhabiting fungal species richness was highest at intermediate to high grazing intensity. Obviously, there were many more dung-inhabiting fungal species on grazed than on abandoned sites. Our study highlights the conservation value of wood-pastures as hotspots of saprotrophic fungi.peerReviewe

Long telomeres in blood leukocytes are associated with a high risk of ascending aortic aneurysm.

Ascending aortic aneurysm is a connective tissue disorder. Even though multiple novel gene mutations have been identified, risk profiling and diagnosis before rupture still represent a challenge. There are studies demonstrating shorter telomere lengths in the blood leukocytes of abdominal aortic aneurysm patients. The aim of this study was to measure whether relative telomere lengths are changed in the blood leukocytes of ascending aortic aneurysm patients. We also studied the expression of telomerase in aortic tissue samples of ascending aortic aneurysms. Relative lengths of leukocyte telomeres were determined from blood samples of patients with ascending aortic aneurysms and compared with healthy controls. Telomerase expression, both at the level of mRNA and protein, was quantified from the aortic tissue samples. Mean relative telomere length was significantly longer in ascending aortic aneurysm blood samples compared with controls (T/S ratio 0.87 vs. 0.61, p<0.001). Expressions of telomerase mRNA and protein were elevated in the aortic aneurysm samples (p<0.05 and p<0.01). Our study reveals a significant difference in the mean length of blood leukocyte telomeres in ascending aortic aneurysm and controls. Furthermore, expression of telomerase, the main compensating factor for telomere loss, is elevated at both the mRNA and protein level in the samples of aneurysmal aorta. Further studies will be needed to confirm if this change in telomere length can serve as a tool for assessing the risk of ascending aortic aneurysm

Increased mesenchymal podoplanin expression is associated with calcification in aortic valves

Abstract Background and aim of the study: Calcific aortic valve disease (CAVD) is a progressive disease starting from mild valvular sclerosis and progressing to severe aortic stenosis (AS) with calcified valves. The origin of the calcification is proposed to be mesenchymal cells which have differentiated towards an osteoblastic phenotype. Podoplanin is a glycoprotein expressed in the endothelium of lymphatic vessels and in osteoblasts and osteocytes, mesenchymal cells, as well as in many carcinomas and aortic atherosclerotic lesions. In CAVD, its expression has been evaluated only as a marker of the lymphatic vasculature. Materials and methods: We determined podoplanin expression in human aortic valves in four patient groups: control (C, n=7), aortic regurgitation (AR, n=8), aortic regurgitation and fibrosis (AR + f, n=15) and AS (n=49) by immunohistochemistry and quantitative real-time PCR (RT-PCR). Results: Immunohistochemically, podoplanin expression was significantly increased in AR + f and AS groups when compared with the control and AR groups and the level of expression positively correlated with the extent of calcification and vascularity. Podoplanin mRNA levels were 1.7-fold higher in the AS group as compared with the control group (P=.05). Podoplanin-positivity was present not only in lymphatic vessel endothelium but also in osteoblasts, osteocytes, chondrocytes, macrophages and extracellular matrix. The majority of the podoplanin-positivity was in spindle cells with a myofibroblastic phenotype, often associated with calcifications. Tricuspid valves had more calcification-associated podoplanin than bi/unicuspid valves (median 1.52 vs 1.16, P&lt;.001). Conclusions: CAVD is characterized by an increased expression of podoplanin; this is associated with the differentiation of valvular interstitial cells into calcium-producing, myofibroblast-like cells. In addition, tricuspid valves express relatively more podoplanin than bi/unicuspid valves

Demographic characteristics of the study groups in the relative telomere length analysis.

<p>Mean age in years, BMI, total-cholesterol, HDL-cholesterol, LDL-cholesterol and triglycerides with standard deviation are shown. For other variables, number of subjects (percentage) is shown. <i>AscAA</i>, ascending aortic aneurysm, <i>BMI,</i> body mass index, <i>CHD,</i> coronary heart disease, <i>NS</i>, not statistically significant.</p