Author Correction: Loss of the adaptor protein ShcA in endothelial cells protects against monocyte macrophage adhesion, LDL-oxydation, and atherosclerotic lesion formation (Scientific Reports DOI: 10.1038/s41598-018-22819-3)

peer reviewe

LRP1 Functions as an Atheroprotective Integrator of TGFβ and PDGF Signals in the Vascular Wall: Implications for Marfan Syndrome

BACKGROUND: The multifunctional receptor LRP1 controls expression, activity and trafficking of the PDGF receptor-β in vascular smooth muscle cells (VSMC). LRP1 is also a receptor for TGFβ1 and is required for TGFβ mediated inhibition of cell proliferation. METHODS AND PRINCIPAL FINDINGS: We show that loss of LRP1 in VSMC (smLRP(−)) in vivo results in a Marfan-like syndrome with nuclear accumulation of phosphorylated Smad2/3, disruption of elastic layers, tortuous aorta, and increased expression of the TGFβ target genes thrombospondin-1 (TSP1) and PDGFRβ in the vascular wall. Treatment of smLRP1(−) animals with the PPARγ agonist rosiglitazone abolished nuclear pSmad accumulation, reversed the Marfan-like phenotype, and markedly reduced smooth muscle proliferation, fibrosis and atherosclerosis independent of plasma cholesterol levels. CONCLUSIONS AND SIGNIFICANCE: Our findings are consistent with an activation of TGFβ signals in the LRP1-deficient vascular wall. LRP1 may function as an integrator of proliferative and anti-proliferative signals that control physiological mechanisms common to the pathogenesis of Marfan syndrome and atherosclerosis, and this is essential for maintaining vascular wall integrity

Large Scale Comparison of Innate Responses to Viral and Bacterial Pathogens in Mouse and Macaque

Viral and bacterial infections of the lower respiratory tract are major causes of morbidity and mortality worldwide. Alveolar macrophages line the alveolar spaces and are the first cells of the immune system to respond to invading pathogens. To determine the similarities and differences between the responses of mice and macaques to invading pathogens we profiled alveolar macrophages from these species following infection with two viral (PR8 and Fuj/02 influenza A) and two bacterial (Mycobacterium tuberculosis and Francisella tularensis Schu S4) pathogens. Cells were collected at 6 time points following each infection and expression profiles were compared across and between species. Our analyses identified a core set of genes, activated in both species and across all pathogens that were predominantly part of the interferon response pathway. In addition, we identified similarities across species in the way innate immune cells respond to lethal versus non-lethal pathogens. On the other hand we also found several species and pathogen specific response patterns. These results provide new insights into mechanisms by which the innate immune system responds to, and interacts with, invading pathogens

Development of Gene Expression Markers of Acute Heat-Light Stress in Reef-Building Corals of the Genus Porites

Coral reefs are declining worldwide due to increased incidence of climate-induced coral bleaching, which will have widespread biodiversity and economic impacts. A simple method to measure the sub-bleaching level of heat-light stress experienced by corals would greatly inform reef management practices by making it possible to assess the distribution of bleaching risks among individual reef sites. Gene expression analysis based on quantitative PCR (qPCR) can be used as a diagnostic tool to determine coral condition in situ. We evaluated the expression of 13 candidate genes during heat-light stress in a common Caribbean coral Porites astreoides, and observed strong and consistent changes in gene expression in two independent experiments. Furthermore, we found that the apparent return to baseline expression levels during a recovery phase was rapid, despite visible signs of colony bleaching. We show that the response to acute heat-light stress in P. astreoides can be monitored by measuring the difference in expression of only two genes: Hsp16 and actin. We demonstrate that this assay discriminates between corals sampled from two field sites experiencing different temperatures. We also show that the assay is applicable to an Indo-Pacific congener, P. lobata, and therefore could potentially be used to diagnose acute heat-light stress on coral reefs worldwide

Preservation of vascular contraction during ageing: dual effect on calcium handling and sensitization

1. The present study was aimed to characterize the effects of ageing on vascular contraction by noradrenaline in rat isolated arteries. The existence of vascular bed heterogeneity was investigated in endothelium-denuded conductance (aorta) and resistance (small mesenteric artery, SMA) arteries, with respect to Ca(2+) handling, Ca(2+) sensitization or Ca(2+)-independent mechanisms. 2. In both arteries, contractions to noradrenaline were not different between adult and aged rats. 3. In Ca(2+)- free medium, noradrenaline elicited a transient increase in tension that was reduced by the Ca(2+) mobilizing agents, ryanodine and thapsigargin, in arteries from adult rats. A loss of the thapsigargin- but not the ryanodine-sensitive component of noradrenaline-induced contraction was observed in the two arteries from aged rats. 4. After depletion of Ca(2+) stores with noradrenaline, addition of exogenous CaCl(2) produced a sustained contraction that was decreased to the same extent by the protein kinase C inhibitor, GF 109203X and the tyrosine kinase inhibitor, tyrphostin A-23, in arteries from adult and aged rats. The Rho-associated protein kinase inhibitor, Y-27632, caused identical relaxation of noradrenaline pre-contracted arteries from both age groups. 5. Basal intracellular calcium ([Ca(2+)](i)) was higher in SMA from aged than from adult rats. In addition, the noradrenaline [Ca(2+)](i)-force relationship was significantly shifted to the right in the SMA from aged rats. 6. Altogether, these data indicate that responsiveness to noradrenaline is preserved both in conductance and resistance arteries with ageing. The latter results from the association of increased basal [Ca(2+)](i), changes in Ca(2+) handling at the level of thapsigargin-sensitive sarcoplasmic reticulum Ca(2+)-ATPases and decreased myofilament sensitivity to Ca(2+)

Activation of TGFβ and PDGF signaling in LRP⁻ mouse aortas are both prevented upon rosiglitazone treatment.

<p>Mice had been cholesterol-fed for 5 weeks in the absence (−Rosi) or presence (+Rosi) of rosiglitazone (GlaxoSmithKline, 25 mg/kg/day) before analysis. Mouse aortas expressing (LRP⁺) or not expressing (LRP⁻) LRP in VSMC were analyzed by western blot (Panel A) and immunohistochemistry (Panel B) for expression of PDGFRβ (d–f), and for activation of Smad2/3 (pSmad2/3, a–c), and Erk1/2 (pErk1/2, g–i). Panel C shows elastic staining of corresponding sections and gaps in elastic fiber continuity (arrows). Bar indicates 40 µm, insert scale bar in B,a indicates 10 µm.</p

Increased pSmad2/3 expression and activation of TGFβ signaling in LRP⁻ mouse aorta.

<p>Longitudinal sections of abdominal aorta from SM22Cre⁺;LRP^flox/flox;LDLR^−/− (LRP⁻) and LRP^flox/flox;LDLR^−/− (LRP⁺) mice were stained with anti-TSP1, anti-TGFβ1, anti-pSmad2/3 and anti-pSmad1 antibodies. Reduced LRP1 expression results in greatly enhanced expression of pSmad2/3 and its target gene, TSP1. By contrast, TGFβ1 levels were slightly reduced, pSmad1 levels did not change. Bar in a indicates 20 µm.</p

Control of TGFβ and PDGF signaling and protection of vascular wall integrity by LRP1.

<p>Absence of LRP1 results in increased activation of TGFβ signaling. This is accompanied by disruption of elastic layers, tortuous aortas and increased fibrosis similar to what is observed in Marfan and Marfan-like syndromes in which the genes for fibrillin-1 or TGFβ receptors are defective. Loss of LRP1 expression leads to increased expression of PDGF receptors. LRP1 also controls PDGFRβ signaling and trafficking through an independent mechanism, and absence of LRP1 promotes VSMC proliferation and severe atherosclerosis. Rosiglitazone blocks TGFβ signaling upstream of PDGFR, which is inhibited by Gleevec. Both drugs are thus effective in reducing arterial wall thickening and atherosclerosis, which are induced by increased PDGFR signaling.</p