scholarly journals SMC Derived Hyaluronan Modulates Vascular SMC-Phenotype in Murine Atherosclerosis

2021 ◽  
Author(s):  
Felicia Hartmann ◽  
Daniel J Gorski ◽  
Alexandra AC Newman ◽  
Susanne Homann ◽  
Anne Petz ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Transition State ◽  
Acute Phase ◽  
Acute Phase Response ◽  
Lineage Tracing ◽  
Phase Response ◽  
Phenotypic Switching ◽  
Plaque Stability ◽  
Specific Deletion

Rationale: Plaque instability remains poorly understood and new therapeutic approaches to reduce plaque rupture and subsequent clinical events are of great interest. Recent studies revealed an important role of phenotypic switching of smooth muscle cells (SMC) in controlling plaque stability, including extracellular matrix (ECM) deposition. Objective: The aim of this study was to elucidate the role of hyaluronan (HA) derived from SMC-HA synthase 3 (Has3), in phenotypic switching and plaque stability in an animal model of atherosclerosis. Methods and Results: A mouse line with SMC-specific deletion of Has3 and simultaneous SMC lineage tracing (eYFP) on an Apoe-/- background was used. Lineage tracing of SMC with eYFP revealed that SMC-specific deletion of Has3 significantly increased the number of galectin-3 (LGALS3+) "transition-state" SMC and decreased alpha-smooth muscle actin (ACTA2+) SMC. Notably, SMC-Has3 deletion led to significantly increased collagen deposition and maturation within the fibrous cap (FC) and the whole lesion, as evidenced by Picrosirius red staining and LC-PolScope analysis. Single-cell RNA sequencing (scRNA-seq) of brachiocephalic artery (BCA) lesions demonstrated that the loss of SMC-Has3 enhanced the transition of SMC to an Lgals3+, ECM-producing phenotype with elevated acute-phase response gene expression. Experiments using cultured murine aortic SMC revealed that blocking cluster of differentiation-44 (CD44), an important HA binding receptor, recapitulated the enhanced acute-phase response and synthesis of fibrous ECM. Conclusions: These studies provide evidence that the deletion of SMC-Has3 results in an ECM-producing "transition state" SMC phenotype (characterized by LGALS3+ expression), likely via reduced CD44 signaling, resulting in increased collagen formation and maturation, an index consistent with increased plaque stability.

Ozone-induced acute phase response in lung versus liver: the role of adrenal-derived stress hormones

2020 ◽  
pp. 1-14
Author(s):  
Devin I. Alewel ◽  
Andres R. Henriquez ◽  
Catherine H. Colonna ◽  
Samantha J. Snow ◽  
Mette C. Schladweiler ◽  
...  
Keyword(s):  
Acute Phase ◽  
Acute Phase Response ◽  
Stress Hormones ◽  
Phase Response

scholarly journals C/EBPα Is Critical for the Neonatal Acute-Phase Response to Inflammation

1998 ◽  
Vol 18 (12) ◽  
pp. 7269-7277 ◽  
Author(s):  
Bonnie L. Burgess-Beusse ◽  
Gretchen J. Darlington
Keyword(s):  
Dna Binding ◽  
Acute Phase ◽  
Acute Phase Response ◽  
Northern Blot Analysis ◽  
Protein Gene ◽  
Phase Response ◽  
Wild Type ◽  
Neonatal Mice ◽  
Enhancer Binding Protein

ABSTRACT Members of the C/EBP (CCAAT/enhancer binding protein) family of transcription factors play important roles in mediating the acute-phase response (APR), an inflammatory process resulting from infection and/or tissue damage. Among the C/EBP family of proteins, C/EBPβ and -δ were thought to be the primary mediators of the APR. The function of C/EBPα in the APR has not been fully characterized to date. Here, we investigate the role of C/EBPα in the APR by using neonatal mice that lack C/EBPα expression. Northern blot analysis of acute-phase protein gene expression in neonatal mice treated with purified bacterial lipopolysaccharide or recombinant interleukin 1β as an inflammation stimulus showed a strong APR in wild-type mice, but a response in C/EBPα null animals was completely lacking. The C/EBPα knockout and wild-type mice demonstrated elevations in C/EBPβ and -δ mRNA expression and DNA binding as well as increased DNA binding of NF-κB, all of which are known to be important in the APR. Null mice, however, failed to activate STAT3 binding in response to lipopolysaccharide. Our results provide the first evidence that C/EBPα is absolutely required for the APR in neonatal mice, is involved in STAT3 regulation, and cannot be compensated for by other C/EBP family members.

The role of eicosanoids in the acute phase response

1991 ◽  
Vol 12 (2) ◽  
pp. 268 ◽  
Author(s):  
H. Rieder ◽  
G. Ramadori ◽  
K.-H.Meyer zum Büschenfelde
Keyword(s):  
Acute Phase ◽  
Acute Phase Response ◽  
Phase Response

The role of macrophages in the acute-phase response: SAA inducer is closely related to lymphocyte activating factor and endogenous pyrogen

1981 ◽  
Vol 63 (1) ◽  
pp. 164-176 ◽  
Author(s):  
Marcelo B. Sztein ◽  
Stefanie N. Vogel ◽  
Jean D. Sipe ◽  
Patrick A. Murphy ◽  
Steven B. Mizel ◽  
...  
Keyword(s):  
Acute Phase ◽  
Acute Phase Response ◽  
Phase Response ◽  
Endogenous Pyrogen

Abstract 149: Pluripotency Factors Krüppel-Like Factor 4 and Octamer-binding Transcription Factor 4 Alter Indices of Plaque Stability in Long Term Western Diet Fed Mice by Regulating Smooth Muscle Cell Phenotypes

2013 ◽  
Vol 33 (suppl_1) ◽  
Author(s):  
Laura S Shankman ◽  
Olga A Cherepanova ◽  
Delphine Gomez ◽  
Gary K Owens
Keyword(s):  
Smooth Muscle ◽  
Foam Cell ◽  
Lineage Tracing ◽  
Phenotypic Switching ◽  
Marker Genes ◽  
Plaque Stability ◽  
Pluripotency Factors ◽  
Fibrous Cap ◽  
Atherosclerotic Lesions ◽  
Life Threatening

The bulk of life threatening thrombotic events have been associated with disruption of the fibrous cap, an atheroprotective layer of smooth muscle α-actin positive (ACTA2+) cells that form around the plaque, and the presence of a large foam cell-laden necrotic core within the plaque. Despite the overwhelming research demonstrating that ACTA2+ cells are beneficial for plaque stability, and cells positive for macrophage-markers are detrimental, there are major ambiguities regarding the origins of these cells, and their role in lesion stability. To clearly define the contribution of smooth muscle cells (SMCs) within atherosclerotic lesions, we generated SMC specific lineage tracing Apoe-/- mice containing a SM myosin heavy chain ( Myh11 ) tamoxifen-inducible cre-recombinase gene and a floxed STOP ROSA eYFP gene ( Myh11 YFP ApoE-/- mice) thus allowing activation of eYFP exclusively in fully differentiated SMCs before the onset of atherosclerosis and subsequent determination of the fate of these cells and their progeny irrespective of continued expression of MYH11 or other SMC marker genes. Remarkably, our results reveal that 86% of SMCs cannot be identified using traditional SMC markers, such as ACTA2, and 23% of presumed macrophages (LGALS3+ cells) are derived from SMC origins. The last finding was confirmed in human coronary atheromas using the ISH-PLA approach. SMC specific knockout (KO) of the pluripotency factor Klf4 in Myh11 YFP ApoE-/- mice did not alter the frequency of phenotypically modulated (ACTA2-eYFP+) SMCs within atherosclerotic lesions of mice fed a high fat diet for 18 weeks, however, decreased the number of ACTA2-eYFP+ SMCs that expressed LGALS3, and increased several indices of plaque stability, suggesting a detrimental role for KLF4 in SMCs within atherosclerotic lesions. Conversely, SMC specific Oct4 KO resulted in a dramatic reduction in the number of ACTA2-eYFP+ SMCs within the lesion with marked decreases in indices of plaque stability. In summary results show that the majority of SMC-derived cells within advanced atherosclerotic lesions cannot be identified using conventional SMC marker genes, and that phenotypic switching of SMC during atherogenesis is differentially regulated by the pluripotency factors KLF4 and OCT4.

Interleukin 1-induced depression of iron and zinc: role of granulocytes and lactoferrin

1987 ◽  
Vol 252 (1) ◽  
pp. E27-E32 ◽  
Author(s):  
S. E. Goldblum ◽  
D. A. Cohen ◽  
M. Jay ◽  
C. J. McClain
Keyword(s):  
Acute Phase ◽  
Acute Phase Response ◽  
Interleukin 1 ◽  
Phase Response ◽  
Human Transferrin ◽  
Carrier Molecule ◽  
Iron And Zinc

The mechanism(s) of stress-induced hypoferremia and hypozincemia remains unclear. We studied the role of granulocytes and lactoferrin (LF) in endotoxin and murine interleukin 1 (IL-1)-induced depression of serum Fe and Zn concentrations in both rabbits and rats. Both endotoxin and IL-1 administration induced significant hypoferremia (P less than 0.01) and hypozincemia (P less than 0.01) after 6 h in both species. Granulocyte depletion before IL-1 infusion significantly (P less than 0.01) diminished the hypoferremia but not the hypozincemia. Moreover, infusion of 5 or 15 mg of human LF into rabbits caused significant hypoferremia (P less than 0.005) without hypozincemia. Significant hypozincemia (P less than 0.01) could only be demonstrated after a 75-mg infusion. In contrast, infusions of human transferrin at equivalent doses (5, 15, and 75 mg) induced neither hypoferremia nor hypozincemia. Therefore endotoxin and IL-1-induced hypoferremia and, to a much lesser degree, hypozincemia are granulocyte dependent. Granulocyte released LF is a specific carrier molecule for transport and removal of Fe from the circulation during the acute phase response. The data suggest a mechanistic dissociation of IL-1-induced hypoferremia and hypozincemia with LF-independent mechanisms for Zn.

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