Time course of histopathology of bleomycin-induced pulmonary fibrosis using an intratracheal sprayer in mice.

Idiopathic pulmonary fibrosis (IPF) is a poor prognosis disease that affects approximately 5 million people worldwide, and the detailed mechanisms underlying the pathogenesis of IPF remain unclear. Bleomycin-induced pulmonary fibrosis has been widely used as a representative animal model of IPF that induces fibrosis in lung tissue. The lungs of rodent consist of five lobes and each bronchus enters each lobe of the lung at a different bifurcation angle, path length, and diameter.

Sortilin enhances fibrosis and calcification in aortic valve disease by inducing interstitial cell heterogeneity.

Aims: Calcific aortic valve disease (CAVD) is the most common valve disease, which consists of a chronic interplay of inflammation, fibrosis, and calcification. In this study, sortilin (SORT1) was identified as a novel key player in the pathophysiology of CAVD, and its role in the transformation of valvular interstitial cells (VICs) into pathological phenotypes is explored.

Methods And Results: An aortic valve (AV) wire injury (AVWI) mouse model with sortilin deficiency was used to determine the effects of sortilin on AV stenosis, fibrosis, and calcification.

Discovery of novel spiro[chromane-2,4'-piperidine] derivatives as potent and orally bioavailable G-protein-coupled receptor 119 agonists.

Herein, we describe the discovery, synthesis, and evaluation of a novel series of spiro[chromane-2,4'-piperidine] derivatives as G-protein-coupled receptor 119 agonists. Their initial design exploited the conformational restriction in the linker-to-tail moiety, which was a key concept in this study, to give lead compound 11 (EC = 369 nM, E = 82%). An extensive structure-activity relationship study resulted in the identification of the optimized drug candidate (R)-29 (EC = 54 nM, E = 181%).

Transcriptional control of intestinal cholesterol absorption, adipose energy expenditure and lipid handling by Sortilin.

The sorting receptor Sortilin functions in the regulation of glucose and lipid metabolism. Dysfunctional lipid uptake, storage, and metabolism contribute to several major human diseases including atherosclerosis and obesity. Sortilin associates with cardiovascular disease; however, the role of Sortilin in adipose tissue and lipid metabolism remains unclear.

Mechanism of lipid-lowering action of the dipeptidyl peptidase-4 inhibitor, anagliptin, in low-density lipoprotein receptor-deficient mice.

Aims/introduction: Dipeptidyl peptidase-4 inhibitors are used for treatment of patients with type 2 diabetes. In addition to glycemic control, these agents showed beneficial effects on lipid metabolism in clinical trials. However, the mechanism underlying the lipid-lowering effect of dipeptidyl peptidase-4 inhibitors remains unclear.

A single injection of gain-of-function mutant PCSK9 adeno-associated virus vector induces cardiovascular calcification in mice with no genetic modification.

Background And Aims: Studying atherosclerotic calcification in vivo requires mouse models with genetic modifications. Previous studies showed that injection of recombinant adeno-associated virus vector (AAV) encoding a gain-of-function mutant PCSK9 into mice promotes atherosclerosis. We aimed to study cardiovascular calcification induced by PCSK9 AAV in C57BL/6J mice.

Sortilin mediates vascular calcification via its recruitment into extracellular vesicles.

Vascular calcification is a common feature of major cardiovascular diseases. Extracellular vesicles participate in the formation of microcalcifications that are implicated in atherosclerotic plaque rupture; however, the mechanisms that regulate formation of calcifying extracellular vesicles remain obscure. Here, we have demonstrated that sortilin is a key regulator of smooth muscle cell (SMC) calcification via its recruitment to extracellular vesicles.

In vivo imaging of leukocyte recruitment to the atheroprone femoral artery reveals anti-inflammatory effects of rosuvastatin.

Objective: To monitor the anti-inflammatory effect of rosuvastatin in leukocyte endothelial interactions in the atheroprone femoral artery in vivo.

Methods And Results: Male Apolipoprotein E null mice (ApoE-/- mice, 6 weeks old) were fed a high-fat diet (20% fat, 1.25% cholesterol) with or without the HMG CoA reductase inhibitor rosuvastatin (10 mg/kg/day) for 6 weeks.

Adipose inflammation initiates recruitment of leukocytes to mouse femoral artery: role of adipo-vascular axis in chronic inflammation.

Background: Although inflammation within adipose tissues is known to play a role in metabolic syndrome, the causative connection between inflamed adipose tissue and atherosclerosis is not fully understood. In the present study, we examined the direct effects of adipose tissue on macro-vascular inflammation using intravital microscopic analysis of the femoral artery after adipose tissue transplantation.

Methods And Results: We obtained subcutaneous (SQ) and visceral (VIS) adipose tissues from C57BL/6 mice fed normal chow (NC) or a high fat diet (HF), then transplanted the tissues into the perivascular area of the femoral artery of recipient C57/BL6 mice.

Combination of amlodipine and atorvastatin synergistically reduces leukocyte recruitment to mechanically injured mouse femoral artery.

Recent studies have demonstrated a potential synergistic effect of the combination of amlodipine with atorvastatin to reduce acute inflammation. The intraluminal wire injury of the mouse femoral artery induced significant leukocyte recruitment to the injured area and oxidative stress within 24 h. Administration of low-dose amlodipine (0.

Oxidative stress in mononuclear cells plays a dominant role in their adhesion to mouse femoral artery after injury.

Leukocyte recruitment plays a pivotal role during inflammation after vascular injury. The importance of oxidative stress in vascular injury and its modulation by angiotensin II receptor blockers (olmesartan) have been demonstrated. We examined the contribution of leukocyte-associated oxidative stress in acute-phase leukocyte recruitment and its modulation by olmesartan.

Real-time imaging of mechanically injured femoral artery in mice reveals a biphasic pattern of leukocyte accumulation.

Wire injury of an artery has been recognized as a standard model of vascular inflammation and atherosclerosis; however, the mechanism of leukocyte recruitment has not been studied in this model. In this study, we documented the recruitment of leukocytes to the murine femoral artery after a wire injury. A transluminal mechanical injury was generated by insertion of a wire into the femoral artery of male C57BL/6J mice.