β-Aminopropionitrile Induces Distinct Pathologies in the Ascending and Descending Thoracic Aortic Regions of Mice.

Background: β-aminopropionitrile (BAPN) is a pharmacological inhibitor of LOX (lysyl oxidase) and LOXLs (LOX-like proteins). Administration of BAPN promotes aortopathies, although there is a paucity of data on experimental conditions to generate pathology. The objective of this study was to define experimental parameters and determine whether equivalent or variable aortopathies were generated throughout the aortic tree during BAPN administration in mice.

β-aminopropionitrile Induces Distinct Pathologies in the Ascending and Descending Thoracic Aortic Regions of Mice.

Background: β-aminopropionitrile (BAPN) is a pharmacological inhibitor of lysyl oxidase and lysyl oxidase-like proteins. Administration of BAPN promotes aortopathies, although there is a paucity of data on experimental conditions to generate pathology. The objective of this study was to define experimental parameters and determine whether equivalent or variable aortopathies were generated throughout the aortic tree during BAPN administration in mice.

Manipulation of components of the renin angiotensin system in renal proximal tubules fails to alter atherosclerosis in hypercholesterolemic mice.

Background And Objective: Whole body manipulation of the renin-angiotensin system (RAS) consistently exerts profound effects on experimental atherosclerosis development. A deficit in the literature has been a lack of attention to the effects of sex. Also, based on data with gene-deleted mice, the site of RAS activity that influences lesion formation is at an unknown distant location.

Functional Exploration of Conserved Sequences in the Distal Face of Angiotensinogen-Brief Report.

Background: Angiotensinogen (AGT) is an essential component in the renin-angiotensin system. AGT has highly conserved sequences in the loop and β-sheet regions among species; however, their functions have not been studied.

Methods: Adeno-associated viral vector (AAV) serotype 2/8 encoding mouse AGT with mutations of conserved sequences in the loop (AAV.

Inhibition of the Renin-Angiotensin System Fails to Suppress β-Aminopropionitrile-Induced Thoracic Aortopathy in Mice-Brief Report.

Background: Cross-linking of lysine residues in elastic and collagen fibers is a vital process in aortic development. Inhibition of lysyl oxidase by BAPN (β-aminopropionitrile) leads to thoracic aortopathies in mice. Although the renin-angiotensin system contributes to several types of thoracic aortopathies, it remains unclear whether inhibition of the renin-angiotensin system protects against aortopathy caused by the impairment of elastic fiber/collagen crosslinking.

Fludrocortisone Induces Aortic Pathologies in Mice.

Background And Objective: In an experiment designed to explore the mechanisms of fludrocortisone-induced high blood pressure, we serendipitously observed aortic aneurysms in mice infused with fludrocortisone. The purpose of this study was to investigate whether fludrocortisone induces aortic pathologies in both normocholesterolemic and hypercholesterolemic mice.

Methods And Results: Male adult C57BL/6J mice were infused with either vehicle (85% polyethylene glycol 400 (PEG-400) and 15% dimethyl sulfoxide (DMSO); = 5) or fludrocortisone (12 mg/kg/day dissolved in 85% PEG-400 and 15% DMSO; = 15) for 28 days.

Second Heart Field-Derived Cells Contribute to Angiotensin II-Mediated Ascending Aortopathies.

Background: The ascending aorta is a common location for aneurysm and dissection. This aortic region is populated by a mosaic of medial and adventitial cells that are embryonically derived from either the second heart field (SHF) or the cardiac neural crest. SHF-derived cells populate areas that coincide with the spatial specificity of thoracic aortopathies.

Deletion of AT1a (Angiotensin II Type 1a) Receptor or Inhibition of Angiotensinogen Synthesis Attenuates Thoracic Aortopathies in Fibrillin1 Mice.

Objective: A cardinal feature of Marfan syndrome is thoracic aortic aneurysm. The contribution of the renin-angiotensin system via AT1aR (Ang II [angiotensin II] receptor type 1a) to thoracic aortic aneurysm progression remains controversial because the beneficial effects of angiotensin receptor blockers have been ascribed to off-target effects. This study used genetic and pharmacological modes of attenuating angiotensin receptor and ligand, respectively, to determine their roles on thoracic aortic aneurysm in mice with fibrillin-1 haploinsufficiency (Fbn1C1041G/+).

Inducible Depletion of Calpain-2 Mitigates Abdominal Aortic Aneurysm in Mice.

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Two Amino Acids Proximate to the Renin Cleavage Site of Human Angiotensinogen Do Not Affect Blood Pressure and Atherosclerosis in Mice-Brief Report.

Objective: Renin cleavage of angiotensinogen has species specificity. As the residues at positions 11 and 12 are different between human angiotensinogen and mouse angiotensinogen, we determined whether these 2 residues in angiotensinogen affect renin cleavage and angiotensin II-mediated blood pressure regulation and atherosclerosis using an adenoassociated viral approach for manipulating angiotensinogen in vivo. Approach and Results: Hepatocyte-specific angiotensinogen deficient (hepAGT) mice in an LDL receptor-deficient background were infected with adenoassociated virals containing a null insert, human angiotensinogen, or mouse angiotensinogen expressing the same residues of the human protein at positions 11 and 12 (mouse angiotensinogen [L11V;Y12I]).

Hypercholesterolemia Accelerates Both the Initiation and Progression of Angiotensin II-induced Abdominal Aortic Aneurysms.

Objective: This study determined whether hypercholesterolemia would contribute to both the initiation and progression of angiotensin (Ang)II-induced abdominal aortic aneurysms (AAAs) in mice.

Methods And Results: To determine whether hypercholesterolemia accelerates the initiation of AAAs, male low-density lipoprotein (LDL) receptor -/- mice were either fed one week of Western diet prior to starting AngII infusion or initiated Western diet one week after starting AngII infusion. During the first week of AngII infusion, mice fed normal diet had less luminal expansion of the suprarenal aorta compared to those initiated Western diet after the first week of AngII infusion.

Angiotensin I Infusion Reveals Differential Effects of Angiotensin-Converting Enzyme in Aortic Resident Cells on Aneurysm Formation.

Background: Angiotensin (Ang)I is cleaved by angiotensin-converting enzyme (ACE) to generate AngII. The purpose of this study was to determine the roles of ACE in endothelial and smooth muscle cells in aortic aneurysms.

Methods and results: AngI infusion led to thoracic and abdominal aortic aneurysms in low-density lipoprotein receptor-deficient mice, which were ablated by ACE inhibition.

miR-146a Deficiency Accelerates Hepatic Inflammation Without Influencing Diet-induced Obesity in Mice.

miR-146a, an anti-inflammatory microRNA, is shown to be a negative regulator of adipocyte inflammation. However, the functional contribution of miR-146a in the development of obesity is not defined. In order to determine whether miR-146a influences diet-induced obesity, mice that were either wild type (WT) or miR-146a deficient (KO) were fed with high (60% kcal) fat diet (HFD) for 16 weeks.

Aortic Strain Correlates with Elastin Fragmentation in Fibrillin-1 Hypomorphic Mice.

Background: High frequency ultrasound has facilitated in vivo measurements of murine ascending aortas, allowing aortic strains to be gleaned from two-dimensional images. Thoracic aortic aneurysms associated with mutations in fibrillin-1 () display elastin fragmentation, which may impact aortic strain. In this study, we determined the relationship between elastin fragmentation and aortic circumferential strain in wild type and fibrillin-1 hypomorphic ( ) mice.

Ultrasound Imaging of the Thoracic and Abdominal Aorta in Mice to Determine Aneurysm Dimensions.

Contemporary high-resolution ultrasound instruments have sufficient resolution to facilitate the measurement of mouse aortas. These instruments have been widely used to measure aortic dimensions in mouse models of aortic aneurysms. Aortic aneurysms are defined as permanent dilations of the aorta, which occur most frequently in the ascending and abdominal regions.

Calpain Inhibition Attenuates Adipose Tissue Inflammation and Fibrosis in Diet-induced Obese Mice.

Adipose tissue macrophages have been proposed as a link between obesity and insulin resistance. However, the mechanisms underlying these processes are not completely defined. Calpains are calcium-dependent neutral cysteine proteases that modulate cellular function and have been implicated in various inflammatory diseases.

Smooth Muscle Cells Derived From Second Heart Field and Cardiac Neural Crest Reside in Spatially Distinct Domains in the Media of the Ascending Aorta-Brief Report.

Objective: Smooth muscle cells (SMCs) of the proximal thoracic aorta are embryonically derived from the second heart field (SHF) and cardiac neural crest (CNC). However, distributions of these embryonic origins are not fully defined. The regional distribution of SMCs of different origins is speculated to cause region-specific aortopathies.

TGF-β Neutralization Enhances AngII-Induced Aortic Rupture and Aneurysm in Both Thoracic and Abdominal Regions.

AngII and TGF-β interact in development of thoracic and abdominal aortic diseases, although there are many facets of this interaction that have not been clearly defined. The aim of the present study was to determine the effects of TGF-β neutralization on AngII induced-aortic pathologies. Male C57BL/6J mice were administered with either a rabbit or mouse TGF-β neutralizing antibody and then infused with AngII.

Angiotensin-Converting Enzyme in Smooth Muscle Cells Promotes Atherosclerosis-Brief Report.

Objective: Angiotensin-converting enzyme (ACE) is present in many cell types of atherosclerotic lesions. This study determined whether ACE activity in endothelial and smooth muscle cells (SMCs), 2 major resident cell types of the aorta, contributes to hypercholesterolemia-induced atherosclerosis.

Approach And Results: All study mice were in low-density lipoprotein receptor(-/-) background.

Leukocyte Calpain Deficiency Reduces Angiotensin II-Induced Inflammation and Atherosclerosis But Not Abdominal Aortic Aneurysms in Mice.

Objective: Angiotensin II (AngII) infusion profoundly increases activity of calpains, calcium-dependent neutral cysteine proteases, in mice. Pharmacological inhibition of calpains attenuates AngII-induced aortic medial macrophage accumulation, atherosclerosis, and abdominal aortic aneurysm in mice. However, the precise functional contribution of leukocyte-derived calpains in AngII-induced vascular pathologies has not been determined.