scholarly journals Sustained Elevated Blood Pressure Accelerates Atherosclerosis Development in a Preclinical Model of Disease

2021 ◽  
Vol 22 (16) ◽  
pp. 8448
Author(s):  
Andrés Gonzalez-Guerra ◽  
Marta Roche-Molina ◽  
Nieves García-Quintáns ◽  
Cristina Sánchez-Ramos ◽  
Daniel Martín-Pérez ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Fold Increase ◽  
Causal Link ◽  
Preclinical Model ◽  
Adeno Associated Virus ◽  
Substantial Impact ◽  
Atherosclerotic Lesions ◽  
Plaque Development ◽  
Viral Particles ◽  
Atherosclerosis Development

The continuous relationship between blood pressure (BP) and cardiovascular events makes the distinction between elevated BP and hypertension based on arbitrary cut-off values for BP. Even mild BP elevations manifesting as high-normal BP have been associated with cardiovascular risk. We hypothesize that persistent elevated BP increases atherosclerotic plaque development. To evaluate this causal link, we developed a new mouse model of elevated BP based on adeno-associated virus (AAV) gene transfer. We constructed AAV vectors to support transfer of the hRenin and hAngiotensinogen genes. A single injection of AAV-Ren/Ang (1011 total viral particles) induced sustained systolic BP increase (130 ± 20 mmHg, vs. 110 ± 15 mmHg in controls; p = 0.05). In ApoE−/− mice, AAV-induced mild BP elevation caused larger atherosclerotic lesions evaluated by histology (10-fold increase vs. normotensive controls). In this preclinical model, atheroma plaques development was attenuated by BP control with a calcium channel blocker, indicating that a small increase in BP within a physiological range has a substantial impact on plaque development in a preclinical model of atherosclerosis. These data support that non-optimal BP represents a risk for atherosclerosis development. Earlier intervention in elevated BP may prevent or delay morbidity and mortality associated with atherosclerosis.

scholarly journals Cell-Based Models for Development of Antiatherosclerotic Therapies

2017 ◽  
Vol 2017 ◽  
pp. 1-8
Author(s):  
Emile R. Zakiev ◽  
Nikita G. Nikiforov ◽  
Alexander N. Orekhov
Keyword(s):  
Ex Vivo ◽  
Cardiovascular Disorder ◽  
Atherosclerotic Plaques ◽  
Cell Models ◽  
Atherosclerosis Progression ◽  
Synthetic Drugs ◽  
Atherosclerotic Lesions ◽  
Plaque Development ◽  
Atherosclerosis Development

The leading cause of death worldwide is cardiovascular disease. Among the conditions related to the term, the most prominent one is the development of atherosclerotic plaques in the walls of arteries. The situation gets even worse with the fact that the plaque development may stay asymptomatic for a prolonged period of time. When it manifests as a cardiovascular disorder, it is already too late: the unfortunate individual is prescribed with a plethora of synthetic drugs, which are of debatable efficacy in the prevention of atherosclerotic lesions and safety. Cell models could be useful for the purpose of screening substances potentially effective against atherosclerosis progression and effective in reduction of already present plaques. In this overview, we present studies making use of in vitro and ex vivo models of atherosclerosis development that can prove valuable for clinical applications.

Detection of viruses by electron microscopy: Increased sensitivity by direct micro-ultracentrifugation of samples

1987 ◽  
Vol 45 ◽  
pp. 908-909
Author(s):  
Alain R. Trudel ◽  
M. Trudel
Keyword(s):  
Electron Microscopy ◽  
Fold Increase ◽  
Observation Time ◽  
Clinical Samples ◽  
Maximum Speed ◽  
Viral Particles ◽  
Structural Details ◽  
Latex Spheres ◽  
Increased Sensitivity ◽  
Size Of Particles

AirfugeR (Beckman) direct ultracentrifugation of viral samples on electron microscopy grids offers a rapid way to concentrate viral particles or subunits and facilitate their detection and study. Using the A-100 fixed angle rotor (30°) with a K factor of 19 at maximum speed (95 000 rpm), samples up to 240 μl can be prepared for electron microscopy observation in a few minutes: observation time is decreased and structural details are highlighted. Using latex spheres to calculate the increase in sensitivity compared to the inverted drop procedure, we obtained a 10 to 40 fold increase in sensitivity depending on the size of particles. This technique also permits quantification of viral particles in samples if an aliquot is mixed with latex spheres of known concentration.Direct ultracentrifugation for electron microscopy can be performed on laboratory samples such as gradient or column fractions, infected cell supernatant, or on clinical samples such as urine, tears, cephalo-rachidian liquid, etc..

scholarly journals Cardiac Overexpression of PDE4B Blunts β-Adrenergic Response and Maladaptive Remodeling in Heart Failure

Circulation ◽  
2020 ◽  
Vol 142 (2) ◽  
pp. 161-174 ◽  
Author(s):  
Sarah Karam ◽  
Jean Piero Margaria ◽  
Aurélia Bourcier ◽  
Delphine Mika ◽  
Audrey Varin ◽  
...  
Keyword(s):  
Heart Failure ◽  
Transgenic Mouse ◽  
Adrenergic Receptor ◽  
Systolic Dysfunction ◽  
Fold Increase ◽  
Aortic Constriction ◽  
Adeno Associated Virus ◽  
Transgenic Mouse Line ◽  
Virus Serotype ◽  
Fractional Shortening

Background: The cyclic AMP (adenosine monophosphate; cAMP)-hydrolyzing protein PDE4B (phosphodiesterase 4B) is a key negative regulator of cardiac β-adrenergic receptor stimulation. PDE4B deficiency leads to abnormal Ca 2+ handling and PDE4B is decreased in pressure overload hypertrophy, suggesting that increasing PDE4B in the heart is beneficial in heart failure. Methods: We measured PDE4B expression in human cardiac tissues and developed 2 transgenic mouse lines with cardiomyocyte-specific overexpression of PDE4B and an adeno-associated virus serotype 9 encoding PDE4B. Myocardial structure and function were evaluated by echocardiography, ECG, and in Langendorff-perfused hearts. Also, cAMP and PKA (cAMP dependent protein kinase) activity were monitored by Förster resonance energy transfer, L-type Ca 2+ current by whole-cell patch-clamp, and cardiomyocyte shortening and Ca 2+ transients with an Ionoptix system. Heart failure was induced by 2 weeks infusion of isoproterenol or transverse aortic constriction. Cardiac remodeling was evaluated by serial echocardiography, morphometric analysis, and histology. Results: PDE4B protein was decreased in human failing hearts. The first PDE4B-transgenic mouse line (TG15) had a ≈15-fold increase in cardiac cAMP-PDE activity and a ≈30% decrease in cAMP content and fractional shortening associated with a mild cardiac hypertrophy that resorbed with age. Basal ex vivo myocardial function was unchanged, but β-adrenergic receptor stimulation of cardiac inotropy, cAMP, PKA, L-type Ca 2+ current, Ca 2+ transients, and cell contraction were blunted. Endurance capacity and life expectancy were normal. Moreover, these mice were protected from systolic dysfunction, hypertrophy, lung congestion, and fibrosis induced by chronic isoproterenol treatment. In the second PDE4B-transgenic mouse line (TG50), markedly higher PDE4B overexpression, resulting in a ≈50-fold increase in cardiac cAMP-PDE activity caused a ≈50% decrease in fractional shortening, hypertrophy, dilatation, and premature death. In contrast, mice injected with adeno-associated virus serotype 9 encoding PDE4B (10 12 viral particles/mouse) had a ≈50% increase in cardiac cAMP-PDE activity, which did not modify basal cardiac function but efficiently prevented systolic dysfunction, apoptosis, and fibrosis, while attenuating hypertrophy induced by chronic isoproterenol infusion. Similarly, adeno-associated virus serotype 9 encoding PDE4B slowed contractile deterioration, attenuated hypertrophy and lung congestion, and prevented apoptosis and fibrotic remodeling in transverse aortic constriction. Conclusions: Our results indicate that a moderate increase in PDE4B is cardioprotective and suggest that cardiac gene therapy with PDE4B might constitute a new promising approach to treat heart failure.

scholarly journals Increased Inflammation in Atherosclerotic Lesions of DiabeticAkita-LDLr−/−Mice Compared to NondiabeticLDLr−/−Mice

2012 ◽  
Vol 2012 ◽  
pp. 1-12 ◽  
Author(s):  
Daniel Engelbertsen ◽  
Fong To ◽  
Pontus Dunér ◽  
Olga Kotova ◽  
Ingrid Söderberg ◽  
...  
Keyword(s):  
High Fat Diet ◽  
Molecular Mechanisms ◽  
Plasma Cholesterol ◽  
Microvascular Complications ◽  
Fold Increase ◽  
Inflammatory Cells ◽  
Glucose Levels ◽  
Atherosclerotic Lesions ◽  
Blood Glucose Levels ◽  
Plaque Inflammation

Background. Diabetes is associated with increased cardiovascular disease, but the underlying cellular and molecular mechanisms are poorly understood. One proposed mechanism is that diabetes aggravates atherosclerosis by enhancing plaque inflammation. TheAkitamouse has recently been adopted as a relevant model for microvascular complications of diabetes. Here we investigate the development of atherosclerosis and inflammation in vessels ofAkitamice onLDLr−/−background.Methods and Results.Akita-LDLr−/−andLDLr−/−mice were fed high-fat diet from 6 to 24 weeks of age. Blood glucose levels were higher in both male and femaleAkita-LDLr−/−mice (137% and 70%, resp.). MaleAkita-LDLr−/−mice had markedly increased plasma cholesterol and triglyceride levels, a three-fold increase in atherosclerosis, and enhanced accumulation of macrophages and T-cells in plaques. In contrast, femaleAkita-LDLr−/−mice demonstrated a modest 29% increase in plasma cholesterol and no significant increase in triglycerides, atherosclerosis, or inflammatory cells in lesions. MaleAkita-LDLr−/−mice had increased levels of plasma IL-1βcompared to nondiabetic mice, whereas no such difference was seen between female diabetic and nondiabetic mice.Conclusion.Akita-LDLr−/−mice display considerable gender differences in the development of diabetic atherosclerosis. In addition, the increased atherosclerosis in maleAkita-LDLr−/−mice is associated with an increase in inflammatory cells in lesions.

Identification of Mep1a as a susceptibility gene for atherosclerosis in mice

Genetics ◽  
2021 ◽  
Author(s):  
Andrew T Grainger ◽  
Nathanael Pilar ◽  
Jun Li ◽  
Mei-Hua Chen ◽  
Ashley M Abramson ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Bioinformatics Analysis ◽  
Susceptibility Gene ◽  
Arterial Disease ◽  
Chromosome 17 ◽  
Chow Diet ◽  
Atherosclerotic Lesions ◽  
Significant Locus ◽  
Atherosclerosis Development ◽  
Peripheral Arterial

Abstract Atherosclerosis is the underlying cause of heart attack, ischemic stroke and peripheral arterial disease, and genetic factors involved remain mostly unidentified. We previously identified a significant locus on mouse chromosome 17 for atherosclerosis, Ath49, in an intercross between BALB/c and SM strains. Ath49 partially overlaps in the confidence interval with Ath22 mapped in an AKR x DBA/2 intercross. Bioinformatics analysis prioritized Mep1a, encoding meprin 1α metalloendopeptidase, as a likely candidate gene for Ath49. To prove causality, Mep1a-/-Apoe-/- mice were generated and compared with Mep1a+/+Apoe-/- mice for atherosclerosis development. Mep1a was found abundantly expressed in atherosclerotic lesions but not in healthy aorta and liver of mice. Mep1a -/- Apoe-/- mice exhibited significant reductions in both early and advanced lesion sizes. Loss of Mep1a led to decreased necrosis but increased macrophage and neutrophil contents in advanced lesions, reduced plasma levels of CXCL5 and an oxidative stress biomarker. In addition, Mep1a-/- mice had a significantly reduced triglyceride levels on a chow diet. Thus, Mep1a is a susceptibility gene for atherosclerosis and aggravates atherosclerosis partially through action on oxidative stress and inflammation.

Abstract P363: Annexin-A1 Deficiency Exaggerates Cardiac Remodeling In Angiotensin II-induced Hypertension

2021 ◽  
Vol 129 (Suppl_1) ◽  
Author(s):  
Kristy Jackson ◽  
Jaideep Singh ◽  
Yen Zhi Ng ◽  
Cheng Peng ◽  
Anida Velagic ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Angiotensin Ii ◽  
Cardiac Remodeling ◽  
Physiological Role ◽  
Preclinical Model ◽  
Annexin A1 ◽  
Ang Ii ◽  
Cardiac Damage ◽  
Induced Hypertension ◽  
Deficient Mice

Introduction: We have previously demonstrated that the naturally-occurring anti-inflammatory and pro-resolving protein Annexin-A1 (Anx-A1) limits the acute inflammatory response post myocardial infarction, but its impact on chronic inflammation, such as hypertension, has not been explored. This study aims to investigate the role of Anx-A1 in a preclinical model of hypertension, induced by angiotensin-II (Ang-II). Methods: 15-week-old male C57BL/6 or ANXA1 -/- were anesthetized (isoflurane, 2-4% v/v) and implanted with an osmotic minipump randomly assigned to receive Ang-II (0.7mg/kg/day) or vehicle (saline). Radiotelemetry recordings of blood pressure were taken at 10 intermittent timepoints from baseline to the end of the 29-day infusion period. Animals were euthanized with pentobarbitone (100mg/kg; i.p.) at endpoint and organ weights recorded and normalized to bodyweight. Left ventricle (LV) samples were stained with picrosirius red to assess total LV collagen deposition. Results: Ang II-induced mice at the end of the study had elevated mean arterial pressure (MAP), cardiac hypertrophy and fibrosis compared to normotensive mice (Table). Anx-A1 deficient mice given Ang II had an even greater increase in MAP and cardiac remodeling compared to WT. Interestingly, MAP of Anx-A1 deficient mice at baseline is significantly higher compare to C57BL/6 counterparts (Table). Conclusion: This is the first study to demonstrate that deficiency of Anx-A1 exaggerates cardiac remodeling in AngII-induced hypertension, suggesting that endogenous Anx-A1 might play previously unappreciated physiological role in regulating blood pressure. This supports the development of Anx-A1 based pharmacotherapy against hypertension-induced cardiac damage.

scholarly journals Hydroxytyrosol Plays Antiatherosclerotic Effects through Regulating Lipid Metabolism via Inhibiting the p38 Signal Pathway

2020 ◽  
Vol 2020 ◽  
pp. 1-12
Author(s):  
Xinxin Zhang ◽  
Yating Qin ◽  
Xiaoning Wan ◽  
Hao Liu ◽  
Chao Iv ◽  
...  
Keyword(s):  
Lipid Metabolism ◽  
Molecular Mechanisms ◽  
Cholesterol Metabolism ◽  
Fold Increase ◽  
Heart Tissue ◽  
Control Group ◽  
Atherosclerotic Lesions ◽  
Serum Crp

Purpose. Hydroxytyrosol (HT) processes multiaspect pharmacological properties such as antithrombosis and antidiabetes. The aim of this study was to explore the antistherosclerotic roles and relevant mechanisms of HT. Methods. Male apoE-/- mice were randomly divided into 2 groups: the control group and the HT group (10 mg/kg/day orally). After 16 weeks, blood tissue, heart tissue, and liver tissue were obtained to detect the atherosclerotic lesions, histological analysis, lipid parameters, and inflammation. And the underlying molecular mechanisms of HT were also studied in vivo and in vitro. Results. HT administration significantly reduced the extent of atherosclerotic lesions in the aorta of apoE-/- mice. We found that HT markedly lowered the levels of serum TG, TC, and LDL-C approximately by 17.4% (p=0.004), 15.2% (p=0.003), and 17.9% (p=0.009), respectively, as well as hepatic TG and TC by 15.0% (p<0.001) and 12.3% (p=0.003), respectively, while inducing a 26.9% (p=0.033) increase in serum HDL-C. Besides, HT improved hepatic steatosis and lipid deposition. Then, we discovered that HT could regulate the signal flow of AMPK/SREBP2 and increase the expression of ABCA1, apoAI, and SRBI. In addition, HT reduced the levels of serum CRP, TNF-α, IL-1β, and IL-6 approximately by 23.5% (p<0.001), 27.8% (p<0.001), 18.4% (p<0.001), and 19.1% (p<0.001), respectively, and induced a 1.4-fold increase in IL-10 level (p=0.014). Further, we found that HT might regulate cholesterol metabolism via decreasing phosphorylation of p38, followed by activation of AMPK and inactivation of NF-κB, which in turn triggered the blockade of SREBP2/PCSK9 and upregulation of LDLR, apoAI, and ABCA1, finally leading to a reduction of LDL-C and increase of HDL-C in the circulation. Conclusion. Our results provide the first evidence that HT displays antiatherosclerotic actions via mediating lipid metabolism-related pathways through regulating the activities of inflammatory signaling molecules.

scholarly journals An Exon-Specific Small Nuclear U1 RNA (ExSpeU1) Improves Hepatic OTC Expression in a Splicing-Defective spf/ash Mouse Model of Ornithine Transcarbamylase Deficiency

2020 ◽  
Vol 21 (22) ◽  
pp. 8735
Author(s):  
Dario Balestra ◽  
Mattia Ferrarese ◽  
Silvia Lombardi ◽  
Nicole Ziliotto ◽  
Alessio Branchini ◽  
...  
Keyword(s):  
Mouse Model ◽  
Protein Function ◽  
Disease Onset ◽  
Fold Increase ◽  
Ornithine Transcarbamylase ◽  
Transduction Efficiency ◽  
Ornithine Transcarbamylase Deficiency ◽  
Adeno Associated Virus ◽  
Early Proof

OTC splicing mutations are generally associated with the severest and early disease onset of ornithine transcarbamylase deficiency (OTCD), the most common urea cycle disorder. Noticeably, splicing defects can be rescued by spliceosomal U1snRNA variants, which showed their efficacy in cellular and animal models. Here, we challenged an U1snRNA variant in the OTCD mouse model (spf/ash) carrying the mutation c.386G > A (p.R129H), also reported in OTCD patients. It is known that the R129H change does not impair protein function but affects pre-mRNA splicing since it is located within the 5′ splice site. Through in vitro studies, we identified an Exon Specific U1snRNA (ExSpeU1O3) that targets an intronic region downstream of the defective exon 4 and rescues exon inclusion. The adeno-associated virus (AAV8)-mediated delivery of the ExSpeU1O3 to mouse hepatocytes, although in the presence of a modest transduction efficiency, led to increased levels of correct OTC transcripts (from 6.1 ± 1.4% to 17.2 ± 4.5%, p = 0.0033). Consistently, this resulted in increased liver expression of OTC protein, as demonstrated by Western blotting (~3 fold increase) and immunostaining. Altogether data provide the early proof-of-principle of the efficacy of ExSpeU1 in the spf/ash mouse model and encourage further studies to assess the potential of RNA therapeutics for OTCD caused by aberrant splicing.

scholarly journals BLOOD PRESSURE, CHOLESTEROL CONTENT OF SERUM AND TISSUES, AND ATHEROGENESIS IN THE RAT

1958 ◽  
Vol 107 (4) ◽  
pp. 581-598 ◽  
Author(s):  
Q. B. Deming ◽  
E. H. Mosbach ◽  
M. Bevans ◽  
M. M. Daly ◽  
L. L. Abell ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Cholesterol Content ◽  
Local Effect ◽  
High Serum ◽  
Atherosclerotic Lesions ◽  
Human Atherosclerosis ◽  
Desoxycorticosterone Acetate ◽  
Tissue Cholesterol ◽  
Atherosclerotic Changes ◽  
Renal Artery Constriction

Rats on a stock diet with added cholesterol, cholic acid, and thiouracil developed increased concentrations of cholesterol, total lipide, and beta lipoprotein in the serum, and an increased content of cholesterol in the liver and carcass, despite the fact that the diet produced a cessation of endogenous cholesterol synthesis. Rats with high serum lipide concentrations developed intimal lesions similar to those of human atherosclerosis. The induction of hypertension by desoxycorticosterone and salt accelerated the development of hypercholesterolemia, hyperlipemia, increase in tissue cholesterol content, and atherosclerotic changes in the intima. Hypertension induced by renal artery constriction also intensified the hypercholesterolemia and hyperlipemia. On the other hand, rats receiving desoxycorticosterone acetate without salt or salt without desoxycorticosterone acetate did not show any intensification of hypercholesterolemia or hyperlipemia. The extent of the atherosclerotic lesions was correlated with the concentration of cholesterol in the serum. There was also a positive correlation between blood pressure and the degree of hypercholesterolemia. It remained uncertain whether the increase in atherosclerosis in the hypertensive animals was dependent on the increased lipide content of serum and tissues or on a local effect of the elevated blood pressure.

Sign in / Sign up

Export Citation Format

Share Document