Atherosclerosis and Thrombosis: Lessons from Animal Models

2001 ◽  
Vol 86 (07) ◽  
pp. 356-365 ◽  
Author(s):  
Lina Badimon
Keyword(s):  
Animal Models ◽  
Vascular Disease ◽  
Clinical Symptoms ◽  
Plaque Rupture ◽  
Disease Process ◽  
Renin Angiotensin System ◽  
Experimental Models ◽  
Therapeutic Interventions ◽  
Plaque Disruption ◽  
Progression Of Atherosclerosis

SummaryAtherothrombosis defines the occurrence of thrombosis on athero-sclerotic lesions. Atherosclerosis is the most prevalent disease of our time and its thrombotic complications are responsible for an exceedingly high number of deaths and disabilities. Over the past few years, experimental investigation and clinical and pathologic observations have led to a better understanding of how a thrombus forms and also of its incidence in acute ischemic syndromes. A thrombus is usually found secondary to atherosclerotic plaque disruption. Mural thrombosis, also at the site of plaque rupture, is an important mechanism in the progression of atherosclerosis even when symptoms are absent. Because atherosclerosis is a silent and asymptomatic disease until complications arise with thrombosis producing clinical symptoms, it is necessary to have models that reproduce the human disease in its early stages. Unfortunately, not all the experimental models of vascular disease have human resemblance and validity. Knowledge of the disease process and of what an experimental animal model can offer is a milestone for a successful investigation. Experimental models of vascular disease have enhanced our understanding of the pathophysiological processes leading to vascular obstruction in both spontaneous and accelerated atherosclerosis and thrombosis. Animal models have provided insight into the role of platelets, lipids, renin-angiotensin system (RAS), cytokines and growth factors in the evolution and progression of atherosclerosis and have suggested potential therapeutic interventions. Significant advances in our understanding of the vascular biology and pathology of atherosclerosis and thrombosis, and of the interactions of blood cells, lipids and proteins with the vascular wall, have allowed us to formulate new experimental hypotheses and to test therapeutic strategies, either pharmacological or surgical.

scholarly journals Mouse models of atherosclerosis and their suitability for the study of myocardial infarction

2020 ◽  
Vol 115 (6) ◽  
Author(s):  
Pelin Golforoush ◽  
Derek M. Yellon ◽  
Sean M. Davidson
Keyword(s):  
Myocardial Infarction ◽  
Coronary Artery ◽  
Animal Models ◽  
Mouse Models ◽  
Vascular Function ◽  
Plaque Rupture ◽  
Coronary Vessels ◽  
Experimental Models ◽  
Therapeutic Interventions ◽  
Great Vessels

AbstractAtherosclerotic plaques impair vascular function and can lead to arterial obstruction and tissue ischaemia. Rupture of an atherosclerotic plaque within a coronary artery can result in an acute myocardial infarction, which is responsible for significant morbidity and mortality worldwide. Prompt reperfusion can salvage some of the ischaemic territory, but ischaemia and reperfusion (IR) still causes substantial injury and is, therefore, a therapeutic target for further infarct limitation. Numerous cardioprotective strategies have been identified that can limit IR injury in animal models, but none have yet been translated effectively to patients. This disconnect prompts an urgent re-examination of the experimental models used to study IR. Since coronary atherosclerosis is the most prevalent morbidity in this patient population, and impairs coronary vessel function, it is potentially a major confounder in cardioprotective studies. Surprisingly, most studies suggest that atherosclerosis does not have a major impact on cardioprotection in mouse models. However, a major limitation of atherosclerotic animal models is that the plaques usually manifest in the aorta and proximal great vessels, and rarely in the coronary vessels. In this review, we examine the commonly used mouse models of atherosclerosis and their effect on coronary artery function and infarct size. We conclude that none of the commonly used strains of mice are ideal for this purpose; however, more recently developed mouse models of atherosclerosis fulfil the requirement for coronary artery lesions, plaque rupture and lipoprotein patterns resembling the human profile, and may enable the identification of therapeutic interventions more applicable in the clinical setting.

Acute renal failure. II. Experimental models of acute renal failure: imperfect but indispensable

2000 ◽  
Vol 278 (1) ◽  
pp. F1-F12 ◽  
Keyword(s):  
Renal Failure ◽  
Acute Renal Failure ◽  
Animal Models ◽  
Renal Injury ◽  
Clinical Studies ◽  
Basic Research ◽  
Experimental Models ◽  
Clinical Syndrome ◽  
Therapeutic Interventions ◽  
Common Disease

Acute renal failure (ARF) due to ischemic 1 or toxic renal injury, a clinical syndrome traditionally referred to as acute tubular necrosis (ATN), is a common disease with a high overall mortality of ∼50%. Little progress has been made since the advent of dialysis more than 30 years ago in improving this outcome. During this same period, a considerable amount of basic research has been devoted to elucidating the pathophysiology of ATN. The ultimate goal of this research is to facilitate the development of therapeutic interventions that either prevent ARF, ameliorate the severity of tubular injury following an acute ischemic or toxic renal insult, or accelerate the recovery of established ATN. This research endeavor has been highly successful in elucidating many vascular and tubular abnormalities that are likely to be involved in ischemic and toxic ARF. This information has led to impressive advances in the development of a number of different pharmacological interventions that are highly effective in ameliorating the renal dysfunction in animal models of ARF. Although these developments are exciting and promising, enthusiasm of investigators involved in this endeavor has been tempered somewhat by the results of a few recent clinical studies of patients with ATN. These trials, designed to examine the efficacy in humans of some of the interventions effective in animal models of ARF, have resulted in little or no benefit. This is therefore an important time to reevaluate the approaches we have taken over the past three to four decades to develop new and effective treatments for ATN in humans. The major goals of this review are 1) to evaluate the relevance and utility of the experimental models currently available to study ischemic and toxic renal injury, 2) to suggest novel experimental approaches and models that have the potential to provide advantages over methods currently available, 3) to discuss ways of integrating results obtained from different experimental models of acute renal injury and of evaluating the relevance of these findings to ATN in humans, and 4) to discuss the difficulties inherent in clinical studies of ATN and to suggest how studies should be best designed to overcome these problems.

scholarly journals Inflammation and autoimmunity in pulmonary hypertension: is there a role for endothelial adhesion molecules? (2017 Grover Conference Series)

2018 ◽  
Vol 8 (2) ◽  
pp. 204589321875759 ◽  
Author(s):  
Wolfgang M. Kuebler ◽  
Sébastien Bonnet ◽  
Arata Tabuchi
Keyword(s):  
Pulmonary Hypertension ◽  
Potential Role ◽  
Disease Process ◽  
Experimental Models ◽  
Therapeutic Interventions ◽  
Pulmonary Resistance ◽  
Resistance Vessels ◽  
Endothelial Adhesion Molecules ◽  
Inflammatory Component

While pulmonary hypertension (PH) has traditionally not been considered as a disease that is directly linked to or, potentially, even caused by inflammation, a rapidly growing body of evidence has demonstrated the accumulation of a variety of inflammatory and immune cells in PH lungs, in and around the wall of remodeled pulmonary resistance vessels and in the vicinity of plexiform lesions, respectively. Concomitantly, abundant production and release of various inflammatory mediators has been documented in both PH patients and experimental models of PH. While these findings unequivocally demonstrate an inflammatory component in PH, they have fueled an intense and presently ongoing debate as to the nature of this inflammatory aspect: is it a mere bystander of or response to the actual disease process, or is it a pathomechanistic contributor or potentially even a trigger of endothelial injury, smooth muscle hypertrophy and hyperplasia, and the resulting lung vascular remodeling? In this review, we will discuss the present evidence for an inflammatory component in PH disease with a specific focus on the potential role of the endothelium in this scenario and highlight future avenues of experimental investigation which may lead to novel therapeutic interventions.

scholarly journals Encapsulating Peritoneal Sclerosis: Pathophysiology and Current Treatment Options

2019 ◽  
Vol 20 (22) ◽  
pp. 5765 ◽  
Author(s):  
Rajesh M. Jagirdar ◽  
Andreas Bozikas ◽  
Sotirios G. Zarogiannis ◽  
Maria Bartosova ◽  
Claus Peter Schmitt ◽  
...  
Keyword(s):  
Intestinal Obstruction ◽  
Animal Studies ◽  
Clinical Symptoms ◽  
Treatment Options ◽  
Renin Angiotensin System ◽  
Mtor Inhibitors ◽  
Current Treatment ◽  
Therapeutic Interventions ◽  
Ultrafiltration Failure

Encapsulating peritoneal sclerosis (EPS) is a life-threatening complication of long-term peritoneal dialysis (PD), which may even occur after patients have switched to hemodialysis (HD) or undergone kidney transplantation. The incidence of EPS varies across the globe and increases with PD vintage. Causative factors are the chronic exposure to bioincompatible PD solutions, which cause long-term modifications of the peritoneum, a high peritoneal transporter status involving high glucose concentrations, peritonitis episodes, and smoldering peritoneal inflammation. Additional potential causes are predisposing genetic factors and some medications. Clinical symptoms comprise signs of intestinal obstruction and a high peritoneal transporter status with incipient ultrafiltration failure. In radiological, macro-, and microscopic studies, a massively fibrotic and calcified peritoneum enclosed the intestine and parietal wall in such cases. Empirical treatments commonly used are corticosteroids and tamoxifen, which has fibrinolytic properties. Immunosuppressants like azathioprine, mycophenolate mofetil, or mTOR inhibitors may also help with reducing inflammation, fibrin deposition, and collagen synthesis and maturation. In animal studies, N-acetylcysteine, colchicine, rosiglitazone, thalidomide, and renin-angiotensin system (RAS) inhibitors yielded promising results. Surgical treatment has mainly been performed in severe cases of intestinal obstruction, with varying results. Mortality rates are still 25–55% in adults and about 14% in children. To reduce the incidence of EPS and improve the outcome of this devastating complication of chronic PD, vigorous consideration of the risk factors, early diagnosis, and timely discontinuation of PD and therapeutic interventions are mandatory, even though these are merely based on empirical evidence.

scholarly journals Experimental animal models of coronary microvascular dysfunction

2020 ◽  
Vol 116 (4) ◽  
pp. 756-770 ◽  
Author(s):  
Oana Sorop ◽  
Jens van de Wouw ◽  
Selena Chandler ◽  
Vahagn Ohanyan ◽  
Johnathan D Tune ◽  
...  
Keyword(s):  
Risk Factors ◽  
Animal Models ◽  
Obstructive Coronary Artery Disease ◽  
Subsequent Development ◽  
Microvascular Dysfunction ◽  
Transgenic Animal ◽  
Experimental Models ◽  
Therapeutic Interventions ◽  
Coronary Microvascular Dysfunction ◽  
Novel Therapeutic

Abstract Coronary microvascular dysfunction (CMD) is commonly present in patients with metabolic derangements and is increasingly recognized as an important contributor to myocardial ischaemia, both in the presence and absence of epicardial coronary atherosclerosis. The latter condition is termed ‘ischaemia and no obstructive coronary artery disease’ (INOCA). Notwithstanding the high prevalence of INOCA, effective treatment remains elusive. Although to date there is no animal model for INOCA, animal models of CMD, one of the hallmarks of INOCA, offer excellent test models for enhancing our understanding of the pathophysiology of CMD and for investigating novel therapies. This article presents an overview of currently available experimental models of CMD—with an emphasis on metabolic derangements as risk factors—in dogs, swine, rabbits, rats, and mice. In all available animal models, metabolic derangements are most often induced by a high-fat diet (HFD) and/or diabetes mellitus via injection of alloxan or streptozotocin, but there is also a wide variety of spontaneous as well as transgenic animal models which develop metabolic derangements. Depending on the number, severity, and duration of exposure to risk factors—all these animal models show perturbations in coronary microvascular (endothelial) function and structure, similar to what has been observed in patients with INOCA and comorbid conditions. The use of these animal models will be instrumental in identifying novel therapeutic targets and for the subsequent development and testing of novel therapeutic interventions to combat ischaemic heart disease, the number one cause of death worldwide.

Experimental Animal Models of Alzheimer’s Disease

2013 ◽  
pp. 810-820
Author(s):  
Dave Morgan
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Animal Models ◽  
Disease Process ◽  
Experimental Models ◽  
Rodent Models ◽  
Clinical Testing ◽  
Experimental Animal Models ◽  
Mechanisms Of Toxicity ◽  
Amyloid Deposits

Animal models of human disease provide opportunities to learn more regarding the mechanisms responsible for the disease process and provide a platform in which to screen therapeutic agents. Earliest rodent models provided platforms in which to test symptomatic treatments. More recent platforms injecting Aβ‎ are providing information regarding mechanisms of toxicity. Finally, the success in finding transgenic amyloid precursor protein constructs that lead to a measureable cognitive phenotype and amyloid deposits resembling those in Alzheimer’s disease permit screening of anti-amyloid agents intended for clinical testing. Although imperfect, these experimental models have permitted scientists to learn a bit more about the mechanisms of dementia.

ACE2 as therapeutic agent

2020 ◽  
Vol 134 (19) ◽  
pp. 2581-2595
Author(s):  
Qiuhong Li ◽  
Maria B. Grant ◽  
Elaine M. Richards ◽  
Mohan K. Raizada
Keyword(s):  
Therapeutic Agent ◽  
Renin Angiotensin System ◽  
Peptide Hormone ◽  
Experimental Models ◽  
Electrolyte Balance ◽  
Ang Ii ◽  
Angiotensin Converting Enzyme 2 ◽  
Beneficial Effects ◽  
Overwhelming Evidence ◽  
Future Challenges

Abstract The angiotensin-converting enzyme 2 (ACE2) has emerged as a critical regulator of the renin–angiotensin system (RAS), which plays important roles in cardiovascular homeostasis by regulating vascular tone, fluid and electrolyte balance. ACE2 functions as a carboxymonopeptidase hydrolyzing the cleavage of a single C-terminal residue from Angiotensin-II (Ang-II), the key peptide hormone of RAS, to form Angiotensin-(1-7) (Ang-(1-7)), which binds to the G-protein–coupled Mas receptor and activates signaling pathways that counteract the pathways activated by Ang-II. ACE2 is expressed in a variety of tissues and overwhelming evidence substantiates the beneficial effects of enhancing ACE2/Ang-(1-7)/Mas axis under many pathological conditions in these tissues in experimental models. This review will provide a succinct overview on current strategies to enhance ACE2 as therapeutic agent, and discuss limitations and future challenges. ACE2 also has other functions, such as acting as a co-factor for amino acid transport and being exploited by the severe acute respiratory syndrome coronaviruses (SARS-CoVs) as cellular entry receptor, the implications of these functions in development of ACE2-based therapeutics will also be discussed.

scholarly journals Are We Paving the Way to Dig Out of the “Pandemic Hole”? A Narrative Review on SARS-CoV-2 Vaccination: From Animal Models to Human Immunization

2021 ◽  
Vol 9 (3) ◽  
pp. 53
Author(s):  
Giuseppe Tardiolo ◽  
Pina Brianti ◽  
Daniela Sapienza ◽  
Pia dell’Utri ◽  
Viviane Di Dio ◽  
...  
Keyword(s):  
Animal Models ◽  
Viral Vector ◽  
Herd Immunity ◽  
Population Level ◽  
Narrative Review ◽  
Therapeutic Interventions ◽  
Preclinical Research ◽  
Inactivated Vaccines ◽  
Preclinical And Clinical Studies ◽  
Social Upheaval

The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is a new pathogen agent causing the coronavirus infectious disease (COVID-19). This novel virus originated the most challenging pandemic in this century, causing economic and social upheaval internationally. The extreme infectiousness and high mortality rates incentivized the development of vaccines to control this pandemic to prevent further morbidity and mortality. This international scenario led academic scientists, industries, and governments to work and collaborate strongly to make a portfolio of vaccines available at an unprecedented pace. Indeed, the robust collaboration between public systems and private companies led to resolutive actions for accelerating therapeutic interventions and vaccines mechanism. These strategies contributed to rapidly identifying safe and effective vaccines as quickly and efficiently as possible. Preclinical research employed animal models to develop vaccines that induce protective and long-lived immune responses. A spectrum of vaccines is worldwide under investigation in various preclinical and clinical studies to develop both individual protection and safe development of population-level herd immunity. Companies employed and developed different technological approaches for vaccines production, including inactivated vaccines, live-attenuated, non-replicating viral vector vaccines, as well as acid nucleic-based vaccines. In this view, the present narrative review provides an overview of current vaccination strategies, taking into account both preclinical studies and clinical trials in humans. Furthermore, to better understand immunization, animal models on SARS-CoV-2 pathogenesis are also briefly discussed.

scholarly journals Upregulation of the Renin–Angiotensin System Pathways and SARS-CoV-2 Infection: The Rationale for the Administration of Zinc-Chelating Agents in COVID-19 Patients

Cells ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 506
Author(s):  
Loris Zamai
Keyword(s):  
Chelating Agents ◽  
Ethylenediaminetetraacetic Acid ◽  
Current Knowledge ◽  
Clinical Manifestations ◽  
Renin Angiotensin System ◽  
Experimental Models ◽  
Zinc Metalloprotease ◽  
Previous Hypothesis ◽  
Zinc Metalloproteases

The article describes the rationale for the administration of zinc-chelating agents in COVID-19 patients. In a previous work I have highlighted that the binding of the SARS-CoV spike proteins to the zinc-metalloprotease ACE2 has been shown to induce ACE2 shedding by activating the zinc-metalloprotease ADAM17, which ultimately leads to systemic upregulation of ACE2 activity. Moreover, based on experimental models, it was also shown the detrimental effect of the excessive systemic activity of ACE2 through its downstream pathways, which leads to “clinical” manifestations resembling COVID-19. In this regard, strong upregulation of circulating ACE2 activity was recently reported in COVID-19 patients, thus supporting the previous hypothesis that COVID-19 may derive from upregulation of ACE2 activity. Based on this, a reasonable hypothesis of using inhibitors that curb the upregulation of both ACE2 and ADAM17 zinc-metalloprotease activities and consequent positive feedback-loops (initially triggered by SARS-CoV-2 and subsequently sustained independently on viral trigger) is proposed as therapy for COVID-19. In particular, zinc-chelating agents such as citrate and ethylenediaminetetraacetic acid (EDTA) alone or in combination are expected to act in protecting from COVID-19 at different levels thanks to their both anticoagulant properties and inhibitory activity on zinc-metalloproteases. Several arguments are presented in support of this hypothesis and based on the current knowledge of both beneficial/harmful effects and cost/effectiveness, the use of chelating agents in the prevention and therapy of COVID-19 is proposed. In this regard, clinical trials (currently absent) employing citrate/EDTA in COVID-19 are urgently needed in order to shed more light on the efficacy of zinc chelators against SARS-CoV-2 infection in vivo.

Measuring Disease Modification in Alzheimer's Disease

CNS Spectrums ◽  
2007 ◽  
Vol 12 (S1) ◽  
pp. 11-14
Author(s):  
Jeffrey L. Cummings
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Immunoglobulin A ◽  
Disease Process ◽  
Underlying Disease ◽  
Therapeutic Interventions ◽  
Disease Modification ◽  
Amyloid Disease ◽  
Therapeutic Modalities ◽  
Disease Modifying

AbstractWe appear to be on the brink of a new epoch of treatment for Alzheimer's disease. Compelling evidence suggests that Aβ42 secretion is the triggering event in the pathogenesis of Alzheimer's disease, and that tau aggregation may be an important secondary event linked to neurodegeneration. Prophylactic administration of anti-amyloid agents designed to prevent Aβ accumulation in persons with subclinical disease is likely to be more effective than therapeutic interventions in established Alzheimer's disease. Drug development programs in Alzheimer's disease focus primarily on agents with anti-amyloid disease-modifying properties, and many different pharmacologic approaches to reducing amyloid pathology and tauopathy are being studied. Classes of therapeutic modalities currently in advanced-stage clinical trial testing include forms of immunotherapy (active β -amyloid immunoconjugate and human intravenous immunoglobulin), a γ-secretase inhibitor, the selective Aβ42-lowering agent R-flurbiprofen, and the anti-aggregation agent tramiprosate. Non-traditional dementia therapies such as the HMG-CoA reductase inhibitors (statins), valproate, and lithium are now being assessed for clinical benefit as anti-amyloid disease-modifying treatments. Positive findings of efficacy and safety from clinical studies are necessary but not sufficient to demonstrate that a drug has disease-modifying properties. Definitive proof of disease-modification requires evidence from validated animal models of Alzheimer's disease; rigorously controlled clinical trials showing a significantly improved, stabilized, or slowed rate of decline in cognitive and global function compared to placebo; and prospectively obtained evidence from surrogate biomarkers that the treatment resulted in measurable biological changes associated with the underlying disease process.

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