Current Drug Targets - Volume 19, Issue 11, 2018

Background: Adipose tissue plays a role in the storage of excess energy as triglycerides (TGs). Excess fat accumulation causes various metabolic and cardiovascular diseases. It has been reported that ectopic fat deposition and excess TG accumulation in non-adipose tissue might be important predictors of cardiometabolic and vascular risk. For example, ectopic fat in perivascular tissue promotes atherosclerotic plaque formation in the arterial wall. Objective: Recently, it has been reported that ectopic fat (adipocyte) in the vascular wall of an abdominal aortic aneurysm (AAA) is present in both human and experimental animal models. The pathological significance of adipocytes in the AAA wall has not been fully understood. In this review, we summarized the functions of adipocytes and discussed potential new drugs that target vascular adipocytes for AAA treatment. Result: Previous studies suggest that adipocytes in vascular wall play an important role in the development of AAA. Conclusion: Adipocytes in the vascular wall could be novel targets for the development of AAA therapeutic drugs.

Abdominal aortic aneurysms (AAA) are a major cause of death. Currently, the mainstay of treatment for AAA is surgical repair and there are no FDA approved medical therapies for AAA. Much research is in progress to discover new medical therapies for AAA. The pathophysiology of AAA is understood to be a complex interplay of inflammatory and proteolytic processes that degenerate the aneurysm wall. Arterial calcification, which is observed in AAA but to a lesser extent than in arterial occlusive disease, occurs in a highly regulated manner in a similar process as mineral deposition in bone. Osteoblasts-like cells are responsible for mineral deposition in atherosclerotic plaques. Recently, osteoclast-like cells – the catabolic counterpart to osteoblasts – were discovered in atherosclerotic plaques. Additionally, osteoclast-like cells are present in the wall of AAA but not in healthy aortas. Osteoclast-like cells secrete matrix metalloproteinases (MMP) – proteases implicated in arterial aneurysm wall degeneration – and may contribute to the degredation of the aneurysm wall. Inhibiting osteoclast-like cells may prevent aneurysm progression by reducing tissue levels of MMPs. In this review, we discuss the pathophysiology of AAA formation and the current role of medical therapy in treatment of AAA. Furthermore, we highlight the emerging hypothesis that osteoclasts play a key role in the development of AAA and discuss therapies to inhibit osteoclastogenesis in AAA.

Objective: This mini-review provides the rationale and updated progress for ongoing randomized controlled trials assessing fenofibrate and telmisartan efficacy to limit abdominal aortic aneurysm (AAA) growth. Methods/Results: There remains an urgent need to identify a drug therapy that will limit AAA growth. Data from preclinical and human studies indicate that fenofibrate and telmisartan have the potential to slow aortic destruction. Fenofibrate has been shown to reduce serum and tissue levels of the proinflammatory protein osteopontin, as well as reducing macrophage recruitment to the aortic wall, both of which are integral processes in the development and progression of AAAs. Telmisartan acts via blockade of the angiotensin II receptor, type 1, and also as a peroxisome proliferator-activated receptor gamma agonist. In turn, this inhibits the production of a range of biomarkers associated with AAA progression, including transforming growth factor-beta one, osteoprotegerin, osteopontin and matrix metalloproteinase- 9. Based on these findings, there are currently three randomized controlled trials assessing both fenofibrate and telmisartan as potential interventions to limit aneurysm growth in AAA patients. Conclusion: Fenofibrate and telmisartan have potential as repurposed medications to limit AAA growth, and randomized trials for further assessment in AAA patients are ongoing.

Background: Abdominal aortic aneurysm (AAA) is one of the leading causes of death in western countries. Surgery is still, at the present time, the sole treatment that has however a significant mortality and cost rate. Many pharmacological agents are under investigation aiming to reduce growth and prevent AAA rupture. These drugs target different pathological pathways and, notably, the excessive production of prostanoids by cyclooxygenases (COX). Intra-aneurysmal thrombus plays an adverse key role in the progression of AAA, platelets being a primary source of prostanoids as thromboxane A2. Objective: In this review, we summarize studies targeting prostanoids production and down-stream pathways in cardiovascular diseases, and more specifically in AAA. Results and Conclusion: Various inhibitors of COX or antagonists of prostanoids receptors have been investigated in AAA animal models with conflicting results. In human AAA, only a few number of studies focused on anti-platelet therapy mostly using acetylsalicylic acid (aspirin, ASA), a COX1 inhibitor. Finally, we report preliminary promising results of a model of AAA in rats receiving a thromboxane A2 inhibitor, BM-573 that induced a reduction of aneurysmal growth.

Background: Abdominal aortic aneurysm (AAA) is a degenerative disease that causes mortality in people aged > 65 years. Increased reactive oxygen species (ROS) and oxidative stress seem to play a pivotal role in AAA pathogenesis. Several sources of ROS have been identified in aortic tissues using experimental models: inflammation, increased activity of NAD(P)H or NOX, over-expression of inducible nitric oxide synthase (iNOS), uncoupled endothelial nitric oxide synthase (eNOS), platelets activation and iron release from hemoglobin. Objectives: Human studies confirmed that oxidative stress and endothelial dysfunction, an important source of ROS production, were well associated with AAA development. Reducing oxidative stress by antioxidants can therefore be a good strategy for limiting AAA development. The objective of the present study is to review literature data favoring or not such a hypothesis. There is currently no evidence showing that strategies using classical low molecular weight antioxidants (vitamins C and E, β- carotene) as target for ROS is effective to reduce human AAA progression. However, recent epidemiological data have highlighted the positive role of a diet enriched in fruits which contain high amounts of antioxidant polyphenols. By their ability to restore endothelial function and also their capacity to stimulate enzymatic antioxidants through activation of the Keap1/Nrf2/ARE pathway, polyphenols can represent a promising treatment target for reducing human AAA progression. Conclusion: Clinical studies are therefore urgently necessary to confirm the potential beneficial effect of polyphenols in preventing or limiting AAA.

Background: Abdominal aortic aneurysm (AAA), a common disease involving the segmental expansion and rupture of the aorta, has a high mortality rate. Therapeutic options for AAA are currently limited to surgical repair to prevent catastrophic rupture. Non-surgical approaches, particularly pharmacotherapy, are lacking for the treatment of AAA. Objective: We review both basic and clinical studies and discuss the current challenges to developing medical therapy that reduces AAA progression. Results: Studies using animal models of AAA progression and human AAA explant cultures have identified several potential targets for preventing AAA growth. However, no clinical studies have convincingly confirmed the efficacy of any pharmacologic treatment against the growth of AAA. Thus, there is as yet no strong recommendation regarding pharmacotherapy to reduce the risk of AAA progression and rupture. Conclusion: This review identifies concerns that need to be addressed for the field to progress and discusses the challenges that must be overcome in order to develop effective pharmacotherapy to reduce AAA progression in the future.

Aortic aneurysms represent a significant clinical problem as they largely go undetected until a rupture occurs. Currently, an understanding of mechanisms leading to aneurysm formation is limited. Numerous studies clearly indicate that vascular smooth muscle cells play a major role in the development and response of the vasculature to hemodynamic changes and defects in these responses can lead to aneurysm formation. The LDL receptor-related protein 1 (LRP1) is major smooth muscle cell receptor that has the capacity to mediate the endocytosis of numerous ligands and to initiate and regulate signaling pathways. Genetic evidence in humans and mouse models reveal a critical role for LRP1 in maintaining the integrity of the vasculature. Understanding the mechanisms by which this is accomplished represents an important area of research, and likely involves LRP1's ability to regulate levels of proteases known to degrade the extracellular matrix as well as its ability to modulate signaling events.

Abdominal aortic aneurysm (AAA), a common disease among elderly individuals, involves the progressive dilatation of the abdominal aorta as a consequence of degeneration. The mechanisms of AAA formation, development and rupture are largely unknown. Surgical repair is the only available method of treatment since the lack of knowledge regarding the pathogenesis of AAA has hindered the development of suitable medical treatments, particularly the development of drugs. In this review, we describe the inflammatory cells and proteases that may be involved in the formation and development of AAA. This knowledge can contribute to the development of new drugs for AAA.

Background: Abdominal aortic aneurysm (AAA), if left untreated, poses the main risks of progressive expansion, rupture, and hemorrhage, leading to death. Large AAA with a risk of rupture is usually treated by graft replacement or endovascular aneurysm repair. Nonsurgical treatment is not an alternative for large AAA, but is potentially beneficial for small AAA which usually requires a watchful waiting approach with medication. Objective: We introduce current clinical research regarding the pharmacological treatment of small AAA and assess the optimal time for starting the treatment. Results: Data from current clinical researches on pharmacological treatment of AAA investigating the efficacy of pharmacological treatment to limit AAA growth were presented and introduced the medicines currently evaluated by randomized controlled trials for their efficacy for AAA. Conclusion: The optimal time to administer pharmacological treatment for AAA is during the stage wherein its diameter is still small. To detect early small-diameter AAA, screening tests are mandatory in high-risk patients. For pharmacological treatment, the drug that shows acceptable results in clinical tests and is the most effective for the patient's condition should be carefully selected. Lifestyle changes should also accompany pharmacological treatment.

Background: Abdominal aortic aneurysm (AAA) refers to localized dilation of abdominal aorta. AAA is largely asymptomatic, but aneurysmal rupture results in a high mortality rate. AAA with a diameter greater than 55 mm carries a high risk of rupture. There are currently no known medical treatments effective in limiting the growth of small AAA. Objective: To review the current status of and challenges faced in limiting AAA growth. Methods: Data from human investigations and animal model studies were summarized. In particular, the ClinicalTrials.gov website was searched for details of ongoing or completed studies related to AAA growth. We searched the key words ‘abdominal aortic aneurysm’ and ‘drugs’ to identify potential target drugs for slowing or stopping AAA growth. Results: These clinical trials involve a number of challenges, including demonstrating the design of the trial, minimizing the participant dropout rate, and developing accurate outcome assessments during the trials. A number of clinical trials have concentrated on pharmaceutical intervention (such as angiotensin- converting enzyme inhibitors, beta-blockers, statins, and antibiotics) that could be effective for AAA patients in delaying or reversing aneurysm expansion and postponing the endpoint for elective surgical repair. Conclusions: Further randomized, controlled, clinical trials are required to develop effective nonsurgical therapies for AAA.

Background: Abdominal aortic aneurysms (AAA) are life-threatening because of the potential for rupture, resulting in death. The current standard treatment for AAA is surgery, comprising laparotomic graft replacement and endovascular repair. However, because surgery carries the risk of major complications and re-intervention, drug therapies are desirable because they may reduce the occurrence of enlargement and rupture. Objective: Recent research shows that the progression of AAA is related to inflammatory reactions, especially those in the NF-ΚB pathway. Omega-3 polyunsaturated fatty acids (PUFA) show antiinflammatory effects. Some derivatives of omega-3 PUFA are known as specialized pro-resolving lipid mediators (SPM) such as resolvins. They play an important role in resolving inflammation. Conclusion: Omega-3 PUFA and SPM may show promised effects for drug treatment of AAA.

Background: Abdominal aortic aneurysm (AAA) is a chronic degenerative inflammatory disease. Multi-factors including genetic, environmental and lifestyle factors determine the onsets and progression of AAAs. Currently surgical repair remains the only effective aneurysm treatment, but no pharmacological therapy is available for limiting further enlargement of small AAAs and fetal rupture. Objective: This article is to review our current understanding of angiotensin II (Ang II) and its type 1 receptor (AT1) in AAA pathogenesis as well as the translational potential of AT1 receptor blocker (ARB) treatment for treating clinical AAA disease. Results: While many pathways or molecules have been shown to associate with AAA formation and progression, accumulating evidence indicates the most significant importance of peptide hormone Ang II and its receptor AT1 in AAA pathogenesis and suggests the translational value of targeting inhibition of AT1 in treating clinical AAA disease. This review summarized the influences of AT1 deficiency and pharmacological ARB treatment on experimental AAAs. A discussion has also been made on whether and how ARB medication in AAA patients changes the natural course of clinical AAAs, including aneurysm enlargement rate, rupture and AAA-specific mortality. Additionally, we provided information on two registered clinical trials which are to test the efficacy of telmisartan and valsartan in limiting small AAA enlargement. Conclusion: Ang II/AT1 pathway plays a critical role in aneurysmal pathogenesis. Targeting AT1 via ARB will help establishing novel pharmacological therapies for limiting continuous enlargement of small AAAs in patients.

Background: An abdominal aortic aneurysm (AAA), which affects approximately 10% of Japanese men aged ≥ 65 years, is frequently associated with hypertension, dyslipidemia, and other lifestyle- related diseases. The development of an AAA is attributed to chronic inflammation concomitant with arteriosclerotic changes. However, an accurate pathomechanism associated with AAA remains uncertain, and questions such as why only a particular group/percentage of patients with arteriosclerosis develop aneurysms and how diabetes suppresses aneurysm development remain unanswered. Objective: We examined a novel mechanism to develop AAA based on histopathological findings following analysis of the human AAA tissues. Additionally, based on these findings, we developed a new animal model of AAA, in which the histopathological characteristics are similar to human AAA tissue. Results: Recently, we identified stenosis of the vasa vasorum (VV) in aortic segments showing dilatation. The aorta is the largest artery in our circulatory system. Under physiological conditions, the inner layer of the aorta is nourished via direct diffusion of nutrients from the luminal blood flow, whereas the outer adventitia is primarily perfused by the VV. Therefore, hypoperfusion of the VV induces hypoxia and subsequent inflammation and tissue degeneration of the aortic wall, resulting in aneurysm formation. Based on these findings, we established an AAA animal model by reducing the blood flow through the VV to the aortic wall. AAA was successfully reproduced in our animal model. Histopathological findings in this model were indistinguishable from those observed in humans, and pronounced abnormality in lipid composition in blood vessel adventitia was also observed. Conclusion: Thus, hypoperfusion of the aortic wall appeared to be sufficient to cause inflammationinduced AAA. These findings may provide potential targets for novel therapeutics for the management of an AAA.

Despite widespread clinical use of anesthetics, the exact mechanisms of anesthetic action are unclear. In terms of physiological action, a broad mechanism of general anesthesia including perturbations of neurotransmission has been suggested. However, the mechanism of anesthetic action at the molecular level is less clear. Specifically, how anesthetics affect neurons and glial cells and which proteins they interact with remains to be explored. Several recent studies have investigated the molecular interactions between proteins and anesthetics. In this review, we summarize the molecular mechanisms of anesthetic action in the intracellular signaling pathways of neuronal and glial cells.

Although β2-receceptor agonists are powerful bronchodilators and are at the forefront of asthma symptom relief, patients who use them frequently develop partial resistance to them. This can be a particularly serious problem during severe attacks, where high dose β2-agonist treatment is the front line therapy. Alternative bronchodilators are urgently needed. In this article we review the evidence for the bronchodilator effects of the cannabinoid CB1 receptor tetrahydrocannabinol (THC) and suggest that the mechanisms of action for these effects are sufficiently independent of the mechanisms of standard bronchodilators to warrant clinical investigation. Specifically, clinical trials testing the bronchodilator effects of THC in β2 agonist resistant asthmatic patients would show whether THC could fill the role of rescue bronchodilator in cases of β2 agonist resistance.