Development of pharmacotherapies for abdominal aortic aneurysms

Weaver, Lauren; Loftin, Charles D.; Zhan, Chang‐Guo

doi:10.1016/j.biopha.2022.113340

Cited by 14 publications

(10 citation statements)

References 194 publications

(330 reference statements)

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“…Three hallmark pathways of AAA etiology encompass vascular smooth muscle cell (VSMC) dysfunction, extracellular matrix (ECM) remodeling, and upregulated inflammation 7 . Progressive damage to VSMCs contribute to weakening of vascular tone through apoptosis and phenotypic switches.…”

Section: Introductionmentioning

confidence: 99%

“…Elastin and collagen provide crucial support to the vessel wall but lose efficacy with negative remodeling. Inflammation remains a key mediator of AAA etiology 7 with prominent inflammatory factors hypothesized to drive AAA formation and progression 7 .…”

Section: Introductionmentioning

confidence: 99%

“…Significant work has been conducted to evaluate novel drugs in treating AAA which we have previously reviewed 7 . Prior clinical trials have examined several drugs to halt AAA progression.…”

Section: Introductionmentioning

confidence: 99%

“…So far, only repurposed drugs have been clinically investigated for the treatment of AAA. Among these, a high number have targeted inflammatory factors implicated in the disease 7 . Canakinumab (ACZ885) is a human anti-IL-1β, pemirolast (CRD007) targets pro-inflammatory mast cells, mesenchymal stem cell therapy is possibly anti-inflammatory, metformin agonizes AMPK to regulate VSMC function and macrophages, and cyclosporin A inhibits T cell activation 10 – 17 .…”

Section: Introductionmentioning

confidence: 99%

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A highly selective mPGES-1 inhibitor to block abdominal aortic aneurysm progression in the angiotensin mouse model

Weaver,

Stewart,

Ding

et al. 2024

Sci Rep

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Abdominal aortic aneurysm (AAA) is a deadly, permanent ballooning of the aortic artery. Pharmacological and genetic studies have pointed to multiple proteins, including microsomal prostaglandin E2 synthase-1 (mPGES-1), as potentially promising targets. However, it remains unknown whether administration of an mPGES-1 inhibitor can effectively attenuate AAA progression in animal models. There are still no FDA-approved pharmacological treatments for AAA. Current research stresses the importance of both anti-inflammatory drug targets and rigor of translatability. Notably, mPGES-1 is an inducible enzyme responsible for overproduction of prostaglandin E2 (PGE2)—a well-known principal pro-inflammatory prostanoid. Here we demonstrate for the first time that a highly selective mPGES-1 inhibitor (UK4b) can completely block further growth of AAA in the ApoE−/− angiotensin (Ang)II mouse model. Our findings show promise for the use of a mPGES-1 inhibitor like UK4b as interventional treatment of AAA and its potential translation into the clinical setting.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

A highly selective mPGES-1 inhibitor to block abdominal aortic aneurysm progression in the angiotensin mouse model

Weaver,

Stewart,

Ding

et al. 2024

Sci Rep

Self Cite

View full text Add to dashboard Cite

show abstract

“…As such, recent studies have investigated whether targeting inflammation signaling pathways can decrease AAA expansion and prevent its rupture (22)(23)(24)(25)(26). Despite early promising data in rodent models, to date there has been very limited translation in humans with AAA, and therefore the search for an inflammation-mediating strategy for AAA management remains critically needed (27).…”

Section: Introductionmentioning

confidence: 99%

Chemokine Receptor 2 Is A Theranostic Biomarker for Abdominal Aortic Aneurysms

Elizondo-Benedetto,

Sastriques-Dunlop,

Detering

et al. 2023

Preprint

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Abdominal aortic aneurysm (AAA) is a degenerative vascular disease impacting aging populations with a high mortality upon rupture. There are no effective medical therapies to prevent AAA expansion and rupture. We previously demonstrated the role of the monocyte chemoattractant protein-1 (MCP-1) / C-C chemokine receptor type 2 (CCR2) axis in rodent AAA pathogenesis via positron emission tomography/computed tomography (PET/CT) using CCR2 targeted radiotracer64Cu-DOTA-ECL1i. We have since translated this radiotracer into patients with AAA. CCR2 PET showed intense radiotracer uptake along the AAA wall in patients while little signal was observed in healthy volunteers. AAA tissues collected from individuals scanned with64Cu-DOTA-ECL1i and underwent open-repair later demonstrated more abundant CCR2+ cells compared to non-diseased aortas. We then used a CCR2 inhibitor (CCR2i) as targeted therapy in our established male and female rat AAA rupture models. We observed that CCR2i completely prevented AAA rupture in male rats and significantly decreased rupture rate in female AAA rats. PET/CT revealed substantial reduction of64Cu-DOTA-ECL1i uptake following CCR2i treatment in both rat models. Characterization of AAA tissues demonstrated decreased expression of CCR2+ cells and improved histopathological features. Taken together, our results indicate the potential of CCR2 as a theranostic biomarker for AAA management.Graphical Abstract

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Effective Hydrogel Vascular Patch Dual‐Loaded with Cycloastragenol Nanostructured Lipid Carriers and Doxycycline for Repairing Extravascular Injury in Abdominal Aortic Aneurysm

Chen,

Song,

Liu

et al. 2024

Adv Healthcare Materials

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Endovascular aneurysm repair (EVAR) plays a crucial role in the treatment of abdominal aortic aneurysm (AAA) in the clinic, but the aneurysm remains in the patient's body after surgery, continuing to pose a risk of progression. Cycloastragenol (CAG) is proven to be an effective anti‐AAA drug, and its vascular protective effects can be further improved when the hydrophobic CAG is encapsulated into nano‐sized formulations to enhance its bioavailability. In this context, this study developed an extravascular patch hydrogel loaded with CAG nanostructured lipid carriers and a hydrophilic drug of doxycycline hydrochloride (DOX). The extravascular patch delivered onto the mouse abdominal aortas can promote local permeation of hydrophilic/hydrophobic drugs at the vessel sites and provide effective vascular protection against AAA injury induced by elastase. This study introduces a novel and promising approach for AAA treatment, which can serve as a supplementary strategy after EVAR surgery.

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Development of pharmacotherapies for abdominal aortic aneurysms

Cited by 14 publications

References 194 publications

A highly selective mPGES-1 inhibitor to block abdominal aortic aneurysm progression in the angiotensin mouse model

A highly selective mPGES-1 inhibitor to block abdominal aortic aneurysm progression in the angiotensin mouse model

Chemokine Receptor 2 Is A Theranostic Biomarker for Abdominal Aortic Aneurysms

Effective Hydrogel Vascular Patch Dual‐Loaded with Cycloastragenol Nanostructured Lipid Carriers and Doxycycline for Repairing Extravascular Injury in Abdominal Aortic Aneurysm

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