Anti-inflammatory effects of endothelin receptor blockade in left atrial tissue of spontaneously hypertensive rats

Bukowska, Alicja; Nikonova, Yulia; Wolke, Carmen; Lendeckel, Uwe; Kockskämper, Jens; Goette, Andreas

doi:10.1016/j.ijcha.2022.101088

Cited by 8 publications

(14 citation statements)

References 47 publications

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“… 59 , 73 , 74 Based on the pharmacogenomic profiling, in silico, and in vitro findings, we found that macitentan is a potent inhibitor of the integrin α9/VCAM-1 interaction. Consistent with the reported anti-inflammatory effects of macitentan, 75 , 76 we found that macitentan inhibited neutrophil adhesion to the activated endothelium at the venous shear rate and reduced DVT severity. Several studies have shown that the pharmacological inhibition of integrin α9 using an anti-integrin α9 antibody improves stroke outcomes, 34 , 43 reduces the severity of rheumatoid arthritis, 62 , 63 inhibits arterial thrombosis, 32 and regulates injury-induced neointimal hyperplasia.…”

Section: Discussionsupporting

confidence: 90%

Interactions between integrin α9β1 and VCAM-1 promote neutrophil hyperactivation and mediate poststroke DVT

Pandey,

Kaur,

Chorawala

et al. 2024

Blood Advances

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Venous thromboembolic events are significant contributors to morbidity and mortality in patients with stroke. Neutrophils are among the first cells in the blood to respond to stroke and are known to promote deep vein thrombosis (DVT). Integrin α9 is a transmembrane glycoprotein, highly expressed on neutrophils and stabilizes neutrophil adhesion to activated endothelium via vascular cell adhesion molecule 1 (VCAM-1). Nevertheless, the causative role of neutrophil integrin α9 in post-stroke DVT remains unknown. Here, we found higher neutrophil integrin α9 and plasma VCAM-1 levels in humans and mice with stroke. Using mice with embolic stroke, we observed enhanced DVT severity in a novel model of post-stroke DVT. Neutrophil-specific integrin α9 deficient mice (α9fl/flMrp8Cre+/−) exhibited a significant reduction in post-stroke DVT severity along with decreased neutrophils and citrullinated histone H3 in thrombi. Unbiased transcriptomics indicated that α9/VCAM-1 interactions induced pathways related to neutrophil inflammation, exocytosis, NF-κB signaling, and chemotaxis. Mechanistic studies revealed that integrin α9/VCAM-1 interactions mediate neutrophil adhesion at the venous shear rate, promote neutrophil hyperactivation, increase phosphorylation of extracellular signal-regulated kinase (ERK), and induce endothelial cell apoptosis. Using pharmacogenomic profiling, virtual screening, and in vitro assays, we identified macitentan as a potent inhibitor of integrin α9/VCAM-1 interactions and neutrophil adhesion to activated endothelial cells. Macitentan reduced DVT severity in control mice with and without stroke, but not in α9fl/flMrp8Cre+/− mice, suggesting that macitentan improves DVT outcomes by inhibiting neutrophil integrin α9. Collectively, we uncovered a previously unrecognized and critical pathway involving the α9/VCAM-1 axis in neutrophil hyperactivation and DVT.-

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Section: Discussionsupporting

confidence: 90%

Interactions between integrin α9β1 and VCAM-1 promote neutrophil hyperactivation and mediate poststroke DVT

Pandey,

Kaur,

Chorawala

et al. 2024

Blood Advances

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“…Meanwhile, the expressions of angiotensinogen and angiotensin-converting enzyme were not significantly increased (fold change = 1.11, p = 0.61; fold change = 1.23, p = 0.23, respectively). Combined with the understanding that ET-1 is expressed in the atria of SHR and DOCA-salt-induced hypertension rats more than in those of WKY [ 11 , 12 ], and that hypertension is one of the significant factors for the square root of ET-1 expression in the human LAA [ 13 ], atrial expression of the ET-1 gene could play a role in blood pressure regulation in humans and rats.…”

Section: Discussionmentioning

confidence: 99%

Detection and identification of factors in the atrium responsible for blood pressure regulation in patients with hypertension

Yoshimura,

Mengyan,

Kume

et al. 2024

Heart Vessels

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Resection of the left atrial appendage reportedly improves blood pressure in patients with hypertension. This study aimed to validate the transcriptional profiles of atrial genes responsible for blood pressure regulation in patients with hypertension as well as to identify the molecular mechanisms in rat biological systems. RNA sequencing data of left atrial appendages from patients with (n = 6) and without (n = 6) hypertension were subjected to unsupervised principal component analysis (PCA). Reduction of blood pressure was reflected by third and ninth principal components PC3 and PC9, and that eighteen transcripts, including endothelin-1, were revealed by PCA-based pathway analysis. Resection of the left atrial appendage in hypertensive rats improved their blood pressure accompanied by a decrease in serum endothelin-1 concentration. Expression of the endothelin-1 gene in the atrium and atrial appendectomy could play roles in blood pressure regulation in humans and rats.

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“…We demonstrated that macitentan could effectively rescue osteochondral damage in a pre-clinical setting, either in acute phase or sub-acute phase of SARS-CoV-2 infection. In addition to the antiinflammatory effect via endothelin receptor blockade 54 , the potential antiviral effect of endothelin receptor antagonists has also been documented to lower influenza and cytomegalovirus viral RNA counts in vitro 55,56 . We observed macitentan could decrease viral spike protein in local joint tissue in infected hamsters in vivo.…”

Section: Discussionmentioning

confidence: 99%

Blockade of Endothelin Receptors Mitigates SARS-CoV-2-induced Osteochondral Damage

Wen

et al. 2023

Preprint

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Joint pain is a common post-acute COVID sequelae. Although pathological bone loss has been documented after SARS-CoV-2 infection, little is known about the damage to articular cartilage capping bone ends. Hereby, we characterise temporal changes of the bone-cartilage functional unit after SARS-CoV-2 infection in a golden Syrian hamster model. We observed cyst formation at osteochondral junction, chondrocyte senescence and subchondral bone loss in infected animals at 4 and 30 days post-infection. Endothelin signalling was upregulated with endothelial dysfunction and leakage of viral spike proteins to subchondral bone, triggering osteoclasts activation and chondrocytes senescence. Blockade of endothelin receptors using macitentan, an FDA-approved medication, alleviated cystic lesions and preserved chondrocyte number in acute phase of viral infection. Delayed macitentan treatment in post-acute infection phase still mitigated subchondral bone loss. Macitentan could also attenuate nociceptive pain induced by viral spike protein receptor binding domain injection in a mouse model. Collectively, macitentan is a repurposable drug candidate for treating SARS-CoV-2-induced joint damage and pain.

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Anti-inflammatory effects of endothelin receptor blockade in left atrial tissue of spontaneously hypertensive rats

Cited by 8 publications

References 47 publications

Interactions between integrin α9β1 and VCAM-1 promote neutrophil hyperactivation and mediate poststroke DVT

Interactions between integrin α9β1 and VCAM-1 promote neutrophil hyperactivation and mediate poststroke DVT

Detection and identification of factors in the atrium responsible for blood pressure regulation in patients with hypertension

Blockade of Endothelin Receptors Mitigates SARS-CoV-2-induced Osteochondral Damage

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