Activated CD47 promotes pulmonary arterial hypertension through targeting caveolin-1

Bauer, Philip M.; Bauer, Eileen; Rogers, Natasha M.; Yao, Mingyi; Feijóo-Cuaresma, Mónica; Pilewski, Joseph M.; Champion, Hunter C.; Zuckerbraun, Brian S.; Calzada, Marı́a J.; Isenberg, Jeffrey S.

doi:10.1093/cvr/cvr356

Cited by 78 publications

(128 citation statements)

References 47 publications

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“…These data are novel and for the first time provide evidence of overexpression of the TSP1-CD47 signaling axis in the distal pulmonary vasculature in human PAH. These findings complement recent reports of increased lung parenchymal 25 and plasma 65 TSP1 expression in the setting of human PAH.…”

Section: Discussionsupporting

confidence: 90%

“…These results are prescient, as we and others have shown that TSP1 is a stress-secreted protein 37 and that TSP1 −/− mice are protected from hypoxia-induced PAH. 25,38 CD47 is expressed widely, 39 and control tissue sections demonstrated a modest level of immunoreactive protein. However, paralleling TSP1 overexpression, CD47 was increased in SCD pulmonary arterial vessels (Fig.…”

Section: Scd-mediated Pah Promotes Vasculopathy In Pulmonary Arteriesmentioning

confidence: 96%

“…1A). The secreted protein TSP1 and its receptor, CD47, have been reported to promote preclinical PAH, 25 and both TSP1 and Representative sections are presented. M: vascular media; Adv: vascular adventitia; NI: neointima.…”

Section: Scd Lungs Have Increased Expression Of Pah-promoting Signal mentioning

confidence: 99%

“…19 Preclinical studies also suggest that an increased inflammatory response, cell adhesion, 20,21 and pathologic reactive oxygen species (ROS) production 22 contribute to SCD-associated vasculopathy. Interestingly, the proadhesive protein thrombospondin 1 (TSP1) was recently reported to inhibit NO signaling 23,24 while promoting PAH in preclinical models 25 and to be upregulated in SCD patient plasma. 26 Although studies have documented the hemodynamics and outcomes of SCD-associated PAH and interrogated the systemic vascular function of these patients, there have been no human studies directly evaluating the pulmonary vasculature.…”

Section: Introductionmentioning

confidence: 99%

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Cellular, Pharmacological, and Biophysical Evaluation of Explanted Lungs from a Patient with Sickle Cell Disease and Severe Pulmonary Arterial Hypertension

et al. 2013

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Pulmonary hypertension is recognized as a leading cause of morbidity and mortality in patients with sickle cell disease (SCD). We now report benchtop phenotyping from the explanted lungs of the first successful lung transplant in SCD. Pulmonary artery smooth muscle cells (PASMCs) cultured from the explanted lungs were analyzed for proliferate capacity, superoxide (O 2 • − ) production, and changes in key pulmonary arterial hypertension (PAH)-associated molecules and compared with non-PAH PASMCs. Upregulation of several pathologic processes persisted in culture in SCD lung PASMCs in spite of cell passage. SCD lung PASMCs showed growth factor-and serum-independent proliferation, upregulation of matrix genes, and increased O 2• − production compared with control cells. Histologic analysis of SCDassociated PAH arteries demonstrated increased and ectopically located extracellular matrix deposition and degradation of elastin fibers. Biomechanical analysis of these vessels confirmed increased arterial stiffening and loss of elasticity. Functional analysis of distal fifth-order pulmonary arteries from these lungs demonstrated increased vasoconstriction to an α1-adrenergic receptor agonist and concurrent loss of both endothelial-dependent and endothelial-independent vasodilation compared with normal pulmonary arteries. This is the first study to evaluate the molecular, cellular, functional, and mechanical changes in endstage SCD-associated PAH.

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Section: Discussionsupporting

confidence: 90%

Section: Scd-mediated Pah Promotes Vasculopathy In Pulmonary Arteriesmentioning

confidence: 96%

Section: Scd Lungs Have Increased Expression Of Pah-promoting Signal mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Cellular, Pharmacological, and Biophysical Evaluation of Explanted Lungs from a Patient with Sickle Cell Disease and Severe Pulmonary Arterial Hypertension

et al. 2013

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“…For example, multiple studies have reported TSP1 induction under hypoxia (11,123,185,187) and in response to ischemia (52,219,241,260) or ischemia-reperfusion injuries (89,125,138,215,217,228,271), situations well known to upregulate ROS. This raises the intriguing hypothesis that ROS signaling may increase TSP1 expression.…”

Section: Tsp1 and Ros Signaling In Vivomentioning

confidence: 99%

Regulation of Cellular Redox Signaling by Matricellular Proteins in Vascular Biology, Immunology, and Cancer

Roberts

Kaur

Isenberg

2017

Antioxidants & Redox Signaling

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Significance: In contrast to structural elements of the extracellular matrix, matricellular proteins appear transiently during development and injury responses, but their sustained expression can contribute to chronic disease. Through interactions with other matrix components and specific cell surface receptors, matricellular proteins regulate multiple signaling pathways, including those mediated by reactive oxygen and nitrogen species and H 2 S. Dysregulation of matricellular proteins contributes to the pathogenesis of vascular diseases and cancer. Defining the molecular mechanisms and receptors involved is revealing new therapeutic opportunities. Recent Advances: Thrombospondin-1 (TSP1) regulates NO, H 2 S, and superoxide production and signaling in several cell types. The TSP1 receptor CD47 plays a central role in inhibition of NO signaling, but other TSP1 receptors also modulate redox signaling. The matricellular protein CCN1 engages some of the same receptors to regulate redox signaling, and ADAMTS1 regulates NO signaling in Marfan syndrome. In addition to mediating matricellular protein signaling, redox signaling is emerging as an important pathway that controls the expression of several matricellular proteins. Critical Issues: Redox signaling remains unexplored for many matricellular proteins. Their interactions with multiple cellular receptors remains an obstacle to defining signaling mechanisms, but improved transgenic models could overcome this barrier. Future Directions: Therapeutics targeting the TSP1 receptor CD47 may have beneficial effects for treating cardiovascular disease and cancer and have recently entered clinical trials. Biomarkers are needed to assess their effects on redox signaling in patients and to evaluate how these contribute to their therapeutic efficacy and potential side effects. Antioxid. Redox Signal. 27, 874-911.

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Tolerating CD47

Isenberg,

Montero

2024

Clinical & Translational Med

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Cluster of differentiation 47 (CD47) occupies the outer membrane of human cells, where it binds to soluble and cell surface receptors on the same and other cells, sculpting their topography and resulting in a pleiotropic receptor‐multiligand interaction network. It is a focus of drug development to temper and accentuate CD47‐driven immune cell liaisons, although consideration of on‐target CD47 effects remain neglected. And yet, a late clinical trial of a CD47‐blocking antibody was discontinued, existent trials were restrained, and development of CD47‐targeting agents halted by some pharmaceutical companies. At this point, if CD47 can be exploited for clinical advantage remains to be determined. Herein an airing is made of the seemingly conflicting actions of CD47 that reflect its position as a junction connecting receptors and signalling pathways that impact numerous human cell types. Prospects of CD47 boosting and blocking are considered along with potential therapeutic implications for autoimmune diseases and cancer.

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Activated CD47 promotes pulmonary arterial hypertension through targeting caveolin-1

Abstract: Activated CD47 is upregulated in experimental and human PAH and promotes disease by limiting Cav-1 inhibition of dysregulated eNOS.

Cited by 78 publications

References 47 publications

Cellular, Pharmacological, and Biophysical Evaluation of Explanted Lungs from a Patient with Sickle Cell Disease and Severe Pulmonary Arterial Hypertension

Cellular, Pharmacological, and Biophysical Evaluation of Explanted Lungs from a Patient with Sickle Cell Disease and Severe Pulmonary Arterial Hypertension

Regulation of Cellular Redox Signaling by Matricellular Proteins in Vascular Biology, Immunology, and Cancer

Tolerating CD47

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