Hypoxia promotes primitive glycosaminoglycan-rich extracellular matrix composition in developing heart valves

Amofa, Dorothy; Hulin, Alexia; Nakada, Yuji; Sadek, Hesham A.; Yutzey, Katherine E.

doi:10.1152/ajpheart.00209.2017

Cited by 15 publications

(12 citation statements)

References 35 publications

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“…While hypoxia is known to regulate collagen as well as glycosaminoglycans in AVs (8, 27), its effects on elastin is not known. We observed fragmented elastic fibers in the ventricularis of both 20 and 13% O 2 AVs compared to fresh AVs.…”

Section: Resultsmentioning

confidence: 99%

“…Here, we demonstrated the effects of hypoxia in aged AVs. Given that almost all studies that investigated role of hypoxia in valve disease employed valves from young animals (5, 8, 27), our major goal was to study aged AVs from pigs and humans to gain better insights on the influence of hypoxia on valve disease. We sought to study porcine AVs because pigs have been shown to be a good model to study heart valve diseases.…”

Section: Discussionmentioning

confidence: 99%

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Hypoxia Stimulates Synthesis of Neutrophil Gelatinase-Associated Lipocalin in Aortic Valve Disease

Swaminathan

Krishnamurthy

Sridhar

et al. 2019

Front. Cardiovasc. Med.

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Objective: Aortic valve disease is commonly found in the elderly population. It is characterized by dysregulated extracellular matrix remodeling followed by extensive microcalcification of the aortic valve and activation of valve interstitial cells. The mechanism behind these events are largely unknown. Studies have reported expression of hypoxia inducible factor-1 alpha (HIF1α) in calcific nodules in aortic valve disease, therefore we investigated the effect of hypoxia on extracellular matrix remodeling in aged aortic valves.Approach and Results: Western blotting revealed elevated expression of HIF1α and the complex of matrix metalloprotease 9 (MMP9) and neutrophil gelatinase-associated lipocalin (NGAL) in aged porcine aortic valves cultured under hypoxic conditions. Consistently, immunofluorescence staining showed co-expression of MMP9 and NGAL in the fibrosa layer of these porcine hypoxic aortic valves. Gelatinase zymography demonstrated that the activity of MMP9-NGAL complex was significantly increased in aortic valves in 13% O2 compared to 20% O2. Importantly, the presence of ectopic elastic fibers in the fibrosa of hypoxic aortic valves, also detected in human diseased aortic valves, suggests altered elastin homeostasis due to hypoxia.Conclusion: This study demonstrates that hypoxia stimulates pathological extracellular matrix remodeling via expression of NGAL and MMP9 by valve interstitial cells.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Hypoxia Stimulates Synthesis of Neutrophil Gelatinase-Associated Lipocalin in Aortic Valve Disease

Swaminathan

Krishnamurthy

Sridhar

et al. 2019

Front. Cardiovasc. Med.

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“…At P7, the formation of a collagen layer starts to be detected in valve leaflets ( Fig. 1A, black arrowheads), in contrast to its low expression at P1 (Amofa et al, 2017), but the primitive leaflets remain thickened ( Fig. 1A).…”

Section: Heterogeneity Of P7 and P30 Heart Cells Is Revealed By Droplmentioning

confidence: 99%

“…At P30, valve leaflets are elongated with regionalized distribution of fibrillar collagen and proteoglycan ( Fig. 1A) (Amofa et al, 2017). Single cell isolations from aortic and mitral valve leaflets were obtained from valves dissected from P7 and P30 mouse pups, which were pooled and dissociated to obtain single cell suspensions.…”

Section: Heterogeneity Of P7 and P30 Heart Cells Is Revealed By Droplmentioning

confidence: 99%

Maturation of heart valve cell populations during postnatal remodeling

et al. 2019

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Heart valve cells mediate extracellular matrix (ECM) remodeling during postnatal valve leaflet stratification, but phenotypic and transcriptional diversity of valve cells in development is largely unknown. Single cell analysis of mouse heart valve cells was used to evaluate cell heterogeneity during postnatal ECM remodeling and leaflet morphogenesis. The transcriptomic analysis of single cells from postnatal day (P)7 and P30 murine aortic (AoV) and mitral (MV) heart valves uncovered distinct subsets of melanocytes, immune and endothelial cells present at P7 and P30. By contrast, interstitial cell populations are different from P7 to P30. P7 valve leaflets exhibit two distinct collagen-and glycosaminoglycan-expressing interstitial cell clusters, and prevalent ECM gene expression. At P30, four interstitial cell clusters are apparent with leaflet specificity and differential expression of complement factors, ECM proteins and osteogenic genes. This initial transcriptomic analysis of postnatal heart valves at single cell resolution demonstrates that subpopulations of endothelial and immune cells are relatively constant throughout postnatal development, but interstitial cell subpopulations undergo changes in gene expression and cellular functions in primordial and mature valves.

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“…The membrane was blocked in 5% milk/TBST for 1 hour and probed with rabbit anti-mouse polyclonal HYAL2 antibody diluted to 1:500 (Abcam #68608; Cambridge, UK) overnight at 4 °C. This antibody has been used to detect HYAL2 in human aortic valve interstitial cells cultured in hypoxia 34 . SOD3 from HPASMCs was probed with mouse-anti-human monoclonal antibody (sc-376948, Santa Cruz Biotech; Dallas, TX).…”

Section: Rt-qpcr For Ha-regulating Gene Expressionmentioning

confidence: 99%

Extracellular Superoxide Dismutase Regulates Early Vascular Hyaluronan Remodeling in Hypoxic Pulmonary Hypertension

Tseng

Allawzi

et al. 2020

Sci Rep

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chronic hypoxia leads to pathologic remodeling of the pulmonary vasculature and pulmonary hypertension (PH). The antioxidant enzyme extracellular superoxide dismutase (SOD3) protects against hypoxia-induced pH. Hyaluronan (HA), a ubiquitous glycosaminoglycan of the lung extracellular matrix, is rapidly recycled at sites of vessel injury and repair. We investigated the hypothesis that SOD3 preserves HA homeostasis by inhibiting oxidative and enzymatic hyaluronidase-mediated HA breakdown. In SOD3-deficient mice, hypoxia increased lung hyaluronidase expression and activity, hyaluronan fragmentation, and effacement of HA from the vessel wall of small pulmonary arteries. Hyaluronan fragmentation corresponded to hypoxic induction of the cell surface hyaluronidase-2 (Hyal2), which was localized in the vascular media. Human pulmonary artery smooth muscle cells (HPASMCs) demonstrated hypoxic induction of Hyal2 and SOD-suppressible hyaluronidase activity, congruent to our observations in vivo. fragmentation of homeostatic high molecular weight HA promoted HpASMc proliferation in vitro, whereas pharmacologic inhibition of hyaluronidase activity prevented hypoxia-and oxidant-induced proliferation. Hypoxia initiates SOD3-dependent alterations in the structure and regulation of hyaluronan in the pulmonary vascular extracellular matrix. these changes occurred soon after hypoxia exposure, prior to appearance of pH, and may contribute to the early pathogenesis of this disease.Pulmonary hypertension (PH) is an incurable and fatal disease characterized by intimal thickening, muscular hypertrophy, excessive matrix deposition, and stiffening of arteries in the lung. Chronic hypoxia is a major cause and consequence of PH in humans. It is the most prevalent etiology of precapillary PH in humans (WHO Group 3 disease). The onset of PH in patients with hypoxia due to intrinsic lung disease portends a grim prognosis for survival, post-transplant outcome, and quality of life 1,2 . Therefore, there is an urgent need for research on the molecular pathogenesis of hypoxic pulmonary hypertension.One facet of this disease is the presence of high oxidative stress within the vessel wall and perivascular matrix 3 . Extracellular superoxide dismutase (SOD3) is crucial for neutralization of this stress. Global knockout 4 , selective deletion from smooth muscle cells 5 , and disrupted matrix-binding single nucleotide polymorphisms 6 of SOD3 result in a great susceptibility to hypoxia-induced vascular inflammation, fibrosis, and PH. On the other hand, lung-specific overexpression of SOD3 7 , adenoviral gene transfer of human SOD3 8 , and treatment with an inorganic metalloporphyrin SOD3 mimetic 9 are protective against PH in rodent models. In the advanced stages of PH in humans, SOD3 levels are epigenetically reduced by histone deacetylation 10 .There is a critical gap in our understanding of how the extracellular oxidative environment can lead to irreversible pulmonary vascular remodeling in chronic hypoxia. Amassing evidence points to a central role f...

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Hypoxia promotes primitive glycosaminoglycan-rich extracellular matrix composition in developing heart valves

Cited by 15 publications

References 35 publications

Hypoxia Stimulates Synthesis of Neutrophil Gelatinase-Associated Lipocalin in Aortic Valve Disease

Hypoxia Stimulates Synthesis of Neutrophil Gelatinase-Associated Lipocalin in Aortic Valve Disease

Maturation of heart valve cell populations during postnatal remodeling

Extracellular Superoxide Dismutase Regulates Early Vascular Hyaluronan Remodeling in Hypoxic Pulmonary Hypertension

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