Hypoxic inhibition of human cardiac fibroblast invasion and MMP-2 activation may impair adaptive myocardial remodelling

Morley, Michael E.; Riches, Kirsten; Peers, Chris; Porter, Karen E.

doi:10.1042/bst0350905

Cited by 19 publications

(11 citation statements)

References 13 publications

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“…Increased matrix metalloproteinase (MMP) activity could reduce the final collagen content, even if collagen synthesis levels remain constant or increase. In human cardiac myofibroblasts, MMP activity reduced at hypoxia, 29,30 which suggests that MMP activity would rather decrease than increase. However, since differences between cell sources are apparent, the effect of hypoxia on MMP activity should be measured for vascular-derived cells to investigate whether this explains the discrepancy between short-term and longterm culture.…”

Section: Discussionmentioning

confidence: 91%

Low Oxygen Concentrations Impair Tissue Development in Tissue-Engineered Cardiovascular Constructs

Vlimmeren

Driessen-Mol²,

Oomens³

et al. 2012

Tissue Engineering Part A

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Cardiovascular tissue engineering has shown considerable progress, but in vitro tissue conditioning to stimulate the development of a functional extracellular matrix still needs improvement. We investigated the environmental factor oxygen concentration for its potential to increase the amount of collagen and collagen cross-links, and therefore improve tissue quality. Cardiovascular tissue engineered (TE) constructs, made of rapidly degrading PGA/P4HB scaffold seeded with human vascular-derived cells, were cultured at 7%, 4%, 2%, 0.5% O(2) for 4 weeks and compared to control cultures at 21% O(2). Tissue properties were evaluated by measuring the extracellular matrix production and mechanical behavior. The culture environment was monitored closely and the oxygen gradient throughout the constructs was simulated with a theoretical model. TE constructs cultured at 21%, 7% and 4% O(2) showed dense and homogeneous tissue formation with comparable strength, stiffness, collagen and collagen cross-link content. At 2% O(2), collagen content and stiffness decreased, whereas at 0.5% O(2), hardly any tissue was formed. Overall, tissue properties deteriorated at the lowest oxygen concentrations, opposing our hypothesis that was based on previous culture at low oxygen concentrations. Further research will focus on establishing the balance between applied oxygen conditions (concentration and exposure time) and optimal tissue outcome.

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Section: Discussionmentioning

confidence: 91%

Low Oxygen Concentrations Impair Tissue Development in Tissue-Engineered Cardiovascular Constructs

Vlimmeren

Driessen-Mol²,

Oomens³

et al. 2012

Tissue Engineering Part A

View full text Add to dashboard Cite

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“…To test whether the increased expression of collagen type I was affiliated with parallel changes in matrix metalloproteinase (MMP) activity, we assessed myocardial activity of MMP-2 [37] and MMP-9 [38] (Figure 7). In WT hearts, MMP-2 activity showed a strong trend to increase with age, but activity levels of 2 mo WT and 2 mo D3KO were comparable.…”

Section: Resultsmentioning

confidence: 99%

The Dopamine D3 Receptor Knockout Mouse Mimics Aging-Related Changes in Autonomic Function and Cardiac Fibrosis

et al. 2013

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Blood pressure increases with age, and dysfunction of the dopamine D3 receptor has been implicated in the pathogenesis of hypertension. To evaluate the role of the D3 receptor in aging-related hypertension, we assessed cardiac structure and function in differently aged (2 mo, 1 yr, 2 yr) wild type (WT) and young (2 mo) D3 receptor knockout mice (D3KO). In WT, systolic and diastolic blood pressures and rate-pressure product (RPP) significantly increased with age, while heart rate significantly decreased. Blood pressure values, heart rate and RPP of young D3KO were significantly elevated over age-matched WT, but similar to those of the 2 yr old WT. Echocardiography revealed that the functional measurements of ejection fraction and fractional shortening decreased significantly with age in WT and that they were significantly smaller in D3KO compared to young WT. Despite this functional change however, cardiac morphology remained similar between the age-matched WT and D3KO. Additional morphometric analyses confirmed an aging-related increase in left ventricle (LV) and myocyte cross-sectional areas in WT, but found no difference between age-matched young WT and D3KO. In contrast, interstitial fibrosis, which increased with age in WT, was significantly elevated in the D3KO over age-matched WT, and similar to 2 yr old WT. Western analyses of myocardial homogenates revealed significantly increased levels of pro- and mature collagen type I in young D3KO. Column zymography revealed that activities of myocardial MMP-2 and MMP-9 increased with age in WTs, but in D3KO, only MMP-9 activity was significantly increased over age-matched WTs. Our data provide evidence that the dopamine D3 receptor has a critical role in the emergence of aging-related cardiac fibrosis, remodeling, and dysfunction.

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“…During the secretion, carboxy- and amino terminal propeptides are cleaved off from the parent molecule by specific proteases (27) releasing the collagen molecule. A balance between synthesis and degradation by matrix metalloproteases determines collagen content in the ventricles (28, 29). Previous studies have shown that ET increases collagen synthesis (30).…”

Section: Discussionmentioning

confidence: 99%

Bosentan attenuates right ventricular hypertrophy and fibrosis in normobaric hypoxia model of pulmonary hypertension

Choudhary

Troncales

Martin

et al. 2011

The Journal of Heart and Lung Transplantation

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Maladaptive right ventricular (RV) hypertrophic responses lead to RV dysfunction and failure in patients with pulmonary arterial hypertension, but the mechanisms responsible for these changes are not well understood. The objective of this study was to evaluate the effect of treatment with bosentan on RV hypertrophy (RVH), fibrosis and expression of protein kinase C (PKC) isoforms in the RV of rats exposed to chronic hypoxia. Methods Adult Sprague Dawley rats were housed in normoxia or hypoxia (FiO2: 10%) and administered vehicle or 100mg/kg/day of bosentan. After 3 weeks, echocardiographic, hemodynamic assessment was performed. PKC, procollagen-1, and collagen expression was assessed using immunoblot or colorimetric assay. Results RV systolic pressure (RVSP) and RVH were higher in hypoxic compared to normoxic animals (RVSP: 72 ± 4 vs. 25 ± 2 mmHg, p<0.05; RVH: 1.2 ± 0.06 vs. 0.5 ± 0.03 mg/g body wt., p<0.05). Bosentan had no effect on RVSP or mass in normoxic animals, but did attenuate RVH in hypoxic animals (Hypoxic/vehicle: 1.2 ± 0.06; Hypoxic/bosentan: 1.0 ± 0.05 mg/g body wt., p<0.05). Hypoxia increased RV procollagen-I, and total collagen expression, effects that were attenuated by bosentan treatment. Hypoxia increased RV total and cytosolic PKC-δ protein expression, but had no effect on PKC-α or -ε isoforms. Administration of bosentan did not affect total PKC-δ protein expression. However, animals treated with bosentan had an increase in membranous PKC-δ when exposed to hypoxia. Conclusion Bosentan inhibits RVH and RV collagen expression in rats exposed to chronic hypoxia possibly via alteration of PKCδ activity.

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Hypoxic inhibition of human cardiac fibroblast invasion and MMP-2 activation may impair adaptive myocardial remodelling

Cited by 19 publications

References 13 publications

Low Oxygen Concentrations Impair Tissue Development in Tissue-Engineered Cardiovascular Constructs

Low Oxygen Concentrations Impair Tissue Development in Tissue-Engineered Cardiovascular Constructs

The Dopamine D3 Receptor Knockout Mouse Mimics Aging-Related Changes in Autonomic Function and Cardiac Fibrosis

Bosentan attenuates right ventricular hypertrophy and fibrosis in normobaric hypoxia model of pulmonary hypertension

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