Mechanisms involved in extracellular matrix remodeling and arterial stiffness induced by hyaluronan accumulation

Lorentzen, Karen A.; Chai, Song; Chen, Hui; Danielsen, Carl Christian; Simonsen, Ulf; Wogensen, Lise

doi:10.1016/j.atherosclerosis.2015.11.016

Cited by 25 publications

(22 citation statements)

References 27 publications

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“…However, our results showing reduced cellular migration are in line with increased PASMC stiffness observed by AFM following exposure to hyaluronan. These observations are consistent with increased vascular stiffness induced by hyaluronan accumulation in the aorta (Lorentzen et al, ). Interestingly, in this study, increased proliferation of vascular smooth muscle cells was also associated with increased hyaluronan accumulation.…”

Section: Discussionsupporting

confidence: 85%

“…Finally we report a significant correlation between increased expression of Nrf2, a marker of increased oxidative stress, and elevated mPAP (Supporting Information Figure S1C). Small MW hyaluronan fragments have been reported to interact with CD44 to mediate pathogenic effects (Lennon and Singleton, ; Lorentzen et al, ) and we therefore measured CD44 levels. However our data appears to show a reduction in CD44 protein levels despite a correlation between increased CD44 and mPAP levels (Supporting Information Figure S1D, E).…”

Section: Resultsmentioning

confidence: 99%

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Inhibition of hyaluronan synthesis attenuates pulmonary hypertension associated with lung fibrosis

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Chen

Hernandez

et al. 2017

British J Pharmacology

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BACKGROUND AND PURPOSEGroup III pulmonary hypertension (PH) is a highly lethal and widespread lung disorder that is a common complication in idiopathic pulmonary fibrosis (IPF) where it is considered to be the single most significant predictor of mortality. While increased levels of hyaluronan have been observed in IPF patients, hyaluronan-mediated vascular remodelling and the hyaluronanmediated mechanisms promoting PH associated with IPF are not fully understood. EXPERIMENTAL APPROACHExplanted lung tissue from patients with IPF with and without a diagnosis of PH was used to identify increased levels of hyaluronan. In addition, an experimental model of lung fibrosis and PH was used to test the capacity of 4-methylumbeliferone (4MU), a hyaluronan synthase inhibitor to attenuate PH. Human pulmonary artery smooth muscle cells (PASMC) were used to identify the hyaluronan-specific mechanisms that lead to the development of PH associated with lung fibrosis. KEY RESULTSIn patients with IPF and PH, increased levels of hyaluronan and expression of hyaluronan synthase genes are present. Interestingly, we also report increased levels of hyaluronidases in patients with IPF and IPF with PH. Remarkably, our data also show that 4MU is able to inhibit PH in our model either prophylactically or therapeutically, without affecting fibrosis. Studies to determine the hyaluronan-specific mechanisms revealed that hyaluronan fragments result in increased PASMC stiffness and proliferation but reduced cell motility in a RhoA-dependent manner. CONCLUSIONS AND IMPLICATIONSTaken together, our results show evidence of a unique mechanism contributing to PH in the context of lung fibrosis. Abbreviations4MU, 4-methylumbelliferone; GEFT, guanine nucleotide exchange factor 25; HABP2, hyaluronan-binding protein 2; HAS, hyaluronan synthase; HYAL, hyaluronidase; IF, immunofluorescence; IHC, immunohistochemistry; IPF, idiopathic pulmonary fibrosis; LVSP, left ventricle systolic pressure; mPAP, mean pulmonary arterial pressure; PASMC, pulmonary artery smooth muscle cell; PH, pulmonary hypertension; RVH, right ventricle hypertrophy; RVSP, right ventricle systolic pressure; αSMA, α-smooth muscle actin

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Section: Discussionsupporting

confidence: 85%

Section: Resultsmentioning

confidence: 99%

Inhibition of hyaluronan synthesis attenuates pulmonary hypertension associated with lung fibrosis

Collum

Chen

Hernandez

et al. 2017

British J Pharmacology

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“…In diverse vascular pathologies, conversion of HMWHW to LMW-oligoHA is associated with inflammatory cell recruitment and activation 13,14 , increased endothelial permeability 15 , enhanced migration and proliferation of vascular smooth muscle cells 16 , and collagenous matrix secretion from adventitial fibroblasts 17 . Finally, the content of HA affects the vessel biomechanical properties such as tissue stiffness, hydration, and oncotic pressure 18,19 . Thus, HA is poised to serve as an important sensor and transducer of the extracellular redox environment around pulmonary vessels.Abnormal HA production and breakdown has been identified in multiple preclinical models of PH and explanted human lungs 20,21 .…”

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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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“…Мы полагаем, что апо(а), связываясь с ЛПНП, перекрывает их апоВ 100 лиганд, сам становится лиган дом и направляет поток ПНЖК к клеткам, которые, функционально пролиферируя, выставляют на плазматической мембрану рецепторы к апо(а). Повышение в плазме крови пациентов с ишемической болезнью сердца (ИБС) апо(а) указывает на активацию пролиферации гладкомышечных клеток в медии артерий эластического типа и акти вацию функции макрофагов в интиме арте рий эластического и смешанного типов [23].…”

Section: безлигандные пальмитиновые лпнп и атероматоз интимы артерий unclassified

Oleic, palmitic triglycerides, very low density lipoproteins. Atherosclerosis, arterial atheromatosis and ischemic heart disease pathogenesis

et al. 2019

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In the clinic and experiment, the basic factor in pathogenesis of hyperlipoproteinemia, atherosclerosis and atheromatosis is disturbance of physicochemical parameters of very low density lipoproteins (VLDLP). They are secreted into the blood flow by hepatocytes in biological reaction of exotrophia, external nutrition, biological function of trophology – nutrition. When there are no genetic disorders, VLDLP parameters are determined mainly by substrate induction, realization of biological reaction of exotrophia. Aphysiological induction of substrate is: a) high content of exogenous palmitic saturated fatty acid and palmitic position forms of triglycerides in the food of Homo sapiens, when a patient uses an excessive amount of meat and little carbohydrates for food. We believe that for primary prevention of ischemic heart disease the following is required: a) as for normalization of biological function of endoecology – to reduce the supply of ligandless palmitic low density lipoproteins in the intima and b) to inhibit atheromatosis of elastic type arteries including coronary artery atheromatosis. To inhibit atherosclerosis, it is necessary to normalize the biological function of nutrition, reduce the amount of meat food, replacing it by fish, while increasing the amount of vegetable food according to parameters of general biology. The basic in prevention of atherosclerosis, atheromatosis and IHD, we suppose, is activation of cognitive biological function. This is positioning of organism in the unity of: a) metabolic reactions in vivo b) exposure of environmental factors and c) social conditions, understanding of the fact that in phylogenesis, the species Homo sapiens was formed as herbivorous species with carnivorous (fish-eating) past in the ocean. If there is no critical understanding of the necessity of optimization of biological nutritional function in patients “meat-eaters”, neither prevention of atherosclerosis and atheromatosis, nor treatment of IHD will be successful. Nothing different in biology or medicine is available.

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Mechanisms involved in extracellular matrix remodeling and arterial stiffness induced by hyaluronan accumulation

Cited by 25 publications

References 27 publications

Inhibition of hyaluronan synthesis attenuates pulmonary hypertension associated with lung fibrosis

Inhibition of hyaluronan synthesis attenuates pulmonary hypertension associated with lung fibrosis

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

Oleic, palmitic triglycerides, very low density lipoproteins. Atherosclerosis, arterial atheromatosis and ischemic heart disease pathogenesis

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