Inhibition of vascular smooth muscle cell calcification by vasorin through interference with TGFβ1 signaling

Luong, Trang T. D.; Estepa, Misael; Boehme, Beate; Pieske, Burkert; Läng, Florian; Voelkl, Jakob; Alesutan, Ioana

doi:10.1016/j.cellsig.2019.109414

Cited by 14 publications

(20 citation statements)

References 55 publications

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“…5,6 Conversely, aging decreases the extracellular anti-inflammatory molecule vasorin, which also contributes to the activation of MMP-2, TGF-β1 profibrogenic signaling, and collagen secretion of VSMCs. 7,8 Profibrotic collagen deposition and cross-linked modification execute a causal role providing cellular signals that regulate the degenerative phenotype of ECs and the migration, invasion, proliferation, and proinflammatory gene expression, and stiffening of VSMCs in vitro. [1][2][3][4]9 Collagen deposition and cross-linking also play etiologic roles in IMT, endothelial dysfunction, and stiffening in vivo, 1-4, [9][10][11] facilitating the development of hypertension and atherosclerosis with aging.…”

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confidence: 99%

Proinflammation, profibrosis, and arterial aging

2020

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Aging is a major risk factor for the morbidity and mortality of quintessential cardiovascular diseases, such as hypertension and atherosclerosis, mainly due to arterial wall structural and functional adverse remodeling, such as intimal medial thickening (IMT) and stiffening. 1-5 The age-associated increase in collagen deposition within the arterial wall is known as arterial profibrosis; and the age-associated increase in sterile inflammation within the wall is known as arterial proinflammation. Proinflammation and profibrosis are the key molecular and cellular events in age-associated IMT and arterial stiffening. It is widely accepted that proinflammatory endothelial cells (ECs) and vascular smooth muscle cells (VSMCs) are mainly responsible for age-associated adverse arterial cellular events; however, the consequence of proinflammation and profibrosis (predisposing collagen deposition) greatly affects the behavior of these cells adversely with a predominant impact on the age-associated arterial stiffening, which is not completely understood. 1-5 Aging increases the proinflammatory molecules angiotensin II (Ang II), milk fat globule-EGF8 (MFG-E8), calpain-1, monocyte chemoattractant protein 1 (MCP-1), non-phagocytic nicotinamide adenine dinucleotide phosphate oxidase (NADPH oxidase), and

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confidence: 99%

Proinflammation, profibrosis, and arterial aging

2020

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“…Primary human aortic smooth muscle cells (HAoSMCs; Fisher Scientific, Vienna, Austria and Sigma Aldrich, Vienna, Austria) were cultured in medium containing 1:1 ratio of Waymouth’s MB 752/1 and Ham’s F-12 nutrient mixture (~19 mM glucose, according to manufacturer’s information), 10% FBS, 100 U/mL of penicillin, and 100 µg/mL of streptomycin (all from Fisher Scientific, Vienna, Austria) [ 30 , 32 , 61 , 62 , 63 ] and used in experiments from passages 4 to 11.…”

Section: Methodsmentioning

confidence: 99%

“…Equal amounts of vehicle were used as the control. HAoSMCs were treated with calcification medium containing 10 mM of β-glycerophosphate and 1.5 mM of CaCl 2 (Sigma-Aldrich, Vienna, Austria) [ 33 , 61 , 62 ]. For long-term treatments, fresh medium with agents were added every 2–3 days.…”

Section: Methodsmentioning

confidence: 99%

“…After the indicated times (for time course experiments), 24 h (for total proteins) or 3 h (for phosphorylated proteins) of treatment, HAoSMCs were lysed with ice-cold IP lysis buffer (Fisher Scientific, Vienna, Austria) containing a complete protease and phosphatase inhibitor cocktail (Fisher Scientific, Vienna, Austria) [ 30 , 61 , 62 ], and the protein concentrations were determined by the Bradford assay (Bio-Rad Laboratories, Vienna, Austria). Equal amounts of proteins were boiled in Roti-Load1 Buffer (Carl Roth, Karlsruhe, Germany) at 100 °C for 10 min, separated on SDS-polyacrylamide gels, and transferred to PVDF membranes.…”

Section: Methodsmentioning

confidence: 99%

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Role of SGK1 in the Osteogenic Transdifferentiation and Calcification of Vascular Smooth Muscle Cells Promoted by Hyperglycemic Conditions

Poetsch

Henze

Estepa

et al. 2020

IJMS

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In diabetes mellitus, hyperglycemia promotes the osteogenic transdifferentiation of vascular smooth muscle cells (VSMCs) to enhance medial vascular calcification, a common complication strongly associated with cardiovascular disease and mortality. The mechanisms involved are, however, still poorly understood. Therefore, the present study explored the potential role of serum- and glucocorticoid-inducible kinase 1 (SGK1) during vascular calcification promoted by hyperglycemic conditions. Exposure to high-glucose conditions up-regulated the SGK1 expression in primary human aortic VSMCs. High glucose increased osteogenic marker expression and activity and, thus, promoted the osteogenic transdifferentiation of VSMCs, effects significantly suppressed by additional treatment with the SGK1 inhibitor EMD638683. Moreover, high glucose augmented the mineralization of VSMCs in the presence of calcification medium, effects again significantly reduced by SGK1 inhibition. Similarly, SGK1 knockdown blunted the high glucose-induced osteogenic transdifferentiation of VSMCs. The osteoinductive signaling promoted by high glucose required SGK1-dependent NF-κB activation. In addition, advanced glycation end products (AGEs) increased the SGK1 expression in VSMCs, and SGK1 inhibition was able to interfere with AGEs-induced osteogenic signaling. In conclusion, SGK1 is up-regulated and mediates, at least partly, the osteogenic transdifferentiation and calcification of VSMCs during hyperglycemic conditions. Thus, SGK1 inhibition may reduce the development of vascular calcification promoted by hyperglycemia in diabetes.

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“…Transforming growth factor-beta 1 (TGF-β1) and bone morphogenetic protein-2 (BMP-2) are identified as pro-osteogenic factors that mediate the osteogenic activity in vascular cells [16][17][18]. Previous studies found that calcified aortic valves have higher levels of TGF-β1 in comparison to non-calcified aortic valves [19].…”

Section: Introductionmentioning

confidence: 99%

MicroRNA-204 Deficiency in Human Aortic Valves Elevates Valvular Osteogenic Activity

Song

Zhai

et al. 2019

IJMS

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Aortic valve interstitial cells (AVICs) play a major role in valvular calcification associated with calcific aortic valve disease (CAVD). Although AVICs from diseased valves display a pro-osteogenic phenotype, the underlying mechanism causing this remains unclear. MicroRNA-204 (miR-204) is a negative regulator of osteoblast differentiation. We sought to analyze miR-204 expression in diseased human aortic valves and determine the role of this miR in AVIC osteogenic activity associated with CAVD pathobiology. In situ hybridization and PCR analysis revealed miR-204 deficiency in diseased valves and in AVICs from diseased valves. MiR-204 mimic suppressed alkaline phosphatase (ALP) expression and calcium deposition in AVICs from diseased valves. MiR-204 antagomir enhanced ALP expression in AVICs from normal valves through induction of Runx2 and Osx, and expression of miR-204 antagomir in mouse aortic valves promoted calcium deposition through up-regulation of Runx2 and Osx. Further, miR-204 mimic suppressed the osteogenic responses to TGF-β1 in AVICs of normal valves. In conclusion, miR-204 deficiency contributes to the mechanism underlying elevated osteogenic activity in diseased aortic valves, and miR-204 is capable of reversing the pro-osteogenic phenotype of AVICs of diseased valves and suppressing AVIC osteogenic response to stimulation. Exogenous miR-204 may have therapeutic potential for inhibiting valvular calcification associated with CAVD progression.

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Inhibition of vascular smooth muscle cell calcification by vasorin through interference with TGFβ1 signaling

Cited by 14 publications

References 55 publications

Proinflammation, profibrosis, and arterial aging

Proinflammation, profibrosis, and arterial aging

Role of SGK1 in the Osteogenic Transdifferentiation and Calcification of Vascular Smooth Muscle Cells Promoted by Hyperglycemic Conditions

MicroRNA-204 Deficiency in Human Aortic Valves Elevates Valvular Osteogenic Activity

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