Azelnidipine Inhibits Msx2-Dependent Osteogenic Differentiation and Matrix Mineralization of Vascular Smooth Muscle Cells

Shimizu, Tomohiro; Tanaka, Toru; Iso, Tatsuya; Kawai-Kowase, Keiko; Kurabayashi, Masahiko

doi:10.1536/ihj.53.331

Cited by 15 publications

(9 citation statements)

References 26 publications

(30 reference statements)

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“…We show that Ox-LDL promotes osteogenic differentiation and calcification of VSMCs and up-regulates Msx2 expression, which is a key factor of vascular calcification [34], [35]. These findings are consistent with previous studies [13], [14], [16].…”

Section: Discussionsupporting

confidence: 93%

Ceramide Mediates Ox-LDL-Induced Human Vascular Smooth Muscle Cell Calcification via p38 Mitogen-Activated Protein Kinase Signaling

et al. 2013

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Vascular calcification is associated with significant cardiovascular morbidity and mortality, and has been demonstrated as an actively regulated process resembling bone formation. Oxidized low density lipoprotein (Ox-LDL) has been identified as a regulatory factor involved in calcification of vascular smooth muscle cells (VSMCs). Additionally, over-expression of recombinant human neutral sphingomyelinase (N-SMase) has been shown to stimulate VSMC apoptosis, which plays an important role in the progression of vascular calcification. The aim of this study is to investigate whether ceramide regulates Ox-LDL-induced calcification of VSMCs via activation of p38 mitogen-activated protein kinase (MAPK) pathway. Ox-LDL increased the activity of N-SMase and the level of ceramide in cultured VSMCs. Calcification and the osteogenic transcription factor, Msx2 mRNA expression were reduced by N-SMase inhibitor, GW4869 in the presence of Ox-LDL. Usage of GW4869 inhibited Ox-LDL-induced apoptosis in VSMCs, an effect which was reversed by C2-ceramide. Additionally, C2-ceramide treatment accelerated VSMC calcification, with a concomitant increase in ALP activity. Furthermore, C2-ceramide treatment enhanced Ox-LDL-induced VSMC calcification. Addition of caspase inhibitor, ZVAD-fmk attenuated Ox-LDL-induced calcification. Both Ox-LDL and C2-ceramide treatment increased the phosphorylation of p38 MAPK. Inhibition of p38 MAPK by SB203580 attenuated Ox-LDL-induced calcification of VSMCs. These data suggest that Ox-LDL activates N-SMase-ceramide signaling pathway, and stimulates phosphorylation of p38 MAPK, leading to apoptosis in VSMCs, which initiates VSMC calcification.

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Section: Discussionsupporting

confidence: 93%

Ceramide Mediates Ox-LDL-Induced Human Vascular Smooth Muscle Cell Calcification via p38 Mitogen-Activated Protein Kinase Signaling

et al. 2013

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“…To investigate whether both calcification models produce similar trans-differentiation we examined the expression of molecular markers associated to this process. We first analyzed the expression of homeobox protein MSX2, a component of the bone morphogenetic protein pathway that promotes cardiovascular calcification (Tyson et al, 2003 ; Shimizu et al, 2012 ). Both Pi and uremic serum exposure induced the expression of MSX2 throughout the treatment (Figure 2A ), with a stronger effect induced by the former.…”

Section: Resultsmentioning

confidence: 99%

Phenotypic Modulation of Cultured Primary Human Aortic Vascular Smooth Muscle Cells by Uremic Serum

et al. 2018

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Patients with chronic kidney disease (CKD) have a markedly increased incidence of cardiovascular disease (CVD). The high concentration of circulating uremic toxins and alterations in mineral metabolism and hormone levels produce vascular wall remodeling and significant vascular damage. Medial calcification is an early vascular event in CKD patients and is associated to apoptosis or necrosis and trans-differentiation of vascular smooth muscle cells (VSMC) to an osteogenic phenotype. VSMC obtained from bovine or rat aorta and cultured in the presence of increased inorganic phosphate (Pi) have been extensively used to study these processes. In this study we used human aortic VSMC primary cultures to compare the effects of increased Pi to treatment with serum obtained from uremic patients. Uremic serum induced calcification, trans-differentiation and phenotypic remodeling even with normal Pi levels. In spite of similar calcification kinetics, there were fundamental differences in osteochondrogenic marker expression and alkaline phosphatase induction between Pi and uremic serum-treated cells. Moreover, high Pi induced a dramatic decrease in cell viability, while uremic serum preserved it. In summary, our data suggests that primary cultures of human VSMC treated with serum from uremic patients provides a more informative model for the study of vascular calcification secondary to CKD.

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“…Yan et al 94 also reported that oxidative stress-mediated decorin glycosaminoglycan (GAG) chain synthesis triggers transforming growth factor-ß signaling and osteogenic differentiation of vascular SMCs in vitro. Shimizu et al 95 further reported that azelnidipine, a dihydropyridine subclass of calcium channel blockers, inhibits Msx2-dependent osteogenic differentiation and matrix mineralization of vascular SMCs in vitro. Using an SMC-specific SM22-Cre line, Speer et al 4 found that SM22-Cre-labeled cells gave rise to osteochondrogenic precursor and chondrocyte-like cells in calcified blood vessels of matrix Gla protein deficient (MGP-/-) mice in vivo.…”

Section: Candidate Populations Of Mesoderm Originmentioning

confidence: 99%

Evaluation of the Cellular Origins of Heterotopic Ossification

Kan¹,

Kessler²

2014

Orthopedics

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Heterotopic ossification (HO), acquired or hereditary, is featured by the formation of bone outside of the normal skeleton. Typical acquired HO is a common, debilitating condition associated with traumatic events. Cardiovascular calcification, an atypical form of acquired HO, is prevalent and associated with high rates of cardiovascular mortality. Hereditary HO syndromes, such as fibrodysplasia ossificans progressiva and progressive osseous heteroplasia, are rare, progressive, life-threatening disorders. The cellular origins of HO remain elusive. Some bona fide contributing cell populations have been found through genetic lineage tracing and other experiments in vivo, and various other candidate populations have been proposed. Nevertheless, because of the difficulties in establishing cellular phenotypes in vivo and other confounding factors, the true identities of these populations are still uncertain. This review critically evaluates the accumulating data in the field. The major focus is on the candidate populations that may give rise to osteochondrogenic lineage cells directly, not the populations that may contribute to HO indirectly. This issue is important not solely because of the clinical implications, but also because it highlights the basic biological processes that govern bone formation.

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Azelnidipine Inhibits Msx2-Dependent Osteogenic Differentiation and Matrix Mineralization of Vascular Smooth Muscle Cells

Cited by 15 publications

References 26 publications

Ceramide Mediates Ox-LDL-Induced Human Vascular Smooth Muscle Cell Calcification via p38 Mitogen-Activated Protein Kinase Signaling

Ceramide Mediates Ox-LDL-Induced Human Vascular Smooth Muscle Cell Calcification via p38 Mitogen-Activated Protein Kinase Signaling

Phenotypic Modulation of Cultured Primary Human Aortic Vascular Smooth Muscle Cells by Uremic Serum

Evaluation of the Cellular Origins of Heterotopic Ossification

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