Estrogen-Related Receptor γ Plays a Key Role in Vascular Calcification Through the Upregulation of BMP2 Expression

Kim, Jihyun; Choi, Youn‐Hee; Do, Ji-Yeon; Choi, Yoo‐Duk; Ha, Chae-Myeong; Jeon, Jae‐Han; Lee, Won-Kee; Choi, Hueng‐Sik; Park, Keun-Gyu; Lee, Inkyu

doi:10.1161/atvbaha.115.306102

Cited by 38 publications

(25 citation statements)

References 30 publications

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“…48,49 The estrogen receptor-related receptors have a demonstrated role in promoting VSMC mineralization and bone formation and hence may be prime candidates for further investigation of these pathways with specific antagonist or silencing studies. 50,51 Interestingly, we found that E2 had site-specific effects on both calcification and ERβ expression. E2 increased plaque calcification and decreased ERβ expression in the aortic sinus but not the innominate artery, in both male and female animals.…”

Section: Discussionmentioning

confidence: 74%

Estrogen Receptor Control of Atherosclerotic Calcification and Smooth Muscle Cell Osteogenic Differentiation

McRobb

McGrath

Tsatralis

et al. 2017

ATVB

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Objective-Vascular calcification is associated with increased risk of myocardial infarction and stroke. The objective of this work was to examine the ability of 17β-estradiol (E2) to stimulate calcification of vascular smooth muscle cells (VSMC) in vivo, using aged apolipoprotein E-null mice with advanced atherosclerotic lesions, and subsequently to explore underlying mechanisms in vitro. Approach and Results-Silastic E2 capsules were implanted into male and female apolipoprotein E-null mice aged 34 weeks.Plaque and calcified area were measured in the aortic sinus and innominate artery after 8 weeks. Immunohistochemical analysis examined expression of the estrogen receptors (estrogen receptor alpha and estrogen receptor beta [ERβ]). VSMC expression of osteogenic markers was examined using digital polymerase chain reaction. Advanced atherosclerotic lesions were present in all mice at the end of 8 weeks. In both male and female mice, E2 increased calcified area in a site-specific manner in the aortic sinus independently of plaque growth or lipid levels and occurred in association with a site-specific decrease in the proportion of ERβ-positive intimal cells. Calcified lesions expressed collagen I and bone sialoprotein, with decreased matrix Gla protein. In vitro, E2 suppressed ERβ expression and increased VSMC mineralization, demonstrating increased collagen I and II, osteocalcin and bone sialoprotein, and reduced matrix Gla protein and osteopontin. Antagonism or RNA silencing of estrogen receptor alpha, ERβ, or both further increased VSMC mineralization. Conclusions-We have demonstrated that E2 can drive calcification in advanced atherosclerotic lesions by promoting the differentiation of VSMC to osteoblast-like cells, a process which is augmented by inhibition of estrogen receptor alpha or ERβ activity. Visual Overview-An online visual overview is available for this article. studies have demonstrated an inhibitory role for E2 in VSMC calcification in vitro. 26,27 In the context of atherosclerosis, studies support a protective effect of E2 on plaque calcification in women, based on the cardiovascular protective effects of E2 that reduce total plaque burden, attributable to modulation of traditional risk factors, such as plasma high-density lipoprotein and low-density lipoprotein. 28,29 In the clinic, studies show low serum E2 levels associate with increased coronary artery calcification (CAC), [30][31][32] whereas E2 replacement in younger menopausal women reduces CAC. 33,34 These findings are supported by animal studies that show E2 protects against atherosclerotic plaque calcification when associated with beneficial effects on plaque progression. 27,35 However, the mechanistic similarities to bone formation suggest that estradiol could promote vascular calcification in certain circumstances. This dilemma continues to raise the question of how estrogens impact on vascular calcification and plaque progression in the longer term, particularly in the aging vasculature, 36,37 where established, more advanced lesions ...

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Section: Discussionmentioning

confidence: 74%

Estrogen Receptor Control of Atherosclerotic Calcification and Smooth Muscle Cell Osteogenic Differentiation

McRobb

McGrath

Tsatralis

et al. 2017

ATVB

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“…BMP2 may accelerate vascular calcification by increased phosphate uptake and inducing VSMCs phenotypes to convert into osteoblast‐like cells, which in turn phosphorylates the regulatory Smad1/5/8 and upregulates downstream key osteogenic transcription factors including Runx2 and Sp7 (osterix). In addition, upregulated Runx2 induces bone‐related matrix proteins, such as osteocalcin, type I collagen α1, and osteopontin . There is evidence that BMP2 is the target gene of Sp1 in the BMP2‐expressing F9 cell model system .…”

Section: Discussionmentioning

confidence: 99%

“…In addition, upregulated Runx2 induces bone-related matrix proteins, such as osteocalcin, type I collagen a1, and osteopontin. [30][31][32][33][34] There is evidence that BMP2 is the target gene of Sp1 in the BMP2-expressing F9 cell model system. 18 Therefore, we analyzed the BMP2 sequence by using the Neural Network Promoter Prediction software to verify the binding site and found the Sp1 binding site, suggesting that Sp1 acts as a potential transcription factor for BMP2 activation.…”

Section: Discussionmentioning

confidence: 99%

Sp1 Plays an Important Role in Vascular Calcification Both In Vivo and In Vitro

Zhang

Qin

et al. 2018

JAHA

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BackgroundVascular calcification and increased cardiovascular morbidity and mortality are closely related in patients with end‐stage renal disease and diabetes mellitus. Specific protein 1 (Sp1) is a transactivation molecule that plays a crucial role in the regulation of apoptosis, fibrosis, angiogenesis, and other pathological disorders. There is evidence that specific protein 1 (Sp1) directly stimulates the transcription of bone morphogenetic protein 2 (BMP2) and that BMP2 plays a key role in the calcification process in the BMP2–expressing F9 cell model system. Here, we investigated whether Sp1 plays an important role in vascular calcification and its potential regulatory mechanism in vascular calcification.Methods and ResultsIn this study, vascular calcification was induced in male Wistar rats by administration of nicotine (25 mg/kg) and vitamin D3 (300 000 IU/kg). These rats were randomly selected for treatment with adenovirus harboring Sp1 knockdown gene or empty virus. The mechanism of Sp1 in vascular smooth muscle cells cultured in high phosphate medium was studied. Based on our findings, the Sp1 gene silencing or inhibition improved calcium deposition, which was partly achieved by inhibiting phenotype switch, apoptosis, and matrix vesicle release of vascular smooth muscle cells. Moreover, Sp1 can activate BMP2 transcription by binding to the Sp1‐binding element of the BMP2 promoter.ConclusionsOverall, elevated Sp1 exerts a pro‐apoptotic effect, promoting BMP2 transcription and further accumulating vascular calcification. Proper and timely regulation of Sp1 expression may be a potential strategy for treatment of aging, end‐stage renal disease, and diabetic‐related macrovascular disease treatment.

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“…Several studies have also suggested that besides ESRRA, ESRRG is also essential for cardiac metabolism and function, and plays an important role in the pathogenesis of cardiovascular diseases, such as cardiac hypertrophy, vascular calcification, heart failure, etc. [113,116,117]. Recently, a natural polyphenolic compound found in red wine, resveratrol, has been shown to improve high-fat diet-induced cardiomyopathy in mice in an ESRRA-dependent manner [118].…”

Section: Esrra As a Target For Cardiovascular Diseasesmentioning

confidence: 99%

Estrogen-Related Receptor Alpha: An Under-Appreciated Potential Target for the Treatment of Metabolic Diseases

Tripathi

Yen

Singh

2020

IJMS

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The estrogen-related receptor alpha (ESRRA) is an orphan nuclear receptor (NR) that significantly influences cellular metabolism.ESRRA is predominantly expressed in metabolically-active tissues and regulates the transcription of metabolic genes, including those involved in mitochondrial turnover and autophagy. Although ESRRA activity is well-characterized in several types of cancer, recent reports suggest that it also has an important role in metabolic diseases. This minireview focuses on the regulation of cellular metabolism and function by ESRRA and its potential as a target for the treatment of metabolic disorders.

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Estrogen-Related Receptor γ Plays a Key Role in Vascular Calcification Through the Upregulation of BMP2 Expression

Cited by 38 publications

References 30 publications

Estrogen Receptor Control of Atherosclerotic Calcification and Smooth Muscle Cell Osteogenic Differentiation

Estrogen Receptor Control of Atherosclerotic Calcification and Smooth Muscle Cell Osteogenic Differentiation

Sp1 Plays an Important Role in Vascular Calcification Both In Vivo and In Vitro

Estrogen-Related Receptor Alpha: An Under-Appreciated Potential Target for the Treatment of Metabolic Diseases

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