Retinoids Repress Human Cardiovascular Cell Calcification With Evidence for Distinct Selective Retinoid Modulator Effects

Rogers, Maximillian A.; Chen, Jiaohua; Nallamshetty, Shriram; Pham, Tan; Goto, Shinji; Muehlschlegel, Jochen D.; Libby, Peter; Aikawa, Masanori; Aïkawa, Elena; Plutzky, Jorge

doi:10.1161/atvbaha.119.313366

Cited by 18 publications

(14 citation statements)

References 67 publications

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“…Interestingly, age-induced cardiac electrophysiology abnormalities in rats are prevented by treatment with a novel microalgaederived carotenoid that acts by increasing RARα expression and shows evidence of RARα in silico [121]. Another recent study in human samples [36] showed that ATRA suppresses the calcification of coronary artery and aortic vascular smooth muscle cell (VSMC), an important driver of coronary heart disease and peripheral arterial disease.…”

Section: Retinoic Acid Receptorsmentioning

confidence: 99%

Untangling the Cooperative Role of Nuclear Receptors in Cardiovascular Physiology and Disease

Paredes¹,

Santos-Clemente²,

Ricote³

2021

IJMS

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The heart is the first organ to acquire its physiological function during development, enabling it to supply the organism with oxygen and nutrients. Given this early commitment, cardiomyocytes were traditionally considered transcriptionally stable cells fully committed to contractile function. However, growing evidence suggests that the maintenance of cardiac function in health and disease depends on transcriptional and epigenetic regulation. Several studies have revealed that the complex transcriptional alterations underlying cardiovascular disease (CVD) manifestations such as myocardial infarction and hypertrophy is mediated by cardiac retinoid X receptors (RXR) and their partners. RXRs are members of the nuclear receptor (NR) superfamily of ligand-activated transcription factors and drive essential biological processes such as ion handling, mitochondrial biogenesis, and glucose and lipid metabolism. RXRs are thus attractive molecular targets for the development of effective pharmacological strategies for CVD treatment and prevention. In this review, we summarize current knowledge of RXR partnership biology in cardiac homeostasis and disease, providing an up-to-date view of the molecular mechanisms and cellular pathways that sustain cardiomyocyte physiology.

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Section: Retinoic Acid Receptorsmentioning

confidence: 99%

Untangling the Cooperative Role of Nuclear Receptors in Cardiovascular Physiology and Disease

Paredes¹,

Santos-Clemente²,

Ricote³

2021

IJMS

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“…However, other studies found that the synthetic selective RARγ agonist NRX204647 could inhibit vascular calcification [ 152 ] and ATRA decreased vitamin D-induced renal calcification in mice [ 153 ]. More recently, it was demonstrated that treatment with ATRA, as well as an acyclic synthetic retinoid, peretinoin, reduced calcification and osteogenic differentiation of primary human coronary SMCs and valve interstitial cells [ 154 ]. This involved a reduced expression of both TNAP/ALP and Runx-2 and an increase in MGP.…”

Section: Role Of Nuclear Receptors In Vascular Calcificationmentioning

confidence: 99%

Roles of Nuclear Receptors in Vascular Calcification

Chinetti-Gbaguidi

Neels

2021

IJMS

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Vascular calcification is defined as an inappropriate accumulation of calcium depots occurring in soft tissues, including the vascular wall. Growing evidence suggests that vascular calcification is an actively regulated process, sharing similar mechanisms with bone formation, implicating both inhibitory and inducible factors, mediated by osteoclast-like and osteoblast-like cells, respectively. This process, which occurs in nearly all the arterial beds and in both the medial and intimal layers, mainly involves vascular smooth muscle cells. In the vascular wall, calcification can have different clinical consequences, depending on the pattern, localization and nature of calcium deposition. Nuclear receptors are transcription factors widely expressed, activated by specific ligands that control the expression of target genes involved in a multitude of pathophysiological processes, including metabolism, cancer, inflammation and cell differentiation. Some of them act as drug targets. In this review we describe and discuss the role of different nuclear receptors in the control of vascular calcification.

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“…The ALP activity assay kit (Beyotime) uses p-nitrophenyl phosphate as a phosphatase substrate, which turns yellow (λ max = 405 nm) when dephosphorylated by ALP. As previously described [55], total proteins of cells were rst extracted by centrifugation in lysis buffer, and then their ALP activity was measured colourimetrically. The results were normalised to total protein levels determined using a bicinchoninic acid (BCA) assay kit (Beyotime).…”

Section: Alp Staining and Alp Activity Assaymentioning

confidence: 99%

Lipoxin Alleviates Diabetic Vascular Calcification via the YAP Pathway

Han

Yang

Liu

et al. 2021

Preprint

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Background: Vascular calcification is highly prevalent in patients with diabetes and has detrimental consequences. However, no effective prevention and treatment methods are currently available. Extensive evidence has demonstrated the protective effect of lipoxin (LX) against vascular diseases. However, whether LX prevents diabetic vascular calcification remains unknown. Here, we tested the hypothesis that LX alleviated osteogenic differentiation and subsequent calcification of vascular smooth muscle cells (VSMCs).Methods: In vitro, human aortic smooth muscle cells (HASMCs) were incubated in osteogenic medium (OM) with advanced glycation end products (AGEs) and LX to further determine the underlying mechanisms. An in vivo diabetic mouse model was established using a combination of a high-fat diet and multiple formulations of low-dose streptozotocin (STZ). Cell culture, alkaline phosphatase (ALP) staining, ALP activity, Alizarin red staining, von kossa staining, determination of calcium content, western blot analysis, immunohistochemistry, and immunofluorescence staining and statistical analysis were used in our study. Results: AGEs dose-dependently induced calcification and expression of osteogenesis-related markers, including Runt-related transcription factor 2 (RUNX2), osteopontin (OPN), and type I collagen (COL1), coupled with the activation of yes-associated protein (YAP). Mechanistically, YAP activation enhanced the AGE-induced osteogenic phenotype and calcification, but inhibition of YAP signalling alleviated this trend. Consistent with the in vitro results, diabetes promoted YAP expression as well as the subcellular localisation of the protein in the nucleus in the arterial tunica media. Interestingly, treatment with LX reduced vascular osteogenesis and calcification in diabetic mice, which was correlated with the reduced YAP levels. In addition, LX significantly inhibited COL1 accumulation and modulated the extracellular matrix. Our results further demonstrated that a pharmacological agonist of YAP reversed LX-mediated protection against osteogenic phenotypic conversion and calcification in VSMCs.Conclusions: These results demonstrate that LX attenuates transdifferentiation and calcification of VSMCs in diabetes mellitus via the YAP signalling axis, suggesting that LX is a potent therapeutic strategy to prevent diabetic vascular calcification.

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Retinoids Repress Human Cardiovascular Cell Calcification With Evidence for Distinct Selective Retinoid Modulator Effects

Cited by 18 publications

References 67 publications

Untangling the Cooperative Role of Nuclear Receptors in Cardiovascular Physiology and Disease

Untangling the Cooperative Role of Nuclear Receptors in Cardiovascular Physiology and Disease

Roles of Nuclear Receptors in Vascular Calcification

Lipoxin Alleviates Diabetic Vascular Calcification via the YAP Pathway

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