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Nicotinate-curcumin inhibits AngII-induced vascular smooth muscle cell phenotype switching by upregulating Daxx expression.

ABSTRACT: Phenotypic switching is the main cause of the abnormal proliferation and migration of vascular smooth muscle cells (VSMCs). We previously showed that Daxx exerted negative regulatory effect on AngII-induced VSMC proliferation and migration. However, the function of Daxx in VSMC phenotype switching remained unknown. Nicotinate-curcumin (NC) is an esterification derivative of niacin and curcumin that can prevent the formation of atherosclerosis. We found that NC significantly decreased AngII-induced VSMC phenotype switching. Furthermore, NC significantly inhibited AngII-induced cell proliferation and migration. Moreover, NC upregulated Daxx expression and regulated the PTEN/Akt signaling pathway. We concluded that NC inhibited AngII-induced VSMC phenotype switching by regulating the PTEN/Akt pathway, and through a mechanism that might be associated with the upregulation of Daxx expression.

SUBMITTER: Sun SY

PROVIDER: S-EPMC8043179 | biostudies-literature | 2021 Dec

REPOSITORIES: biostudies-literature

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Nicotinate-curcumin inhibits AngII-induced vascular smooth muscle cell phenotype switching by upregulating Daxx expression.

Sun Si-Yu SY Cao Yu-Mei YM Huo Yan-Jie YJ Qiu Fei F Quan Wen-Juan WJ He Chao-Ping CP Chen Yu Y Liao Duan-Fang DF Tuo Qin-Hui QH

Cell adhesion & migration 20211201 1

Phenotypic switching is the main cause of the abnormal proliferation and migration of vascular smooth muscle cells (VSMCs). We previously showed that Daxx exerted negative regulatory effect on AngII-induced VSMC proliferation and migration. However, the function of Daxx in VSMC phenotype switching remained unknown. Nicotinate-curcumin (NC) is an esterification derivative of niacin and curcumin that can prevent the formation of atherosclerosis. We found that NC significantly decreased AngII-induc ...[more]

PMID: 33843453

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Project description:Rationale: Arterial remodeling serves as a pivotal mechanism underlying the development of diseases such as hypertension. Fibulin-7 (FBLN7), an adhesion protein, remains enigmatic regarding its role in these pathological processes. This study aims to explore whether FBLN7 influences vascular remodeling and its underlying mechanisms. Methods: We generated FBLN7 knockout mice and smooth muscle-specific FBLN7 overexpression mice. Vascular remodeling models were established by administering angiotensin II (Ang II) for 28 days. RNA sequencing, western blot, and immunofluorescence assays were employed to investigate the biological function of FBLN7 in vascular smooth muscle cells (VSMCs). The interaction mechanism between FBLN7 and cell membrane receptors was explored through mass spectrometry analysis, co-immunoprecipitation techniques and molecular dynamics simulations. Results: Bioinformatics analysis revealed an upregulation of FBLN7 expression in the vascular remodeling model, with FBLN7 predominantly localized in VSMCs. Subsequent in vivo validation demonstrated that FBLN7 knockout attenuated Ang II-induced vascular remodeling, reducing aortic wall thickness and collagen formation. Conversely, VSMC-specific overexpression of FBLN7 via AAV vectors exacerbating the remodeling phenotype. Functionally speaking, FBLN7 potentiates Ang II-mediated phenotypic transformation. Mechanistically, FBLN7 interacts with the extracellular and transmembrane domains of syndecan-4 (SDC4) via its C-terminal region, affecting SDC4 signaling and dimer formation. This interaction inhibits SDC4-mediated activation of the Rho-associated protein kinase pathway, subsequently reducing nuclear translocation of myocardin-related transcription factor A, leading to decreased transcription of genes associated with the contractile VSMCs phenotype. Conclusions: These findings reveal FBLN7 promotes the transition of VSMCs from a contractile to a synthetic phenotype, thereby aggravating vascular remodeling. This provides further insights into the pathogenesis of vascular remodeling and potential therapeutic strategies.

Project description:The cardiovascular disease of atherosclerosis is characterised by aged vascular smooth muscle cells and compromised cell survival. Analysis of human and murine plaques highlights markers of DNA damage such as p53, Ataxia telangiectasia mutated (ATM), and defects in mitochondrial oxidative metabolism as significant observations. The antiageing protein Klotho could prolong VSMC survival in the atherosclerotic plaque and delay the consequences of plaque rupture by improving VSMC phenotype to delay heart attacks and stroke. Comparing wild-type VSMCs from an ApoE model of atherosclerosis with a flox'd Pink1 knockout of inducible mitochondrial dysfunction we show WT Pink1 is essential for normal cell viability, while Klotho mediates energetic switching which may preserve cell survival. Wild-type ApoE VSMCs were screened to identify potential drug candidates that could improve longevity without inducing cytotoxicity. The central regulator of cell metabolism AMP Kinase was used as a readout of energy homeostasis. Functional energetic switching between oxidative and glycolytic metabolism was assessed using XF24 technology. Live cell imaging was then used as a functional readout for the WT drug response, compared with Pink1 (phosphatase-and-tensin-homolog (PTEN)-induced kinase-1) knockout cells. Candidate drugs were assessed to induce pACC, pAMPK, and pLKB1 before selecting Klotho for its improved ability to perform energetic switching. Klotho mediated an inverse dose-dependent effect and was able to switch between oxidative and glycolytic metabolism. Klotho mediated improved glycolytic energetics in wild-type cells which were not present in Pink1 knockout cells that model mitochondrial dysfunction. Klotho improved WT cell survival and migration, increasing proliferation and decreasing necrosis independent of effects on apoptosis. Klotho plays an important role in VSMC energetics which requires Pink1 to mediate energetic switching between oxidative and glycolytic metabolism. Klotho improved VSMC phenotype and, if targeted to the plaque early in the disease, could be a useful strategy to delay the effects of plaque ageing and improve VSMC survival.

Dataset Information

Nicotinate-curcumin inhibits AngII-induced vascular smooth muscle cell phenotype switching by upregulating Daxx expression.

Publications

Nicotinate-curcumin inhibits AngII-induced vascular smooth muscle cell phenotype switching by upregulating Daxx expression.

Similar Datasets

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