Aldosterone enhances high phosphate–induced vascular calcification through inhibition of AMPK‐mediated autophagy

Gao, Jingwei; He, Wanbing; Xie, Changming; Gao, Ming; Feng, Leiyu; Liu, Zhaoyu; Wang, Jingfeng; Huang, Hui; Liu, Pin‐Ming

doi:10.1111/jcmm.15813

Cited by 22 publications

(22 citation statements)

References 39 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…VSMCs were randomly divided into ten groups. (1) Control group: normal culture in a normoxic incubator with 12% FBS; (2) Con+U group: U50,488H (Sigma, USA, 40 mm/L), a selective κ-opioid receptor agonist, was administered on the foundation of the control group; (3) β-GP group: β-glycerol (Sigma-Aldrich, USA, 10 mmol/L) was administered for ten days to establish a calcification model according to the literature [ 49 ]; (4) β-GP+U group: U50,488H (40 mm/L) was administered 10 min before treatment with β-glycerol; (5) β-GP+N+U group: nor-binaltorphimine, MCE, USA, 5 mm/L), a selective κ-opioid receptor antagonist, was administered 20 min before treatment with β-GP. After the administration of nor-BNI for 10 min, U50,488H was administered; (6) β-GP+U+IOX2 group: IOX2, MCE, USA, 5 mm/L), a selective PHD2 antagonist, was administered 15 min before treatment with β-GP.…”

Section: Methodsmentioning

confidence: 99%

κ-opioid receptor stimulation alleviates rat vascular smooth muscle cell calcification via PFKFB3-lactate signaling

Niu

Zhang

et al. 2021

Aging

View full text Add to dashboard Cite

In the present study, the effects and mechanism of action of U50,488H (a selective κ-opioid receptor agonist) on calcification of rat vascular smooth muscle cells (VSMCs) induced by β-glycerophosphate (β-GP) were investigated. VSMCs were isolated and cultured in traditional FBS-based media. A calcification model was established in VSMCs under hyperphosphatemia and intracellular calcium contents. Alkaline phosphatase (ALP), lactate dehydrogenase (LDH), and lactate were detected in cell culture supernatants before and after treatment. Alizarin red staining was used to detect the degree of calcification of VSMCs. Expression levels of key molecules of osteogenic markers, fructose-2,6-biphosphatase 3 (PFKFB3), and proline hydroxylase 2 (PHD2), were determined using western blotting. Further, vascular calcification was induced by vitamin D3 plus nicotine in rats and isolated thoracic aortas, calcium concentration was assessed in rat aortic rings in vitro . We demonstrated that U50,488H inhibited VSMC calcification in a concentration-dependent manner. Moreover, U50,488H significantly inhibited osteogenic differentiation and ALP activity in VSMCs pretreated with β-GP. Further studies confirmed that PFKFB3 expression, LDH level, and lactate content significantly increased during calcification of VSMCs; U50,488H reversed these changes. PHD2 expression showed the opposite trend compared to PFKFB3 expression. nor-BNI or 3-PO abolished U50,488H protective effects. Besides, U50,488H inhibited VSMC calcification in rat aortic rings ex vivo . Collectively, our experiments show that κ-opioid receptor activation inhibits VSMC calcification by reducing PFKFB3 expression and lactate content, providing a potential drug target and strategy for the clinical treatment of vascular calcification.

show abstract

Section: Methodsmentioning

confidence: 99%

κ-opioid receptor stimulation alleviates rat vascular smooth muscle cell calcification via PFKFB3-lactate signaling

Niu

Zhang

et al. 2021

Aging

View full text Add to dashboard Cite

show abstract

“…To evaluate whether autophagy inhibition could reverse the protective effects of BHB on VC, the autophagosome inhibitor 3-methyladenine (Selleck, USA), at a concentration of 20 μM, and the autophagic flux inhibitor chloroquine (Selleck, USA), at a concentration of 10 μM, were administrated to the calcification models with BHB intervention ( 25 ).…”

Section: Methodsmentioning

confidence: 99%

“…Von Kossa staining was used to detect the calcified depositions of arterial rings. The staining experiments were performed as previously described ( 25 ). The calcium deposits displayed black or dark brown colors under the microscope.…”

Section: Methodsmentioning

confidence: 99%

β-Hydroxybutyric Inhibits Vascular Calcification via Autophagy Enhancement in Models Induced by High Phosphate

Liang

Huang

et al. 2021

Front. Cardiovasc. Med.

Self Cite

View full text Add to dashboard Cite

Background: Vascular calcification (VC) is a landmark of aging, while β-hydroxybutyric acid (BHB) induced by calorie restriction has been identified as a promising factor to extend the lifespan. However, the effect of BHB on VC and the potential mechanism remain unknown.Methods: A total of 160 subjects with or without metabolic abnormalities (MAs) were assigned to four groups according to different calcification severities. The association between BHB, MAs, and VC was investigated via mediation analysis. Then, with high phosphate-induced calcification models, the effect of BHB on arterial ring calcification and osteogenic phenotypic differentiation of vascular smooth muscle cells (VSMCs) was investigated. Hereafter the expressions of autophagy biomarkers, autophagy flux, and effects of autophagy inhibitors on VC were detected.Results: Severe VC was observed in the elderly, accompanied with a higher proportion of hypertension, chronic kidney disease, and lower estimated glomerular filtration rate. The serum BHB level was an independent influencing factor of VC severities. With mediation analysis, BHB was determined as a significant mediator in the effects of MAs on VC, and the indirect effect of BHB accounted for 23% of the total effect. Furthermore, BHB directly inhibited arterial ring calcification and osteogenic phenotypic differentiation in VSMCs, accompanied with autophagy enhancement in VSMCs. In accordance, the inhibition of autophagy counteracted the protective effect of BHB on VC.Conclusion: The present study demonstrated that BHB mediated the effects of MAs on VC; then, it further elucidated that BHB could inhibit arterial and VSMC calcification via autophagy enhancement.

show abstract

“…By activating AMPK with melatonin ( 41 ) or ghrelin ( 36 ), the process of autophagy was enhanced, which resulted in reduced VSMC osteoblastic differentiation both in cell culture ( 41 ) and rat models of VC ( 36 ). On the other hand, treatment of aldosterone or advanced glycation end products (AGEs) facilitated VC by inhibiting AMPK-dependent autophagy ( 46 ). Pretreatment of AMPK activator AICAR could upregulate the autophagy level and reverse the effect of AGEs on osteoblastic differentiation of VSMCs ( 41 , 47 ).…”

Section: The Protective Role Of Ampk Against Vcmentioning

confidence: 99%

AMPK: Potential Therapeutic Target for Vascular Calcification

Lü

Yuan

Min

et al. 2021

Front. Cardiovasc. Med.

View full text Add to dashboard Cite

Vascular calcification (VC) is an urgent worldwide health issue with no available medical treatment. It is an active cell-driven process by osteogenic differentiation of vascular cells with complex mechanisms. The AMP-activated protein kinase (AMPK) serves as the master sensor of cellular energy status. Accumulating evidence reveals the vital role of AMPK in VC progression. AMPK is involved in VC in various ways, including inhibiting runt-related transcription factor 2 signaling pathways, triggering autophagy, attenuating endoplasmic reticulum stress and dynamic-related protein 1-mediated mitochondrial fission, and activating endothelial nitric oxide synthase. AMPK activators, like metformin, are associated with reduced calcification deposits in certain groups of patients, indicating that AMPK is a potential therapeutic target for VC.

show abstract

Aldosterone enhances high phosphate–induced vascular calcification through inhibition of AMPK‐mediated autophagy

Cited by 22 publications

References 39 publications

κ-opioid receptor stimulation alleviates rat vascular smooth muscle cell calcification via PFKFB3-lactate signaling

κ-opioid receptor stimulation alleviates rat vascular smooth muscle cell calcification via PFKFB3-lactate signaling

β-Hydroxybutyric Inhibits Vascular Calcification via Autophagy Enhancement in Models Induced by High Phosphate

AMPK: Potential Therapeutic Target for Vascular Calcification

Contact Info

Product

Resources

About