Lack of Endothelial Nitric Oxide Synthase Accelerates Ectopic Calcification in Uremic Mice Fed an Adenine and High Phosphorus Diet

Oe, Yuji; Mitsui, Shohei; Sato, Emiko; Shibata, Naoko; Kisu, Kazuaki; Sekimoto, Akiyo; Miyazaki, Mariko; Sato, Hiroshi; Ito, Sadayoshi; Takahashi, Nobuyuki

doi:10.1016/j.ajpath.2020.10.012

Cited by 15 publications

(17 citation statements)

References 48 publications

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“…Indeed, we found that concomitant L‐NAME administration significantly aggravated the calcification process in warfarin fed rats. Very recently, Oe et al concluded, in accordance with our results, that loss of endothelial NO accelerated ectopic calcification in a CKD mouse model 28 . Furthermore, L‐NAME administration has been shown to increase calcification in aortic valve disease 29,30 .…”

Section: Discussionsupporting

confidence: 91%

“…Very recently, Oe et al concluded, in accordance with our results, that loss of endothelial NO accelerated ectopic calcification in a CKD mouse model. 28 Furthermore, L-NAME administration has been shown to increase calcification in aortic valve disease. 29,30 From a clinical viewpoint, it is striking that endothelial dysfunction highly present in those populations at risk to develop arterial calcifications, that is, CKD and diabetes patients.…”

Section: Discussionmentioning

confidence: 99%

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Endothelial dysfunction aggravates arterial media calcification in warfarin administered rats

et al. 2022

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Arterial media calcification is an active cell process. This encompasses osteochondrogenic transdifferentiation of vascular smooth muscle cells followed by the deposition of calcium‐phosphate crystals. Increasing evidence suggests a significant role for endothelial cells (ECs) in the development of arterial media calcification. This manuscript explores a role for endothelial dysfunction in the disease progression of arterial media calcification. Male rats were randomly assigned to four different groups. The first group received standard chow. The second group was given L‐NAME (≈50 mg kg−1 · d−1), to induce endothelial dysfunction, in addition to standard chow. The third group and fourth group received a warfarin‐supplemented diet to induce mild calcification and the latter group was co‐administered L‐NAME. Prior to sacrifice, non‐invasive measurement of aortic distensibility was performed. Animals were sacrificed after 6 weeks. Arterial media calcification was quantified by measuring aortic calcium and visualized on paraffin‐embedded slices by the Von Kossa method. Arterial stiffness and aortic reactivity was assessed on isolated carotid segments using specialized organ chamber setups. Warfarin administration induced mineralization. Simultaneous administration of warfarin and L‐NAME aggravated the arterial media calcification process. Through organ chamber experiments an increased vessel tonus was found, which could be linked to reduced basal NO availability, in arteries of warfarin‐treated animals. Furthermore, increased calcification because of L‐NAME administration was related to a further compromised endothelial function (next to deteriorated basal NO release also deteriorated stimulated NO release). Our findings suggest early EC changes to impact the disease progression of arterial media calcification.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Endothelial dysfunction aggravates arterial media calcification in warfarin administered rats

et al. 2022

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“…A direct comparison of the blood parameters between different studies is also hampered by variations in ingredients of the experimental diet used; these ingredients do not only vary in concentration [ 11 ], but also in their source, which is relevant as, e.g., the intestinal resorption of phosphorus varies depending on the source. In our study, we used a diet containing 1% phosphate which did not result in elevated phosphate plasma concentration, while other protocols often used hyperphosphatemia inducing phosphate concentration (up to 2% phosphate) [ 14 , 15 , 28 ]. Tani et al recently compared 0.8% phosphate vs. high phosphate concentration (1.8%) in C57/BL6 mice.…”

Section: Discussionmentioning

confidence: 99%

“…As some studies already exists for C57/BL6 mouse strains and CKD induction upon adenine diet [ 15 , 16 , 28 ], the current protocol should be transferable to other strains. A correlation between blood and pulse pressure changes with the extent of MAC was successfully shown in an adenine rat model [ 12 ].…”

Section: Discussionmentioning

confidence: 99%

Uremic mouse model to study vascular calcification and “inflamm-aging”

Tölle

Henkel²,

Herrmann³

et al. 2022

J Mol Med

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Calcification and chronic inflammation of the vascular wall is a high-risk factor for cardiovascular mortality, especially in patients with chronic uremia. For the reduction or prevention of rapid disease progression, no specific treatment options are currently available. This study aimed to evaluate an adenine-based uremic mouse model for studying medial vessel calcification and senescence-associated secretory phenotype (SASP) changes of aortic tissue to unravel molecular pathogenesis and provide a model for therapy testing. The dietary adenine administration induced a stable and similar degree of chronic uremia in DBA2/N mice with an increase of uremia blood markers such as blood urea nitrogen, calcium, creatinine, alkaline phosphatase, and parathyroid hormone. Also, renal fibrosis and crystal deposits were detected upon adenine feeding. The uremic condition is related to a moderate to severe medial vessel calcification and subsequent elastin disorganization. In addition, expression of osteogenic markers as Bmp-2 and its transcription factor Sox-9 as well as p21 as senescence marker were increased in uremic mice compared to controls. Pro-inflammatory uremic proteins such as serum amyloid A, interleukin (Il)-1β, and Il-6 increased. This novel model of chronic uremia provides a simple method for investigation of signaling pathways in vascular inflammation and calcification and therefore offers an experimental basis for the development of potential therapeutic intervention studies. Graphical abstract

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“…Genetic lack of eNOS was associated with raised atherosclerotic lesions and valvular calcification in mice models ( 67 , 68 ). A recent study revealed that eNOS deficiency was also associated with the exacerbation of aortic calcification ( 69 ). On the other hand, exercise training prevented eNOS down-regulation and resulted in fewer calcification deposits in rat VC models ( 70 ).…”

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.

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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.

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Lack of Endothelial Nitric Oxide Synthase Accelerates Ectopic Calcification in Uremic Mice Fed an Adenine and High Phosphorus Diet

Cited by 15 publications

References 48 publications

Endothelial dysfunction aggravates arterial media calcification in warfarin administered rats

Endothelial dysfunction aggravates arterial media calcification in warfarin administered rats

Uremic mouse model to study vascular calcification and “inflamm-aging”

AMPK: Potential Therapeutic Target for Vascular Calcification

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