Functional alterations in endothelial NO, PGI2 and EDHF pathways in aorta in ApoE/LDLR−/− mice

Cserni, Gábor; Gajda, Mariusz; Franczyk-Żarów, Magdalena; Kostogrys, Renata B.; Gwóźdź, Paweł; Mateuszuk, Łukasz; Sternak, Magdalena; Wojcik, Luiza; Zalewska, Teresa; Walski, M; Chłopicki, Stefan

doi:10.1016/j.prostaglandins.2012.02.002

Cited by 47 publications

(39 citation statements)

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“…In this model, endothelial dysfunction is present at the age of 2 months, in the absence of visible atherosclerotic plaques. The first lesions, composed mostly of fatty streaks and infiltrating macrophages, appear at the age of 3 months and subsequently develop into advanced atherosclerotic plaques at the age of 4 months (Csányi et al, 2012). Accordingly, the antiatherosclerotic effects of MNA and NicA demonstrated here have clinical relevance and indicate the inhibition of progression of atherosclerosis, not prevention of atherosclerosis as if the treatment had been initiated before atherosclerotic plaque development.…”

Section: Discussionmentioning

confidence: 70%

“…It is also unlikely that MNA has an affinity to GPR109 A receptors. Perhaps a GPR109 A -dependent action of NicA is important in the early development of atherosclerosis, when monocytes are infiltrating the vascular wall, but not in the late stage of plaque development, when significant macrophage content is seen in the plaques of 4-month old ApoE/LDLR 2/2 mice (Csányi et al, 2012). Indeed, unlike in our experiment (reversal of atherosclerosis), Lukasova et al (2011a,b) used a preventive treatment of atherosclerosis to investigate the GPR109 A -dependent effect of NicA, in which LDLR 2/2 mice were treated with NicA starting at the age of 2 months, prior to the appearance of visible lesions.…”

Section: Discussionmentioning

confidence: 99%

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Antiatherosclerotic Effects of 1-Methylnicotinamide in Apolipoprotein E/Low-Density Lipoprotein Receptor-Deficient Mice: A Comparison with Nicotinic Acid

Mateuszuk

Jasztal

Maślak

et al. 2015

Journal of Pharmacology and Experimental Therapeutics

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1-Methylnicotinamide (MNA), the major endogenous metabolite of nicotinic acid (NicA), may partially contribute to the vasoprotective properties of NicA. Here we compared the antiatherosclerotic effects of MNA and NicA in apolipoprotein E (ApoE)/ low-density lipoprotein receptor (LDLR)-deficient mice. ApoE/ LDLR 2/2 mice were treated with MNA or NicA (100 mg/kg). Plaque size, macrophages, and cholesterol content in the brachiocephalic artery, endothelial function in the aorta, systemic inflammation, platelet activation, as well as the concentration of MNA and its metabolites in plasma and urine were measured. MNA and NicA reduced atherosclerotic plaque area, plaque inflammation, and cholesterol content in the brachiocephalic artery. The antiatherosclerotic actions of MNA and NicA were associated with improved endothelial function, as evidenced by a higher concentration of 6-keto-prostaglandin F 1a and nitrite/nitrate in the aortic ring effluent, inhibition of platelets (blunted thromboxane B 2 generation), and inhibition of systemic inflammation (lower plasma concentration of serum amyloid P, haptoglobin). NicA treatment resulted in an approximately 2-fold higher concentration of MNA and its metabolites in urine and a 4-fold higher nicotinamide/MNA ratio in plasma, compared with MNA treatment. In summary; MNA displays pronounced antiatherosclerotic action in ApoE/LDLR 2/2 mice, an effect associated with an improvement in prostacyclin-and nitric oxide-dependent endothelial function, inhibition of platelet activation, inhibition of inflammatory burden in plaques, and diminished systemic inflammation. Despite substantially higher MNA availability after NicA treatment, compared with an equivalent dose of MNA, the antiatherosclerotic effect of NicA was not stronger. We suggest that detrimental effects of NicA or its metabolites other than MNA may limit beneficial effects of NicA-derived MNA.

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Section: Discussionmentioning

confidence: 70%

Section: Discussionmentioning

confidence: 99%

Antiatherosclerotic Effects of 1-Methylnicotinamide in Apolipoprotein E/Low-Density Lipoprotein Receptor-Deficient Mice: A Comparison with Nicotinic Acid

Mateuszuk

Jasztal

Maślak

et al. 2015

Journal of Pharmacology and Experimental Therapeutics

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“…This is an interesting observation, as it clearly demonstrates the important interaction between diet and renal function necessary to induce endothelial dysfunction. Prior reports of endothelial dysfunction are limited to the double knockout of LDLr -/-with apoE -/-mice (83,84). These mice, whether on HFD or not, fail to exhibit reduced cholinergic vasodilation (85)(86)(87).…”

Section: Discussionmentioning

confidence: 99%

Myeloperoxidase-derived oxidants damage artery wall proteins in an animal model of chronic kidney disease–accelerated atherosclerosis

Zeng

Mathew

Byun

et al. 2018

Journal of Biological Chemistry

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Increased myeloperoxidase (MPO) levels and activity are associated with increased cardiovascular risk among individuals with chronic kidney disease (CKD). However, a lack of good animal models for examining the presence and catalytic activity of MPO in vascular lesions has impeded mechanistic studies into CKD-associated cardiovascular diseases. Here, we show for the first time that exaggerated atherosclerosis in a pathophysiologically relevant CKD mouse model is associated with increased macrophage-derived MPO activity. Male 7-week-old LDL receptordeficient mice underwent sham (control mice) or 5/6 nephrectomy and were fed either a low-fat or high-fat, high-cholesterol diet for 24 weeks, and the extents of atherosclerosis and vascular reactivity were assessed. MPO expression and oxidation products, and the protein-bound oxidized tyrosine moieties 3-chlorotyrosine, 3-nitrotyrosine, and o,o′-dityrosine were examined with immunoassays and confirmed with mass spectrometry (MS). As anticipated, the CKD mice had significantly higher plasma creatinine, urea nitrogen, and intact parathyroid hormone along with lower hematocrit and body weight. On both the diet regimens, CKD mice did not have hypertension but had lower cholesterol and triglyceride levels than the control mice. Despite the lower cholesterol levels, CKD mice had increased aortic plaque areas, fibrosis, and luminal narrowing. They also exhibited increased MPO expression and activity (i.e., increased oxidized tyrosines) that co-localized with infiltrating lesional macrophages and diminished vascular reactivity. In summary, unlike non-CKD mouse models of atherosclerosis, CKD mice exhibit increased MPO expression and catalytic activity in atherosclerotic lesions, which colocalize with lesional macrophages. These results implicate macrophage-derived MPO in CKDaccelerated atherosclerosis.Chronic kidney disease (CKD) affects 15% of Americans, and cardiovascular disease (CVD) continues to be the leading cause of mortality in Myeloperoxidase oxidizes artery proteins in kidney disease2 these patients (>10-fold mortality compared to the general population) (1-6). An increased risk for CVD is evident even in milder and non-albuminuric forms of CKD and cannot be fully explained by traditional risk factors (7-10). Furthermore, control of established risk factors such as hyperlipidemia results in substantially lower risk reduction in CKD patients compared to the general population (11). Recent evidence supports the key role of nontraditional risk factors (e.g., oxidative stress) in the pathogenesis of CVD in CKD (12-17), suggesting that CKD-specific mechanisms are responsible for CVD in kidney patients.Atherosclerosis, the major cause of CVD, is a chronic inflammatory disease characterized by the infiltration of lipids and inflammatory cells, such as monocyte-derived macrophages and Tlymphocytes, into the artery wall (18). While elevated levels of low-density lipoprotein (LDL) are known to increase the risk of atherosclerosis greatly (19), in vitro studies sugges...

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“…[ LDL receptor double knock-out mice are considered as one of the best animal model of atherosclerosis as they demonstrate severe hypercholesterolemia and develop advanced atherosclerotic lesions similar to human, that is preceded by development of endothelial dysfunction [26]. We chose this animal model as an object of study since many previous papers clearly indicate that the renin-angiotensin system with, in particular, its final product Ang II, plays a pivotal role in atherogenesis [13,[27][28][29][30].…”

Section: Analytementioning

confidence: 99%

Development of a sensitive, accurate and robust liquid chromatography/mass spectrometric method for profiling of angiotensin peptides in plasma and its application for atherosclerotic mice

Olkowicz

Radulska

Suraj³

et al. 2015

Journal of Chromatography A

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Functional alterations in endothelial NO, PGI2 and EDHF pathways in aorta in ApoE/LDLR−/− mice

Cited by 47 publications

References 50 publications

Antiatherosclerotic Effects of 1-Methylnicotinamide in Apolipoprotein E/Low-Density Lipoprotein Receptor-Deficient Mice: A Comparison with Nicotinic Acid

Antiatherosclerotic Effects of 1-Methylnicotinamide in Apolipoprotein E/Low-Density Lipoprotein Receptor-Deficient Mice: A Comparison with Nicotinic Acid

Myeloperoxidase-derived oxidants damage artery wall proteins in an animal model of chronic kidney disease–accelerated atherosclerosis

Development of a sensitive, accurate and robust liquid chromatography/mass spectrometric method for profiling of angiotensin peptides in plasma and its application for atherosclerotic mice

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