Statins Promote Potent Systemic Antioxidant Effects Through Specific Inflammatory Pathways

Shishehbor, Mehdi H.; Brennan, Marie Luise; Aviles, Ronnier J.; Fu, Xiaoming; Penn, Marc S.; Sprecher, Dennis L.; Hazen, Stanley L.

doi:10.1161/01.cir.0000080895.05158.8b

Cited by 368 publications

(255 citation statements)

References 44 publications

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“…The mechanisms behind the antiarrhythmic effect of statins remain unclear but are possibly attributable to improvement in inflammation, oxidative stress, and endothelial dysfunction 32, 33, 34. Nonimprovement in endothelial function by atorvastatin treatment in this study likely affected the lack of benefit for arrhythmia recurrence.…”

Section: Discussionmentioning

confidence: 99%

Age‐Dependent Predictive Value of Endothelial Dysfunction for Arrhythmia Recurrence Following Pulmonary Vein Isolation

Matsuzawa

Suleiman

Guddeti

et al. 2016

JAHA

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BackgroundThe mechanisms of atrial fibrillation (AF) are highly divergent. The prevalence of AF increases significantly with age, and underling mechanisms might vary with age. Endothelial dysfunction may be associated with AF and atrial arrhythmia recurrence after catheter ablation. We tested the hypothesis that the impact of endothelial dysfunction on arrhythmia recurrence following catheter ablation is age dependent.Methods and ResultsThis study enrolled 92 participants with AF undergoing catheter ablation. Endothelial function was assessed by peripheral arterial tonometry before ablation, and the natural logarithmic transformation of reactive hyperemia index was calculated. Endothelial dysfunction was defined as a natural logarithmic transformation of reactive hyperemia index <0.618 (median). Participants were followed for atrial tachycardia, flutter, and fibrillation recurrence for a median of 14 months. The mean age was 57±10 years. There was significant interaction between age and endothelial dysfunction in association with recurrence of AF (P=0.029) and any atrial arrhythmia (P=0.015), and the risk associated with endothelial dysfunction for arrhythmia recurrence was higher in younger versus older participants. Participants were divided into 2 age groups at a threshold of 60 years. Among participants aged ≤60 years, multivariate Cox proportional hazards analysis revealed the independent association between endothelial dysfunction and increased risk of arrhythmia recurrence (hazard ratio for AF 4.18 [95% CI 1.33–15.82], P=0.014, and for any atrial arrhythmia 3.62 [95% CI 1.29–11.81], P=0.014). Kaplan–Meier analysis showed that participants with endothelial dysfunction had significantly higher rates of recurrence of AF (P=0.01) and any atrial arrhythmia (P=0.002).ConclusionsThe risk associated with endothelial dysfunction for arrhythmia recurrence following catheter ablation was age dependent and was higher in younger participants.

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Section: Discussionmentioning

confidence: 99%

Age‐Dependent Predictive Value of Endothelial Dysfunction for Arrhythmia Recurrence Following Pulmonary Vein Isolation

Matsuzawa

Suleiman

Guddeti

et al. 2016

JAHA

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“…More importantly, elevated plasma MPO levels predict the risk of cardiovascular events and mortality in patients with unstable angina, chest pain (37), acute coronary syndrome, or peripheral arterial disease (37)(38)(39)(40). Systemic levels of 3-nitrotyrosine have also been found to be higher among patients with CVD compared to those with healthy arteries (41)(42)(43). We have recently demonstrated that plasma MPO levels and MPO oxidation products are elevated in autoimmune diseases such as rheumatoid arthritis and systemic lupus erythematous, both of which carry an increased risk of CVD (44,45).…”

Section: Myeloperoxidase Oxidizes Artery Proteins In Kidney Diseasementioning

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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“…Systemic or intraperitoneal injection of CYP induces a reproducible dose-dependant chemical cystitis in both mice and rats and therefore has been used as an experimental model of cystitis 11 . Although statins are not employed in the treatment of HC, we hypothesized that their use may be useful due to their pleiotropic anti-inflammatory effects 12 . We did not find reports in the literature on the use of statins in clinical and experimental studies involving HC induced by CYP.…”

Section: Introductionmentioning

confidence: 99%

Protective effect of simvastatin in the cyclophosphamide-induced hemohrragic cystitis in rats

et al. 2010

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PURPOSE: Cyclophosphamide (CYP) is an antineoplastic agent used for the treatment of many neoplastic and inflammatory diseases. Hemorrhagic cystitis is a frequent side effect of CYP. Several studies show that simvastatin has important pleiotropic (anti-inflammatory and immunomodulatory) effects. The purpose of the study was to investigate the effect of simvastatin on bladder, ureter and kidney injury caused by CYP. METHODS: Adult male Wistar rats were randomly divided into three groups. The CYP/SIM group received simvastatin microemulsion by gavage during 7 days (10 mg/kg body wt) before the administration of CYP and the CYP/SAL group rats received saline 0.9%. The control rats were not treated. After that, all rats were treated with a single dose of CYP 200 mg/kg body wt intraperitoneally. The rats were killed 24 h after CYP administration. Plasma cytokines (TNF-α, IL-1β, IL-6) were measured by ELISA. Macro and light microscopic study was performed in the bladder, kidney and ureter. RESULTS: In the bladders of CYP/SIMV treated rats edema of lamina propria with epithelial and sub-epithelial hemorrhage were lower than in CYP/SAL treated rats. The scores for macroscopic and microscopic evaluation of bladder and ureter were significantly lower in CYP/SIMV rats than in CYP/SAL rats. The kidney was not affected. The expression of TNF-α, IL-1β and IL-6 was significatly lower in CF/SINV rats (164.8±22, 44.8±8 and 52.4±13) than in CF/SAL rats (378.5±66, 122.9±26 e 123.6±18), respectively. CONCLUSION: The results of the current study suggest that simvastatin pretreatment attenuated CYP-induced urotelium inflammation and decreased the activities of cytokines.

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Statins Promote Potent Systemic Antioxidant Effects Through Specific Inflammatory Pathways

Cited by 368 publications

References 44 publications

Age‐Dependent Predictive Value of Endothelial Dysfunction for Arrhythmia Recurrence Following Pulmonary Vein Isolation

Age‐Dependent Predictive Value of Endothelial Dysfunction for Arrhythmia Recurrence Following Pulmonary Vein Isolation

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

Protective effect of simvastatin in the cyclophosphamide-induced hemohrragic cystitis in rats

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