Circulating Lipocalin-2 and Retinol-Binding Protein 4 Are Associated with Intima-Media Thickness and Subclinical Atherosclerosis in Patients with Type 2 Diabetes

Xiao, Yang; Xu, Aimin; Hui, Xiaoyan; Zhou, Pengcheng; Li, Xing; Zhong, Hui; Tang, Weili; Huang, Gan; Zhang, Zhou

doi:10.1371/journal.pone.0066607

Cited by 53 publications

(48 citation statements)

References 36 publications

(43 reference statements)

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“…Elevated LCN2 levels have been found to be associated with several markers of CVD, such as intima-media thickness of arteries and the degree of severity. 10,13 In addition to its circulating levels, plaque levels of LCN2 tended to be higher when intraplaque hemorrhage or luminal thrombus was present.…”

Section: Discussionmentioning

confidence: 99%

“…8,9 The association between LCN2 and presence and severity of atherosclerosis was confirmed in cross-sectional study. 10 However, prospective studies addressing the cause-effect relationship between LCN2 and CVD are still lacking. In the present study, we investigated the development of CVD events in relation to the baseline LCN2 levels in a population-based cohort recruited from the Shanghai Diabetes Study.…”

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confidence: 99%

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Elevated Circulating Lipocalin-2 Levels Independently Predict Incident Cardiovascular Events in Men in a Population-Based Cohort

Fang

et al. 2014

ATVB

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Objective-Adipose tissue inflammation and perturbation of adipokine secretion may contribute to the pathogenesis of cardiovascular diseases (CVD). Lipocalin-2 (LCN2), mainly released from adipocytes, has been shown to be positively associated with CVD in cross-sectional studies. We aimed to evaluate the association of LCN2 with CVD involving a population-based cohort recruited from the Shanghai Diabetes Study. Approach and Results-Serum LCN2 levels were measured using ELISA. Independent predictors of CVD development were identified using Cox proportion hazards regression. The predictive performances of the various models were assessed by Kaplan-Meier analysis. At baseline, circulating LCN2 was significantly associated with a cluster of traditional cardiovascular risk factors. Baseline LCN2 levels in male subjects who developed CVD events during follow-up were significantly higher than those who did not develop CVD events (P=0.012). However, such difference was not significant in female subjects. LCN2 was a predictor of CVD in men, which remained statistically significant after adjustment for traditional cardiovascular risk factors (hazard ratio, 1.038 [95% confidence interval, 1.017-1.060]). LCN2 remained significantly associated with incident CVD even after adjustment for renal function, adiponectin, and high-sensitivity C-reactive protein levels. Kaplan-Meier analysis suggested combination of LCN2 and high-sensitivity C-reactive protein might improve the prediction of CVD events in male subjects. Conclusions-Elevated circulating LCN2 level is an independent predictor of CVD events in men in a population-based cohort and adds to the prognostic value of high-sensitivity C-reactive protein, which is currently the most extensively studied biomarker of CVD. Measurement of serum LCN2 might be useful for early detection and intervention of CVD. (Arterioscler Thromb Vasc Biol. 2014;34:2457-2464.)

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Elevated Circulating Lipocalin-2 Levels Independently Predict Incident Cardiovascular Events in Men in a Population-Based Cohort

Fang

et al. 2014

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“…[26][27][28][29] Moreover, elevated circulating NGAL concentrations predict adverse cardiovascular events in patients. 29,30 We and others, have previously showed that Lcn2/NGAL is a direct target gene of the aldosterone/MR signaling pathway in the cardiovascular system.…”

Section: Discussionmentioning

confidence: 99%

Neutrophil Gelatinase–Associated Lipocalin, a Novel Mineralocorticoid Biotarget, Mediates Vascular Profibrotic Effects of Mineralocorticoids

et al. 2015

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A ldosterone via the activation of the mineralocorticoid receptor (MR) is a main actor of renal sodium reabsorption and water homeostasis. Extra-renal effects of the mineralocorticoid pathway have now been characterized, especially in the cardiovascular system, opening on new dimensions of the aldosterone/MR pathway in physiology, pathophysiology, and diseases. In the cardiovascular system, mineralocorticoid signaling has been shown to play an important role in the progression of cardiovascular diseases (CVDs). Previous reports using transgenic mouse models or pharmacological approaches demonstrated adverse effects of aldosterone on cardiac remodeling and fibrosis, inflammation, and hypertension.1 These features are prevented by the pharmacological blockade of the MR. In humans, several clinical studies showed the beneficial effects of MR antagonism in addition to standard care, to reduce mortality and morbidity in patients with severe 2 or mild heart failure (HF) 3 or after acute myocardial infarction. 4 Understanding the molecular mechanisms of mineralocorticoid activation pathway in cardiovascular pathophysiology remains incomplete. Indeed, a better knowledge of the underlying mechanisms may highlight novel mediators of the MR signaling cascade. These newly identified intermediates could be good candidates as biotargets for novel pharmacological approaches, especially in diseases where the aldosterone/MR pathway is involved. Moreover, these biotargets may as well be considered as potent biomarkers of MR activation, Abstract-Activation of the mineralocorticoid receptor has been shown to be deleterious in cardiovascular diseases (CVDs).We have recently shown that lipocalin 2 (Lcn2), or neutrophil gelatinase-associated lipocalin (NGAL), is a primary target of aldosterone/mineralocorticoid receptor in the cardiovascular system. Lcn2 is a circulating protein, which binds matrix metalloproteinase 9 and modulates its stability. We hypothesized that Lcn2 could be a mediator of aldosterone/ mineralocorticoid receptor profibrotic effects in the cardiovascular system. Correlations between aldosterone and profibrotic markers, such as procollagen type I N-terminal peptide, were investigated in healthy subjects and subjects with abdominal obesity. The implication of Lcn2 in the mineralocorticoid pathway was studied using Lcn2 knockout mice subjected to a nephrectomy/aldosterone/salt (NAS) challenge for 4 weeks. In human subjects, NGAL/matrix metalloproteinase 9 was positively correlated with plasma aldosterone and fibrosis biomarkers. In mice, loss of Lcn2 prevented the NAS-induced increase of plasma procollagen type I N-terminal peptide, as well as the increase of collagen fibers deposition and collagen I expression in the coronary vessels and the aorta. The lack of Lcn2 also blunted the NAS-induced increase in systolic blood pressure. Ex vivo, treatment of human fibroblasts with recombinant Lcn2 induced the expression of collagen I and the profibrotic galectin-3 and cardiotrophin-1 molecules. allowing a better selectio...

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“…Cabré et al (19) observed that RBP4 would increase in patients with T2DM complicated with coronary heart diseases, and that if levels of RBP4 increased by 1/4, the risk of cardiovascular diseases would increase by 2.5 times. A recent study (20) demonstrated that the levels of RBP4 had already increased in the early stages of the development of T2DM complicated with atherosclerosis. In the present study, RBP4 was positively correlated with TG, LDL-c, FINS, HOMA-IR, PFM, AIP, NF-κB and SBP, and negatively correlated with HDL-c following correlation analysis.…”

Section: Discussionmentioning

confidence: 99%

Expression of retinol binding protein 4 and nuclear factor-κB in diabetic rats with atherosclerosis and the intervention effect of pioglitazone

Zhou

2016

Experimental and Therapeutic Medicine

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Abstract. This study aims to investigate the expression of retinol binding protein 4 (RBP4) and the activity of nuclear factor-kappa B (NF-κB) in diabetic rats with atherosclerosis, and to evaluate the intervention effect of pioglitazone. A total of 75 Wistar rats were randomly divided into four groups: Normal control (NC), diabetic rats (DM1), diabetic rats with atherosclerosis (DM2) and diabetic rats treated with pioglitazone (DM + Pio). The activity of NF-κB, the levels of serum and adipose tissue RBP4, fasting plasma glucose (FPG), fasting insulin (FINS), low-density lipoprotein cholesterol (LDL-c), high-density lipoprotein cholesterol (HDL-c), triglycerides (TG) and arteria caudilis systolic blood pressure (SBP) were measured. Percentage of fat mass (PFM), atherogenic index of plasma (AIP) and homeostasis model assessment of insulin resistance (HOMA-IR) were calculated. Compared with the NC and DM + Pio groups, all the parameters mentioned above increased significantly in the DM1 and DM2 groups, with the exception that HDL-c decreased. Pearson analysis showed that RBP4 in serum and adipose tissue were positively associated with TG, LDL-c, FINS, PFM, AIP, HOMA-IR, NF-κB, SBP and negatively associated with HDL-c. Multivariable logistic regression analysis showed that serum RBP4 and TG were predictors for the presence of diabetic atherosclerosis. In conclusion, RBP4 may be an effective predictor for diabetic atherosclerosis; pioglitazone is able to decrease RBP4 and NF-κB, which may partly contribute to its protective effect against diabetic atherosclerosis.

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Circulating Lipocalin-2 and Retinol-Binding Protein 4 Are Associated with Intima-Media Thickness and Subclinical Atherosclerosis in Patients with Type 2 Diabetes

Cited by 53 publications

References 36 publications

Elevated Circulating Lipocalin-2 Levels Independently Predict Incident Cardiovascular Events in Men in a Population-Based Cohort

Elevated Circulating Lipocalin-2 Levels Independently Predict Incident Cardiovascular Events in Men in a Population-Based Cohort

Neutrophil Gelatinase–Associated Lipocalin, a Novel Mineralocorticoid Biotarget, Mediates Vascular Profibrotic Effects of Mineralocorticoids

Expression of retinol binding protein 4 and nuclear factor-κB in diabetic rats with atherosclerosis and the intervention effect of pioglitazone

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