CKD frequently leads to chronic cardiac dysfunction. This complex relationship has been termed as cardiorenal syndrome type 4 or cardio-renal link. Despite numerous studies and reviews focused on the pathophysiology and therapy of this syndrome, the role of arterial stiffness has been frequently overlooked. In this regard, several pathogenic factors, including uremic toxins (i.e., uric acid, phosphates, endothelin-1, advanced glycation end-products, and asymmetric dimethylarginine), can be involved. Their effect on the arterial wall, direct or mediated by chronic inflammation and oxidative stress, results in arterial stiffening and decreased vascular compliance. The increase in aortic stiffness results in increased cardiac workload and reduced coronary artery perfusion pressure that, in turn, may lead to microvascular cardiac ischemia. Conversely, reduced arterial stiffness has been associated with increased survival. Several approaches can be considered to reduce vascular stiffness and improve vascular function in patients with CKD. This review primarily discusses current understanding of the mechanisms concerning uremic toxins, arterial stiffening, and impaired cardiac function, and the therapeutic options to reduce arterial stiffness in patients with CKD.

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We have evaluated circulating miRNAs (-195-5p and -451a) in subjects with acute ischemic stroke (AIS) and in patients with transient ischemic attack (TIA). In this study, 18 subjects with AIS and 18 patients with TIA were enrolled and examined at admission (T0) and at 24 h and 48 h after admission, and compared to 20 controls (C). At T0, circulating miRNA-195-5p and -451a were significantly upregulated in both AIS and TIA patients, compared to C. We also observed a progressive reduction of circulating miRNA levels at 24 h and 48 h in both AIS and TIA patients. Hypoxia inducible factor 1alpha (HIF-1α) serum level was significantly increased at T0, in both AIS and TIA patients, in comparison to C (both p < 0.01 vs. C) and it decreased in both AIS and TIA patients at 24 h and at 48 h, in comparison to T0 (both p < 0.01 vs. T0). Vascular endothelial growth factor (VEGF) serum level was significantly decreased at T0, in both AIS and TIA patients, if compared to C (both p < 0.01 vs. C) and increased, in both AIS and TIA patients, at 24 h and 48 h, if compared to T0 (both p < 0.01 vs. T0). The elevated expression of miRNA-195-5p and miRNA-451a significantly decreased over time at 24 h and 48 h, and it is associated with decreased HIF-α levels and increased VEGF serum levels. These data may suggest a role for this miRNAs as biomarker in the pathogenesis and prognosis of AIS patients and for the first time also in TIA patients.

ABSTRACT. Adiponectin (ADPN), which is a secretory protein of adipose tissue, attenuates endothelial inflammatory responses in vitro. Among human subjects, plasma ADPN concentrations are reduced among patients with atherosclerotic complications but are substantially increased among patients with advanced renal failure. The clinical and biochemical correlates of plasma ADPN levels were investigated and the predictive power of ADPN levels with respect to survival rates and cardiovascular events was prospectively tested in a cohort of 227 hemodialysis patients, who were monitored for 31 ± 13 mo. Plasma ADPN levels were 2.5 times higher (P < 0.0001) among dialysis patients (15.0 ± 7.7 μg/ml) than among healthy subjects (6.3 ± 2.0 μg/ml), were independent of age, and were higher (P = 0.03) among women (15.2 ± 7.9 μg/ml) than among men (14.0 ± 7.4 μg/ml). For both genders, plasma ADPN levels were inversely related to body mass index values, plasma leptin levels, insulin levels, serum triglyceride levels, and homeostatic model assessment index values. Furthermore, plasma ADPN levels were directly related to HDL cholesterol levels and inversely related to von Willebrand factor levels. Plasma ADPN levels were lower (P < 0.05) among patients who experienced new cardiovascular events (13.7 ± 7.3 μg/ml) than among event-free patients (15.8 ± 7.8 μg/ml). There was a 3% risk reduction for each 1 μg/ml increase in plasma ADPN levels, and the relative risk of adverse cardiovascular events was 1.56 times (95% confidence interval, 1.12 to 1.99 times) higher among patients in the first ADPN tertile, compared with those in the third tertile. Plasma ADPN levels are an inverse predictor of cardiovascular outcomes among patients with end-stage renal disease. Furthermore, ADPN is related to several metabolic risk factors in a manner consistent with the hypothesis that this protein acts as a protective factor for the cardiovascular system.

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Triple-negative breast cancer (TNBCs) account for 15–20% of all breast cancers and represent the most aggressive subtype of this malignancy. Early tumor relapse and progression are linked to the enrichment of a sub-fraction of cancer cells, termed breast tumor-initiating cells (BTICs), that undergo epithelial to mesenchymal transition (EMT) and typically exhibit a basal-like CD44high/CD24low and/or ALDH1high phenotype with critical cancer stem-like features such as high self-renewal capacity and intrinsic (de novo) resistance to standard of care chemotherapy. One of the major mechanisms responsible for the intrinsic drug resistance of BTICs is their high ALDH1 activity leading to inhibition of chemotherapy-induced apoptosis. In this study, we demonstrated that aurora-A kinase (AURKA) is required to mediate TGF-β-induced expression of the SNAI1 gene, enrichment of ALDH1high BTICs, self-renewal capacity, and chemoresistance in TNBC experimental models. Significantly, the combination of docetaxel (DTX) with dual TGF-β and AURKA pharmacologic targeting impaired tumor relapse and the emergence of distant metastasis. We also showed in unique chemoresistant TNBC cells isolated from patient-derived TNBC brain metastasis that dual TGF-β and AURKA pharmacologic targeting reversed cancer plasticity and enhanced the sensitivity of TNBC cells to DTX-based-chemotherapy. Taken together, these findings reveal for the first time the critical role of AURKA oncogenic signaling in mediating TGF-β-induced TNBC plasticity, chemoresistance, and tumor progression.

ABSTRACT. Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide (NO) synthase that has been linked to endothelial dysfunction and atherosclerosis in the general population. ADMA is also elevated in end-stage renal disease and may contribute to the high cardiovascular risk in patients with chronic renal failure. A prospective cohort study was performed to investigate the relationship between plasma ADMA, C-reactive protein (CRP), and intima-media thickness (IMT) in 90 patients undergoing hemodialysis. In the baseline study, plasma ADMA was directly related to IMT both on univariate analysis (r = 0.32, P = 0.002) and on multiple regression analysis (β = 0.23, P = 0.01). In the follow-up study (15 mo) IMT changes were significantly related to ADMA (r = 0.51, P = 0.02) and serum CRP (r = 0.53, P = 0.01) in patients with initially normal IMT. In these patients, ADMA and CRP were strongly interrelated (r = 0.64, P = 0.002), and on multiple regression analysis the interaction between ADMA and CRP emerged as the sole independent predictor of the progression of intimal lesions. Independently of other risk factors, plasma ADMA in patients on hemodialysis is significantly related to IMT. Furthermore, in patients with initially normal IMT, ADMA and CRP are interacting factors in the progression of carotid intimal lesions. These data support the hypothesis that accumulation of this endogenous inhibitor of NO synthase is an important risk factor for cardiovascular disease in chronic renal failure and suggest a possible link between ADMA and inflammation.