Dipeptidyl peptidase-4 (DPP-4) cleaves N-terminal dipeptides, with Pro, Ala or Ser at the penultimate position, and, in that way, modulates biological activity of certain polypeptides. Due to its ubiquitous distribution, many pathological processes are associated with altered DPP-4 expression and activity. Besides the regulation of glucose metabolism, DPP-4 also exhibits many other systemic effects, and the inhibition of its activity might lead to cardiovascular and renal protection. Mechanisms underlying these protective effects of DPP-4 inhibition are ascribed to elevated bioavailability of its substrates, to impacts on mediators and signaling pathways that ameliorate cardiovascular and renal function through the suppression of oxidative stress, inflammation, fibrosis and apoptosis, improved endothelial function and tissue reparation. Inflammation contributes to and promotes progression of cardiovascular and renal disorders. Herein, we discuss cellular and molecular mechanisms mediating the anti-inflammatory activity of clinically used DPP-4 inhibitors in cardiovascular and renal protection.

Background: Patients with heart failure (HF) with preserved ejection fraction (HFpEF) typically develop dyspnea and pulmonary congestion upon exercise. Lung ultrasound is a simple diagnostic tool, providing semiquantitative assessment of extravascular lung water through B-lines. It has been shown that patients with HFpEF develop B-lines upon submaximal exercise stress echocardiography; however, whether exercise-induced pulmonary congestion carries prognostic implications is unknown. This study aimed at evaluating the prognostic value of B-line assessment during exercise in patients with HFpEF. Methods: Sixty-one New York Heart Association class I to II patients with HFpEF underwent standard echocardiography, lung ultrasound (28-scanning point method), and BNP (B-type natriuretic peptide) assessment during supine exercise echocardiography (baseline and peak exercise). The primary end point was a composite of cardiovascular death or HF hospitalization at 1 year. Results: B-lines, E/e′, and BNP significantly increased during exercise ( P <0.001 for all). By multivariable analysis, both peak (hazard ratio, 1.50 [95% CI, 1.21–1.85], P <0.001), and change (hazard ratio 1.34 [95% CI, 1.12–1.62], P =0.002) B-lines were retained as independent predictors of outcome (hazard ratios per 1 B-line increment), along with BNP and E/e′ ratio. Importantly, adding peak B-line on top of a clinical model significantly improved prognostic accuracy (C-index increase, 0.157 [0.056–0.258], P =0.002) and net reclassification (continuous net reclassification improvement, 0.51 [0.09–0.74], P =0.016), with similar results for B-line change. Conclusions: Detection of exercise-induced pulmonary congestion by lung ultrasound is an independent predictor of outcome in patients with HFpEF; its use may help refining the routine risk stratification of these patients on top of well-established clinical variables.

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Purine nucleotide liberation and their metabolic rate of interconversion may be important in the development of hypertension and its renal consequences. In the present study, blood triphosphate (ATP), adenosine diphosphate (ADP), and adenosine monophosphate (AMP) breakdown pathway was evaluated in relation to uric acid concentration and xanthine dehydrogenase/xanthine oxidase (XDH/XO) in patients with essential hypertension, patients with chronic renal diseases on dialysis, and control individuals. The pattern of nucleotide catabolism was significantly shifted toward catabolic compounds, including ADP, AMP, and uric acid in patients on dialysis program. A significant fall of ATP was more expressed in a group of patients on dialysis program, compared with the control value (p<0.001), while ADP and AMP were significantly increased in both groups of patients compared with control healthy individuals (p<0.001), together with their final degradation product, uric acid (p<0.001). The index of ATP/ADP and ATP/uric acid showed gradual significant fall in both the groups, compared with the control value (p<0.001), near five times in a group on dialysis. Total XOD was up-regulated significantly in a group with essential hypertension, more than in a group on dialysis. The activity of XO, which dominantly contributes reactive oxygen species (ROS) production, significantly increased in dialysis group, more than in a group with essential hypertension. In conclusion, the examination of the role of circulating purine nucleotides and uric acid in pathogenesis of hypertension and possible development of renal disease, together with XO role in ROS production, may help in modulating their liberation and ROS production in slowing progression from hypertension to renal failure.

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