Adipokines, ageing, and vascular damage

Abstract

The main physiologic function of adipokines on the energy metabolism and the cardiovascular homeostasis, among others, are well known. In the last years, our laboratory is providing increasing evidence about the possible role of adipokines as mediators of vascular damage, by inducing different pro-inflammatory and pro-senescent mechanisms. The secretion of adipokines like visfatin or dipeptidylpeptidase-4 (DPP4) by adipose tissue, particularly by the visceral fat, is enhanced in obese and type 2 diabetic patients. Both adipokines are enzymes metabolically active that can induce the activation of specific receptors, namely type 4 “toll like receptors” (TLR4) for visfatin and “protease activated receptor 2” (PAR2) for DPP4. Stimulation of such receptors is triggering well known pro-inflammatory and pro-senescent mechanisms, like the nuclear transcription factor-κB (NF-κB) or the inflammasome NLRP3 (“nucleotide-binding, leucine-rich-repeat, pyrin domain containing 3”), a cell structure that transforms the immature forms of classic cytokines in their active derivates, interleukin-1β (IL-1β) or interleukin 18 (IL-18). It is worth to note that these classic cytokines are the final effectors for the harmful effects of the adipokines and its blockade can be a very relevant therapeutic approach. In our experiments, the specific antagonism of IL-1 receptors with anakinra prevents the inflammatory and senescent effects evoked by visfatin and DPP4. Moreover, this finding is in agreement with data from other researchers, as well as with the results of the CANTOS clinical trial, which demonstrate a very important cardioprotective cardiovascular effect mediated by the anti-inflammatory effect of the monoclonal antibody canakinumab. On the other hand, we have also provided experimental evidence about possible vasculopotective adipokines, such angiotensin-(1-7), which is able to induce, through activation of Mas receptors, the expression of klotho protein and the activation of antioxidant pathways, like the well known Nrf2-HO-1 (“nuclear factor erythroid-2 y hemoygenase-1”).