DPP4 Promotes Human Endothelial Cell Senescence and Dysfunction via the PAR2–COX-2–TP Axis and NLRP3 Inflammasome Activation

Abstract

Background: Abnormal accumulation of senescent cells in the vessel wall leads to a compromised vascular function contributing to vascular aging. Soluble DPP4 (dipeptidyl peptidase 4; sDPP4) secretion from visceral adipose tissue is enhanced in obesity, now considered a progeric condition. sDPP4 triggers vascular deleterious effects, albeit its contribution to vascular aging is unknown. We aimed to explore sDPP4 involvement in vascular aging, unraveling the molecular pathway by which sDPP4 acts on the endothelium. Methods: Human endothelial cell senescence was assessed by senescence-associated β-galactosidase assay, visualization of DNA damage, and expression of prosenescent markers, whereas vascular function was evaluated by myography over human dissected microvessels. In visceral adipose tissue biopsies from a cohort of obese patients, we explored several age-related parameters in vitro and ex vivo. Results: By a common mechanism, sDPP4 triggers endothelial cell senescence and endothelial dysfunction in isolated human resistance arteries. sDPP4 activates the metabotropic receptor PAR2 (protease-activated receptor 2), COX-2 (cyclooxygenase 2) activity, and the production of TXA 2 (thromboxane A2) acting over TP (thromboxane receptor) receptors (PAR2–COX-2–TP axis), leading to NLRP3 (nucleotide-binding oligomerization domain, leucine-rich repeat, and pyrin domain-containing 3) inflammasome activation. Obese patients exhibited impaired microarterial functionality in comparison to control nonobese counterparts. Importantly, endothelial dysfunction in obese patients positively correlated with greater expression of DPP4, prosenescent, and proinflammatory markers in visceral adipose tissue nearby the resistance arteries. Moreover, when DPP4 activity or sDPP4-induced prosenescent mechanism was blocked, endothelial dysfunction was restored back to levels of healthy subjects. Conclusions: These results reveal sDPP4 as a relevant mediator in early vascular aging and highlight its capacity activating main proinflammatory mediators in the endothelium that might be pharmacologically tackled.

DPP4 inhibition impairs senohemostasis to improve plaque stability in atherosclerotic mice

“…Subsequently, DPP4 was implicated in alleviating metabolism-related diseases like obesity, chronic liver disease, and atherosclerosis (53)(54)(55)(56). Interestingly, DPP4 inhibitors have been proven effective at reducing atherosclerosis in mice independently of their canonical impact on glucose metabolism, suggesting that DPP4 has important functions in non-metabolic tissues and cells (13,57). As mentioned, recent studies have identified DPP4 on the surface of senescent cells, and soluble DPP4 was found to trigger endothelial senescence, demonstrating that DPP4 may contribute to the development of the senescent phenotype (11,57).…”

“…Interestingly, DPP4 inhibitors have been proven effective at reducing atherosclerosis in mice independently of their canonical impact on glucose metabolism, suggesting that DPP4 has important functions in non-metabolic tissues and cells (13,57). As mentioned, recent studies have identified DPP4 on the surface of senescent cells, and soluble DPP4 was found to trigger endothelial senescence, demonstrating that DPP4 may contribute to the development of the senescent phenotype (11,57). In cultured cells, we found that inhibiting DPP4 on the surface of senescent VSMCs suppressed complement and coagulation programs that foment cell survival, while in mice, inhibiting DPP4 generally reduces the presence of senescent cells and factors that contribute to plaque vulnerability.…”

DPP4 as a Potential Candidate in Cardiovascular Disease

“… 56 Besides, DPP4 inhibitor inhibits the expression of gp91 phox , p47 phox and p67 phox subunits of NADPH oxidase, thereby reducing NADPH-related oxidative stress. 57 , 58 Notably, DDP4 inhibitor also alleviates oxidative stress by activating the GLP-1R/AMPKa/UCP2 signaling cascade to reverse COX-2 overexpression, ultimately attenuating endothelium-dependent contractions. 59 Fifthly, B-type natriuretic peptide (BNP), another substrate of DPP4, has vasodilatory activity.…”

Factors and Pathways Modulating Endothelial Cell Senescence in Vascular Aging

“…C1q/tumor necrosis factor-related protein 9 (CTRP9), an emerging potential cardiokine, contributes to the inhibition of hyperglycemia-induced endothelial senescence through an AMPKα/ Krüppel-like factor 4 (KLF4)-dependent signaling pathway [ 143 ]. Soluble dipeptidyl peptidase 4 (DPP4), secreted from visceral adipose tissue, induces EC senescence through the protease-activated receptor 2 (PAR2)–cyclooxygenase2 (COX-2)–thromboxane receptor (TP) axis and activates the NLRP3 inflammasome [ 144 ]. In cultured HAECs, senescence induced by apoC3-rich low-density lipoprotein (AC3RL) is mediated by intracellular ROS formation, H2A.X variant histone (H2AX) deposition, and F-box only protein 31 (FBXO31) activation, resulting in the inhibition of mouse double minute 2 homolog (MDM2), p53, and p21 activation [ 145 ].…”