Carlos Félix Sánchez-Ferrer

Background: Chronic obstructive pulmonary disease (COPD), a prevalent age-related condition, ranks among the leading causes of global mortality. It is characterized by chronic inflammation, cellular senescence, and irreversible lung tissue damage, with no curative treatments currently available. Angiotensin-(1-7) [Ang-(1-7)] has demonstrated anti-inflammatory and regenerative potential in preclinical models. This study aimed to investigate the therapeutic effects of oral Ang-(1-7) on senescence, inflammation, and tissue regeneration in a model of elastase-induced pulmonary emphysema.Methods: Male C57BL/6 mice were subjected to emphysema induction through three intratracheal instillations of porcine pancreatic elastase (PPE). One week after the final elastase instillation, the mice were treated with Ang-(1-7) encapsulated in hydroxypropyl-β-cyclodextrin to enhance its bioavailability. The treatment was administered daily for 4 weeks. Histological assessments, gene expression analysis, and protein quantification through Western blot were performed to evaluate lung architecture, inflammation, and senescence markers.Results: The results showed that elastase exposure led to significant lung damage, including enlarged airspaces, increased collagen deposition and upregulated expression of collagen I/III and MMP9. Markers of inflammation and senescence were significantly elevated in the untreated emphysema group. However, treatment with Ang-(1-7) reversed these changes, reducing collagen deposition, restoring alveolar structure, and suppressing inflammation and senescence. Additionally, Ang-(1-7) modulated key signaling pathways, reactivating the Wnt/β-catenin pathway for tissue regeneration and inhibiting NF-κB activation, critical for inflammation suppression.Conclusion: These findings suggest that Ang-(1-7), when administered after disease establishment, demonstrates potential to reverse structural lung damage and suppress chronic inflammation in experimental models, indicating a promising direction for future translational and clinical research in COPD.

Hyperinflammation, hypercoagulation, and endothelial injury are major findings in acute and post-Covid-19. The SARS-CoV-2 S protein has been detected as an isolated element in human tissues reservoirs and is the main product of mRNA Covid-19 vaccines. In this review, we analyzed whether the S protein alone triggers pro-inflammatory and pro-coagulant responses in primary cultures of two human cell types deeply affected by SARS-CoV-2, such are monocytes and endothelial cells. Indeed, viral S protein activated NF-κB, promoted pro-inflammatory cytokines release, and triggered the priming and activation of the NLRP3 inflammasome system resulting in mature IL-1β formation. This was paralleled by enhanced production of coagulation factors such as von Willebrand factor (vWF), factor VIII, or tissue factor. Additionally, S protein failed to enhance ADAMTS-13 levels to counteract the pro-coagulant activity of vWF multimers. Our data also indicate that these effects of the S protein are mediated by toll like-receptors-4 in monocytes, but not in endothelial cells. On the other hand, it is known that premature vascular aging and endothelial cell senescence are major risk factors for cardiovascular diseases and atherothrombotic disturbances, which are main complications of both acute and long Covid-19. The S protein of SARS-CoV2 enhanced cell senescence and DNA damage response markers (senescence-associated-β galactosidase, γH2AX), as well as growth-arrest effectors (p53, p21, p16). In parallel, the S protein reduced the availability of cytoprotective proteins, such as the anti-aging protein klotho, Nrf2 or heme oxygenase-1. In conclusion, S protein behaves both as a pro-inflammatory and pro-coagulant stimulus in human monocytes and endothelial cells. Furthermore, treating the cells with recombinant klotho or angiotensin-(1-7) protected against the S protein induced pro-senescence, pro-inflammatory, and pro-oxidant actions. Globally, our data proposes novel mechanisms of disease for Covid-19 and its vascular sequelae and provides pharmacological clues to prevent such complications.

Premature vascular aging and endothelial cell senescence are major risk factors for cardiovascular diseases and atherothrombotic disturbances, which are main complications of both acute and long COVID-19. The S protein of SARS-CoV2, which acts as the receptor binding protein for the viral infection, is able to induce endothelial cells inflammation and it has been found as an isolated element in the circulation and in human tissues reservoirs months after infection. Here, we investigated whether the S protein is able to directly induce endothelial cell senescence and deciphered some of the mechanisms involved. In primary cultures of human umbilical vein endothelial cells (HUVEC), SARS-CoV-2 S protein enhanced in a concentration-dependent manner the cellular content of senescence and DNA damage response markers (senescence-associated-β galactosidase, γH2AX), as well as growth-arrest effectors (p53, p21, p16). In parallel, the S protein reduced the availability of cytoprotective proteins, such as the anti-aging protein klotho, Nrf2 or heme oxygenase-1, and caused functional harm by impairing ex vivo endothelial-dependent vasorelaxation in murine microvessels. These effects were prevented by the pharmacological inhibition of the NLRP3 inflammasome with MCC950. Furthermore, the supplementation with either recombinant klotho or angiotensin-(1-7), equally protected against the pro-senescence, pro-inflammatory and pro-oxidant action of the S protein. Globally, this study proposes novel mechanisms of disease in the context of COVID-19 and its vascular sequelae and provides pharmacological clues in order to prevent such complications.

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”).

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 A ₂ ) 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.

Despite the great advances in medicine, mortality from cardiovascular diseases keeps on growing. This tendency is not likely to change considering the pandemic proportions of obesity and diabetes. Besides, the global population is more aged as life expectancy increases, and vascular aging plays a key role in the increased risk of vascular disease. In light of recent trials, namely the CANTOS study, showing the enormous potential of anti-inflammatory therapies and in particular those targeted to IL-1β, a change in therapeutical management of cardiovascular diseases is coming about. The NLRP3 inflammasome is a multiprotein complex that assembles to engage the innate immune defense by processing the maturation of pro-inflammatory cytokines IL-1β and IL-18. Substantial evidence has positioned the NLRP3 inflammasome at the center of vascular disease progression, with a particular significance in the context of aging and the low-grade chronic inflammation associated (inflammaging). Therefore, pharmacological blockade of the NLRP3 inflammasome and its end products has arisen as an extremely promising tool to battle vascular disease. In this review, we discuss the mechanisms by which the NLRP3 inflammasome contributes to vascular disease, with particular attention to the consequences of aging, and we enumerate the therapeutic options available to combat this recurrent villain.