IL-1β inhibition in cardiovascular complications associated to diabetes mellitus

Diabetes mellitus (DM) is a chronic disease that affects nowadays millions of people worldwide. In adults, type 2 diabetes mellitus (T2DM) accounts for the majority of all diagnosed cases of diabetes. The course of the T2DM is characterized by insulin resistance and a progressive loss of β-cell mass. DM is associated with a number of related complications, among which cardiovascular complications and atherosclerosis are the main cause of morbidity and mortality in patients suffering from the disease. DM is acknowledged as a low-grade chronic inflammatory state characterized by the over-secretion of pro-inflammatory cytokines, including interleukin (IL)-1β, which reinforce inflammatory signals thus contributing to the development of complications. In this context, the pharmacological approaches to treat diabetes should not only correct hyperglycaemia, but also attenuate inflammation and prevent the development of metabolic and cardiovascular complications. Over the last years, novel biological drugs have been developed to antagonize the pathophysiological actions of IL-1β. The drugs currently used in clinical practice are anakinra, a recombinant form of the naturally occurring IL-1 receptor antagonist, the soluble decoy receptor rilonacept and the monoclonal antibodies canakinumab and gevokizumab. This review will summarize the main experimental and clinical findings obtained with pharmacological IL-1β inhibitors in the context of the cardiovascular complications of DM, and discuss the perspectives of IL-1β inhibitors as novel therapeutic tools for treating these patients.This work was supported by grants from Ministerio de Economía y Competitividad (SAF2014-52762-R) and Banco de Santander-Universidad Autónoma de Madrid (CEAL-AL/2015-17

Visfatin/PBEF/Nampt: A New Cardiovascular Target?

In the last years, a growing interest has emerged toward understanding the role of adipocytokines in the development of cardio-metabolic complications. Five years ago, visfatin/PBEF/Nampt was identified as a novel adipocytokine. In the context of metabolic disorders, extracellular visfatin/PBEF/Nampt was initially claimed as a potentially beneficial molecule due to its insulin-mimetic and glucose-lowering properties. Nevertheless, growing evidence has since then unveiled that visfatin/PBEF/Nampt may rather be a biomarker of inflammation and endothelial damage, and also a direct regulator of the cardiovascular system that modulates cell proliferation and survival, extracellular matrix, vascular reactivity, and inflammation. On one side, the blockade of the deleterious cardiovascular actions of visfatin/PBEF/Nampt is being regarded as a potential approach to prevent and treat, not only cardio-metabolic complications, but also other pathologies implying excessive angiogenesis. Conversely, the administration of visfatin/PBEF/Nampt has shown beneficial effects in different ischemic conditions. Further research is required to evaluate the real value of visfatin/PBEF/Nampt as a pharmacological target

El hidrógeno como vector energético: Mucho hecho pero casi todo por hacer

Los autores desarrollan, muy brevemente, los aspectos esenciales de lo que globalmente se denomina “Sistema Energético Solar-Hidrógeno” o a veces “Economía del hidrógeno”. El hidrógeno, obtenido por descomposición del agua mediante energías primarias renovables (solar, eólica…) se convierte en transportador de energía (vector energético) y en combustible limpio. Se discute la conveniencia del uso del hidrógeno en el contexto energético actual, así como los tres pilares fundamentales del uso del hidrógeno como vector energético: su producción usando fuentes renovables, su acumulación mediante diferentes métodos y, finalmente, su combustió

DPP4 and ACE2 in diabetes and COVID-19: Therapeutic targets for cardiovascular complications?

COVID-19 outbreak, caused by severe acute respiratory syndrome (SARS)-CoV-2 coronavirus has become an urgent health and economic challenge. Diabetes is a risk factor for severity and mortality of COVID-19. Recent studies support that COVID-19 has effects beyond the respiratory tract, with vascular complications arising as relevant factors worsening its prognosis, then making patients with previous vascular disease more prone to severity or fatal outcome. Angiotensin-II converting enzime-2 (ACE2) has been proposed as preferred receptor for SARS-CoV-2 host infection, yet specific proteins participating in the virus entry are not fully known. SARS-CoV-2 might use other co-receptor or auxiliary proteins allowing virus infection. In silico experiments proposed that SARS-CoV-2 might bind dipeptidyl peptidase 4 (DPP4/CD26), which was established previously as receptor for MERS-CoV. The renin–angiotensin–aldosterone system (RAAS) component ACE2 and DPP4 are proteins dysregulated in diabetes. Imbalance of the RAAS and direct effect of soluble DPP4 exert deleterious vascular effects. We hypothesize that diabetic patients might be more affected by COVID-19 due to increased presence ACE2 and DPP4 mediating infection and contributing to a compromised vasculature. Here, we discuss the role of ACE2 and DPP4 as relevant factors linking the risk of SARS-CoV-2 infection and severity of COVID-19 in diabetic patients and present an outlook on therapeutic potential of current drugs targeted against RAAS and DPP4 to treat or prevent COVID-19-derived vascular complications. Diabetes affects more than 400 million people worldwide, thus better understanding of how they are affected by COVID-19 holds an important benefit to fight against this disease with pandemic proportionsIV is the recipient of a FPU fellowship (FPU16/02612). TR and JE are supported by KomIT-Center of Competence for Innovative Diabetes Therapy- funded by EFRE-NRW. CP and CS-F are supported by a grant from Plan Nacional de I+D (SAF2017-84776-R

IL-1β Inhibition in Cardiovascular Complications Associated to Diabetes Mellitus

Diabetes mellitus (DM) is a chronic disease that affects nowadays millions of people worldwide. In adults, type 2 diabetes mellitus (T2DM) accounts for the majority of all diagnosed cases of diabetes. The course of the T2DM is characterized by insulin resistance and a progressive loss of β-cell mass. DM is associated with a number of related complications, among which cardiovascular complications and atherosclerosis are the main cause of morbidity and mortality in patients suffering from the disease. DM is acknowledged as a low-grade chronic inflammatory state characterized by the over-secretion of pro-inflammatory cytokines, including interleukin (IL)-1β, which reinforce inflammatory signals thus contributing to the development of complications. In this context, the pharmacological approaches to treat diabetes should not only correct hyperglycaemia, but also attenuate inflammation and prevent the development of metabolic and cardiovascular complications. Over the last years, novel biological drugs have been developed to antagonize the pathophysiological actions of IL-1β. The drugs currently used in clinical practice are anakinra, a recombinant form of the naturally occurring IL-1 receptor antagonist, the soluble decoy receptor rilonacept and the monoclonal antibodies canakinumab and gevokizumab. This review will summarize the main experimental and clinical findings obtained with pharmacological IL-1β inhibitors in the context of the cardiovascular complications of DM, and discuss the perspectives of IL-1β inhibitors as novel therapeutic tools for treating these patients

Visfatin Impairs Endothelium-Dependent Relaxation in Rat and Human Mesenteric Microvessels through Nicotinamide Phosphoribosyltransferase Activity

Visfatin, also known as extracellular pre–B-cell colony–enhancing factor (PBEF) and nicotinamide phosphoribosyltransferase (Nampt), is an adipocytokine whose circulating levels are enhanced in metabolic disorders, such as type 2 diabetes mellitus and obesity. Circulating visfatin levels have been positively associated with vascular damage and endothelial dysfunction. Here, we investigated the ability of visfatin to directly impair vascular reactivity in mesenteric microvessels from both male Sprague-Dawley rats and patients undergoing non-urgent, non-septic abdominal surgery. The pre-incubation of rat microvessels with visfatin (50 and 100 ng/mL) did not modify the contractile response to noradrenaline (1 pmol/L to 30 µmol/L), as determined using a small vessel myograph. However, visfatin (10 to 100 ng/mL) concentration-dependently impaired the relaxation to acetylcholine (ACh; 100 pmol/L to 3 µmol/L), without interfering with the endothelium-independent relaxation to sodium nitroprusside (1 nmol/L to 3 µmol/L). In both cultured human umbilical vein endothelial cells and rat microvascular preparations, visfatin (50 ng/mL) stimulated nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity, as determined by lucigenin-derived chemiluminiscence. The relaxation to ACh impaired by visfatin was restored by the NADPH oxidase inhibitor apocynin (10 µmol/L). Additionally, the Nampt inhibitor APO866 (10 mmol/L to 10 µmol/L), but not an insulin receptor-blocking antibody, also prevented the stimulation of NADPH oxidase and the relaxation impairment elicited by visfatin. Accordingly, the product of Nampt activity nicotinamide mononucleotide (100 nmol/L to 1 mmol/L) stimulated endothelial NADPH oxidase activity and concentration-dependently impaired ACh-induced vasorelaxation. In human mesenteric microvessels pre-contracted with 35 mmol/L potassium chloride, the endothelium-dependent vasodilation to bradykinin (1 nmol/L to 3 µmol/L) was equally impaired by visfatin and restored upon co-incubation with APO866. In conclusion, visfatin impairs endothelium-dependent relaxation through a mechanism involving NADPH oxidase stimulation and relying on Nampt enzymatic activity, and therefore arises as a potential new player in the development of endothelial dysfunction

The angiotensin-(1-7)/mas axis counteracts angiotensin II-dependent and -independent pro-inflammatory signaling in human vascular smooth muscle cells

Background and Aims: Targeting inflammation is nowadays considered as a challenging pharmacological strategy to prevent or delay the development of vascular diseases. Angiotensin-(1-7) is a member of the renin-angiotensin system (RAS) that binds Mas receptors and has gained growing attention in the last years as a regulator of vascular homeostasis. Here, we explored the capacity of Ang-(1-7) to counteract human aortic smooth muscle cell (HASMC) inflammation triggered by RAS-dependent and -independent stimuli, such as Ang II or interleukin (IL)-1β. Methods and Results: In cultured HASMC, the expression of inducible nitric oxide synthase (iNOS) and the release of nitric oxide were stimulated by both Ang II and IL-1β, as determined by Western blot and indirect immunofluorescence or the Griess method, respectively. iNOS induction was inhibited by Ang-(1-7) in a concentration-dependent manner. This effect was equally blocked by two different Mas receptor antagonists, A779 and D-Pro7-Ang-(1-7), suggesting the participation of a unique Mas receptor subtype. Using pharmacological inhibitors, the induction of iNOS was proven to rely on the consecutive upstream activation of NADPH oxidase and nuclear factor (NF)-κB. Indeed, Ang-(1-7) markedly inhibited the activation of the NADPH oxidase and subsequently of NF-κB, as determined by lucigenin-derived chemiluminescence and electromobility shift assay, respectively. Conclusion: Ang-(1-7) can act as a counter-regulator of the inflammation of vascular smooth muscle cells triggered by Ang II, but also by other stimuli beyond the RAS. Activating or mimicking the Ang-(1-7)/Mas axis may represent a pharmacological opportunity to attenuate the pro-inflammatory environment that promotes and sustains the development of vascular diseases.This work was funded by grants from Ministerio de Economía y Competitividad (SAF2014-52762-R