The Role of Nrf2 Signaling in PPARβ/δ-Mediated Vascular Protection against Hyperglycemia-Induced Oxidative Stress

Hyperglycemia induces oxidative stress and plays a substantial role in the progression of vascular diseases. Here, we demonstrated the potentiality of peroxisome proliferator-activated receptor (PPAR)β/δ activation in attenuating high glucose-induced oxidative stress in endothelial cells and diabetic rats, pointing to the involvement of nuclear factor erythroid 2-related factor 2 (Nrf2). HUVECs exposed to high glucose showed increased levels of reactive oxygen species (ROS) and upregulated NOX-2, NOX-4, Nrf2, and NQO-1 effects that were significantly reversed by the PPARβ/δ agonists GW0742 and L165041. Both PPARβ/δ agonists, in a concentration-dependent manner, induced transcriptional and protein upregulation of heme oxygenase-1 (HO-1) under low- and high-glucose conditions. All effects of PPARβ/δ agonists were reversed by either pharmacological inhibition or siRNA-based downregulation of PPARβ/δ. These in vitro findings were confirmed in diabetic rats treated with GW0742. In conclusion, PPARβ/δ activation confers vascular protection against hyperglycemia-induced oxidative stress by suppressing NOX-2 and NOX-4 expression plus a direct induction of HO-1; with the subsequent downregulation of the Nrf2 pathway. Thus, PPARβ/δ activation could be of interest to prevent the progression of diabetic vascular complications.This work was supported by Grants from Ministerio de Economía y Competitividad and Fondo Europeo de Desar- rollo Regional (FEDER) (SAF2010-22066-C02-01, SAF2010-22066-C02-02, SAF2011-28150, SAF2014-55523- R), Junta de Andalucía (Proyecto de excelencia, P12-CTS- 2722), and Instituto de Salud Carlos III (RIC RD12/0042/ 0011), Spain

Protective Effects of Probiotic Consumption in Cardiovascular Disease in Systemic Lupus Erythematosus

The prevalence of renal and cardiovascular disease (CVD) in patients with systemic lupus erythematosus (SLE) is higher than in general populations. Recently, a causal role of gut microbiota on the development of immune responses in SLE has been described. Probiotic consumption changes the composition of gut microbiota, preventing SLE progression. The aim of this review is to explore the role of the gut microbiota in the development of renal and cardiovascular disease in SLE and how probiotics could be a therapeutic option. Despite strong evidence on the beneficial effects of probiotics in the development of autoimmunity and nephritis in SLE, only a few studies described the protective effects of Lactobacillus in important risk factors for CVD, such as endothelial dysfunction and hypertension in mice. The preventive effects of probiotics in renal and CVD in humans have not been established yet.This work was supported by grants from Comisión Interministerial de Ciencia y Tecnología, Ministerio de Economía y competitividad (MINECO) (SAF2014-55523-R, SAF2017-84894-R) and Junta de Andalucía (Proyecto de excelencia P12-CTS-2722, and CTS 164), with funds from the European Union, and by the Ministerio de Economia y Competitividad, Instituto de Salud Carlos III (CIBER-CV). I.R.-V. is a predoctoral fellow of MINECO; N.d.l.V. is a predoctoral fellow of Junta de Andalucía and Fondo Social Europeo “FEDER una manera de hacer Europa”, and M.T. is a postdoctoral fellow of Instituto de Salud Carlos III (Sara Borrell Program)

Mycophenolate mediated remodeling of gut microbiota and improvement of gut-brain axis in spontaneously hypertensive rats

This work was supported by Grants from Comisi´on Interministerial de Ciencia y Tecnología, Ministerio de Economía y competitividad (SAF2017-84894-R), Junta de Andalucía (CTS-164) with funds from the European Union, Ministerio de Economia y Competitividad, Instituto de Salud Carlos III (CIBER-CV), Spain. M.T. is a postdoctoral fellow of Instituto de Salud Carlos III (Sara Borrell Program). I.R.-V. is a predoctoral fellow of MINECO. The cost of this publication was paid in part with funds from the European Union (Fondo Europeo de Desarrollo Regional, FEDER, “FEDER una manera de hacer Europa”).Microbiota has a role in the host blood pressure (BP) regulation. The immunosuppressive drug mofetil mycophenolate (MMF) ameliorates hypertension. The present study analyzes whether MMF improves dysbiosis in a genetic model of hypertension. Twenty weeks old male spontaneously hypertensive rats (SHR) and Wistar Kyoto rats (WKY) were randomly divided into three groups: untreated WKY, untreated SHR, and SHR treated with MMF for 5 weeks. MMF treatment restored gut bacteria from the phyla Firmicutes and Bacteroidetes, and acetate- and lactate-producing bacteria to levels similar to those found in WKY, increasing butyrate-producing bacteria. MMF increased the percentage of anaerobic bacteria in the gut. The improvement of gut dysbiosis was associated with an enhanced colonic integrity and a decreased sympathetic drive in the gut. MMF inhibited neuroinflammation in the paraventricular nuclei in the hypothalamus. MMF increased the lower regulatory T cells proportion in mesenteric lymph nodes and Th17 and Th1 infiltration in aorta, improved aortic endothelial function and reduced systolic BP. This study demonstrates for the first time that MMF reduces gut dysbiosis in SHR. This effect could be related to its capability to improve gut integrity due to reduced sympathetic drive in the gut associated to the reduced brain neuroinflammation.Comision Interministerial de Ciencia y Tecnologia, Ministerio de Economia y competitividad SAF201784894RJunta de Andalucia CTS-164European CommissionSpanish GovernmentInstituto de Salud Carlos III (CIBERCV) , SpainEuropean Union (Fondo Europeo de Desarrollo Regional, FEDER, "FEDER una manera de hacer Europa"

Critical Role of the Interaction Gut Microbiota – Sympathetic Nervous System in the Regulation of Blood Pressure

Association between gut dysbiosis and neurogenic diseases, such as hypertension, has been described. The aim of this study was to investigate whether changes in the gut microbiota alter gut-brain interactions inducing changes in blood pressure (BP). Recipient normotensive Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR) were orally gavaged with donor fecal contents from SHR and WKY. We divided the animals into four groups: WKY transplanted with WKY microbiota (W-W), SHR with SHR (S-S), WKY with SHR (W-S) and SHR with WKY (S-W). Basal systolic BP (SBP) and diastolic BP (DBP) were reduced with no change in heart rate as a result of fecal microbiota transplantation (FMT) from WKY rats to SHR. Similarly, FMT from SHR to WKY increased basal SBP and DBP. Increases in both NADPH oxidase-driven reactive oxygen species production and proinflammatory cytokines in brain paraventricular nucleus linked to higher BP drop with pentolinium and plasmatic noradrenaline (NA) levels were found in the S-S group as compared to the W-W group. These parameters were reduced by FMT from WKY to SHR. Increased levels of pro-inflammatory cytokines, tyrosine hydroxylase mRNA levels and NA content in the proximal colon, whereas reduced mRNA levels of gap junction proteins, were found in the S-S group as compared to the W-W group. These changes were inhibited by FMT from WKY to SHR. According to our correlation analyses, the abundance of Blautia and Odoribacter showed a negative correlation with high SBP. In conclusion, in SHR gut microbiota is an important factor involved in BP control, at least in part, as consequence of its effect on neuroinflammation and the sympathetic nervous system activity.This work was funded by grants from Comisión Interministerial de Ciencia y Tecnología, Ministerio de Economía y Competitividad (MINECO) (SAF2017-8489-R, AGL2015-67995- C3-3-R, and SAF2014-55523-R), Junta de Andalucía (Proyecto de Excelencia P12-CTS-2722 and CTS-164) with support from the European Union, and Ministerio de Economía y Competitividad, Instituto de Salud Carlos III (CIBER-CV, CIBER-EHD), Spain. MS is a postdoctoral fellow of Junta de Andalucía. MR is postdoctoral fellow of University of Granada. IR-V is a predoctoral fellow of MINECO. The cost of this publication was paid in part with FEDER funds

Mineralocorticoid receptor blockade improved gut microbiota dysbiosis by reducing gut sympathetic tone in spontaneously hypertensive rats.

Microbiota has a crucial role in the host blood pressure (BP) regulation. The present study analyzes whether the mineralocorticoid receptor antagonist spironolactone ameliorates the dysbiosic state in a genetic model of neurogenic hypertension. Twenty-week-old male Wistar Kyoto rats (WKY) and spontaneously hypertensive rats (SHR) were randomly allocated into three groups: untreated WKY, untreated SHR, and SHR treated with spironolactone for 5 weeks. Spironolactone restored the Firmicutes/Bacteroidetes proportion, and acetate-producing bacteria populations to WKY levels. Spironolactone reduced the percentage of intestinal aerobic bacteria. The amelioration of gut dysbiosis was linked to a reduction in the gut pathology, an enhanced colonic integrity, a reduced gut permeability and an attenuated sympathetic drive in the gut. Spironolactone was unable to reduce neuroinflammation and oxidative stress in the paraventricular nuclei in the hypothalamus. Spironolactone reduced the higher Th17 cells proportion in mesenteric lymph nodes and Th17 infiltration in aorta, improved aortic endothelial function and reduced systolic BP. This study demonstrates for the first time that spironolactone reduces gut dysbiosis in SHR. This effect could be related to its capability to improve gut integrity and pathology due to reduced sympathetic drive in the gut.This work was supported by Grants from Comision ´ Interministerial de Ciencia y Tecnología, Ministerio de Economía y competitividad (PID2020-116347RB-I00), and Junta de Andalucía (CTS 164, P20_00193, A-CTS-318-UGR20) with funds from the European Union, and by the Ministerio de Economia y Competitividad, Instituto de Salud Carlos III (CIBER-CV), Spain. M.T. and I.R.-V. are postdoctoral fellow of Instituto de Salud Carlos III (Juan de la Cierva Incorporacion ´ Program, and Juan de la Cierva Formacion ´ Program, respectively). J.M. is a predoctoral fellow of MINECO, and C.G.-C. and S.M. are predoctoral fellow of Junta de Andalucía. The cost of this publication was paid in part with funds from the European Union (Fondo Europeo de Desarrollo Regional, FEDER, “FEDER una manera de hacer Europa”).S

Targeting the gut microbiota with dietary fibers: a novel approach to prevent the development cardiovascular complications linked to systemic lupus erythematosus in a preclinical study

This work was supported by Grants from Ministry of Science and Innovation of Spain (MCIN) (Ref. PID2020-116347RB- I00 funded by MCIN/AEI/10.13039/501100011033, PID2021- 122490NB-I00 funded by MCIN/AEI/10.13039/ 501100011033) co-funded by the European Regional Development Fund FEDER, Consejería de Universidad, Investigación e Innovación de la Junta de Andalucía (Ref. CTS 164, P20_00193) with funds from the European Union, and by the Instituto de Salud Carlos III (CIBER-CV). IR-V is postdoctoral funded by MINECO (FJC2021-048099-I). JM is a predoctoral fellow of MINECO (FPU18/02561), and CG-C and SM are predoctoral fellow of Junta de Andalucía. The cost of this publication was paid in part with funds from the European Union (Fondo Europeo de Desarrollo Regional, FEDER, “FEDER una manera de hacer Europa”).This study is to investigate whether dietary fiber intake prevents vascular and renal damage in a genetic mouse model of systemic lupus erythematosus (SLE), and the contribution of gut microbiota in the protective effects. Female NZBWF1 (SLE) mice were treated with resistantstarch (RS) or inulin-type fructans (ITF). In addition, inoculation of fecal microbiota from these experimental groups to recipient normotensive female C57Bl/6J germ-free (GF) mice was performed. Both fiber treatments, especially RS, prevented the development of hypertension, renal injury, improved the aortic relaxation induced by acetylcholine, and the vascular oxidative stress. RS and ITF treatments increased the proportion of acetate- and butyrate-producing bacteria, respectively, improved colonic inflammation and integrity, endotoxemia, and decreased helper T (Th)17 proportion in mesenteric lymph nodes (MLNs), blood, and aorta in SLE mice. However, disease activity (splenomegaly and anti-ds-DNA) was unaffected by both fibers. T cell priming and Th17 differentiation in MLNs and increased Th17 infiltration was linked to aortic endothelial dysfunction and hypertension after inoculation of fecal microbiota from SLE mice to GF mice, without changes in proteinuria and autoimmunity. All these effects were lower in GF mice after fecal inoculation from fiber-treated SLE mice. In conclusion, these findings support that fiber consumption prevented the development of hypertension by rebalancing of dysfunctional gutimmune system-vascular wall axis in SLE.Grants from Ministry of Science and Innovation of Spain (MCIN) (Ref. PID2020-116347RB- I00 funded by MCIN/AEI/10.13039/501100011033, PID2021- 122490NB-I00 funded by MCIN/AEI/10.13039/ 501100011033)European Regional Development Fund FEDER, Consejería de Universidad, Investigación e Innovación de la Junta de Andalucía (Ref. CTS 164, P20_00193) with funds from the European Union, and by the Instituto de Salud Carlos III (CIBER-CV)MINECO (FJC2021-048099-I)MINECO (FPU18/02561)Junta de AndalucíaEuropean Union (Fondo Europeo de Desarrollo Regional, FEDER, “FEDER una manera de hacer Europa”

Changes in Gut Microbiota Induced by Doxycycline Influence in Vascular Function and Development of Hypertension in DOCA-Salt Rats

Previous experiments in animals and humans show that shifts in microbiota and its metabolites are linked to hypertension. The present study investigates whether doxycycline (DOX, a broad-spectrum tetracycline antibiotic) improves dysbiosis, prevent cardiovascular pathology and attenuate hypertension in deoxycorticosterone acetate (DOCA)-salt rats, a renin-independent model of hypertension. Male Wistar rats were randomly assigned to three groups: control, DOCA-salt hypertensive rats, DOCA-salt treated with DOX for 4 weeks. DOX decreased systolic blood pressure, improving endothelial dysfunction and reducing aortic oxidative stress and inflammation. DOX decreased lactate-producing bacterial population and plasma lactate levels, improved gut barrier integrity, normalized endotoxemia, plasma noradrenaline levels and restored the Treg content in aorta. These data demonstrate that DOX through direct effects on gut microbiota and its non-microbial effects (anti-inflammatory and immunomodulatory) reduces endothelial dysfunction and the increase in blood pressure in this low-renin form of hypertension.Grants from Comisión Interministerial de Ciencia y Tecnología, Ministerio de Economía y competitividad (SAF2017-84894-R)Ministerio de Ciencia e Innovación (PID2020-116347RB-I00)Junta de Andalucía (CTS-164, P20_00193)European Union, and by the Ministerio de Economia y Competitividad, Instituto de Salud Carlos III (CIBER-CV; Ciberes)Instituto de Salud Carlos III (Sara Borrell Program)European Union (Fondo Europeo de Desarrollo Regional, FEDER, “FEDER una manera de hacer Europa”

Music Therapy and Musical Stimulation in Preterm Infants in Neonatal Intensive Care Units

Cada año, se producen más de 15 millones de partos prematuros, de los cuales, una fracción considerable es ingresada en la unidad de cuidados intensivos neonatales. La conjunción de un período crítico en el desarrollo neurocognitivo, el aislamiento parental y un entorno hostil hacen de estos pacientes una población vulnerable a diferentes discapacidades de tipo cognitivo, motor, lingüístico, comportamental y socio-económico, que también afecta a su entorno. Por ello, se proponen la musicoterapia y la terapia musical como alternativas no invasivas en aras de mejorar las variables relacionadas con nutrición, respuestas de dolor y estrés, parámetros fisiológicos del neonato, así como de lactancia materna.Every year, more than 15 million preterm infants are born of which a significant number is admitted to the Neonatal Intensive Care Unit. The combination of a critical period in neurocognitive development, parental isolation and a hostile environment makes these patients particularly vulnerable to various cognitive, motor, linguistic, behavioral and socio-economic disabilities. Therefore, music therapy is proposed as a non-invasive alternative to improve variables related to nutrition, pain and stress response, the physiological parameters of the newborn and breastfeeding

Gut Microbiota Has a Crucial Role in the Development of Hypertension and Vascular Dysfunction in Toll-like Receptor 7-Driven Lupus Autoimmunity

Our group has investigated the involvement of gut microbiota in hypertension in a murine model of systemic lupus erythematosus induced by Toll-like receptor (TLR)-7 activation. Female BALB/c mice were randomly assigned to four experimental groups: an untreated control (CTR), a group treated with the TLR7 agonist imiquimod (IMQ), IMQ-treated with vancomycin, and IMQtreated with a cocktail of broad-spectrum antibiotics. We carried out faecal microbiota transplant (FMT) from donor CTR or IMQ mice to recipient IMQ or CTR animals, respectively. Vancomycin inhibited the increase in blood pressure; improved kidney injury, endothelial function, and oxidative stress; and reduced T helper (Th)17 infiltration in aortas from IMQ-treated mice. The rise in blood pressure and vascular complications present in IMQ mice were also observed in the CTR mice recipients of IMQ microbiota. Reduced relative populations of Sutterella and Anaerovibrio were associated with high blood pressure in our animals, which were increased after stool transplantation of healthy microbiota to IMQ mice. The reduced endothelium-dependent vasodilator responses to acetylcholine induced by IMQ microbiota were normalized after interleukin-17 neutralization. In conclusion, gut microbiota plays a role in the TLR7-driven increase in Th17 cell, endothelial dysfunction, vascular inflammation, and hypertension. The vascular changes induced by IMQ microbiota were initiated by Th17 infiltrating the vasculature.Comisión Interministerial de Ciencia y Tecnología, Ministerio de Economía y competitividad (MINECO) (SAF2017-84894-R, PID2020-116347RBI00)Junta de Andalucía (CTS 164, P20_00193) with funds from the European Union, and by the Ministerio de Economia y Competitividad, Instituto de Salud Carlos III (CIBER-CV)Instituto de Salud Carlos III (Sara Borrell Program)MINECOEuropean Union (Fondo Europeo de Desarrollo Regional, FEDER

Targeting the gut microbiota with dietary fibers: a novel approach to prevent the development cardiovascular complications linked to systemic lupus erythematosus in a preclinical study.

This study is to investigate whether dietary fiber intake prevents vascular and renal damage in a genetic mouse model of systemic lupus erythematosus (SLE), and the contribution of gut microbiota in the protective effects. Female NZBWF1 (SLE) mice were treated with resistant-starch (RS) or inulin-type fructans (ITF). In addition, inoculation of fecal microbiota from these experimental groups to recipient normotensive female C57Bl/6J germ-free (GF) mice was performed. Both fiber treatments, especially RS, prevented the development of hypertension, renal injury, improved the aortic relaxation induced by acetylcholine, and the vascular oxidative stress. RS and ITF treatments increased the proportion of acetate- and butyrate-producing bacteria, respectively, improved colonic inflammation and integrity, endotoxemia, and decreased helper T (Th)17 proportion in mesenteric lymph nodes (MLNs), blood, and aorta in SLE mice. However, disease activity (splenomegaly and anti-ds-DNA) was unaffected by both fibers. T cell priming and Th17 differentiation in MLNs and increased Th17 infiltration was linked to aortic endothelial dysfunction and hypertension after inoculation of fecal microbiota from SLE mice to GF mice, without changes in proteinuria and autoimmunity. All these effects were lower in GF mice after fecal inoculation from fiber-treated SLE mice. In conclusion, these findings support that fiber consumption prevented the development of hypertension by rebalancing of dysfunctional gut-immune system-vascular wall axis in SLE.This work was supported by Grants from Ministry of Science and Innovation of Spain (MCIN) (Ref. PID2020-116347RBI00 funded by MCIN/AEI/10.13039/501100011033, PID2021- 122490NB-I00 funded by MCIN/AEI/10.13039/ 501100011033) co-funded by the European Regional Development Fund FEDER, Consejería de Universidad, Investigación e Innovación de la Junta de Andalucía (Ref. CTS 164, P20_00193) with funds from the European Union, and by the Instituto de Salud Carlos III (CIBER-CV). IR-V is postdoctoral funded by MINECO (FJC2021-048099-I). JM is a predoctoral fellow of MINECO (FPU18/02561), and CG-C and SM are predoctoral fellow of Junta de Andalucía. The cost of this publication was paid in part with funds from the European Union (Fondo Europeo de Desarrollo Regional, FEDER, “FEDER una manera de hacer Europa”).S