PPARγ is a gatekeeper for extracellular matrix and vascular cell homeostasis: beneficial role in pulmonary hypertension and renal/cardiac/pulmonary fibrosis.

PURPOSE OF REVIEW: Pulmonary arterial hypertension (PAH) is characterized by pulmonary arterial endothelial cell (PAEC) dysfunction and apoptosis, pulmonary arterial smooth muscle cell (PASMC) proliferation, inflammation, vasoconstriction, and metabolic disturbances that include disrupted bone morphogenetic protein receptor (BMPR2)-peroxisome proliferator-activated receptor gamma (PPARγ) axis and DNA damage. Activation of PPARγ improves many of these mechanisms, although erroneous reports on potential adverse effects of thiazolidinedione (TZD)-class PPARγ agonists reduced their clinical use in the past decade. Here, we review recent findings in heart, lung, and kidney research related to the pathobiology of vascular remodeling and tissue fibrosis, and also potential therapeutic effects of the PPARγ agonist pioglitazone. RECENT FINDINGS: Independent of its metabolic effects (improved insulin sensitivity and fatty acid handling), PPARγ activation rescues BMPR2 dysfunction, inhibits TGFβ/Smad3/CTGF and TGFβ/pSTAT3/pFoxO1 pathways, and induces the PPARγ/apoE axis, inhibiting vascular remodeling. PPARγ activation dampens mtDNA damage via PPARγ/UBR5/ATM pathway, improves function of endothelial progenitor cells (EPCs), and decrease renal fibrosis by repressing TGFβ/pSTAT3 and TGFβ/EGR1. SUMMARY: Pharmacological PPARγ activation improves many hallmarks of PAH, including dysfunction of BMPR2-PPARγ axis, PAEC, PASMC, EPC, mitochondria/metabolism, and inflammation. Recent randomized controlled trials, including IRIS (Insulin Resistance Intervention After Stroke Trial), emphasize the beneficial effects of PPARγ agonists in PAH patients, leading to recent revival for clinical use

Circulating Reelin promotes inflammation and modulates disease activity in acute and long COVID-19 cases

Thromboembolic complications and excessive inflammation are frequent in severe COVID-19, potentially leading to long COVID. In non-COVID studies, we and others demonstrated that circulating Reelin promotes leukocyte infiltration and thrombosis. Thus, we hypothesized that Reelin participates in endothelial dysfunction and hyperinflammation during COVID-19. We showed that Reelin was increased in COVID-19 patients and correlated with the disease activity. In the severe COVID-19 group, we observed a hyperinflammatory state, as judged by increased concentration of cytokines (IL-1α, IL-4, IL-6, IL-10 and IL-17A), chemokines (IP-10 and MIP-1β), and adhesion markers (E-selectin and ICAM-1). Reelin level was correlated with IL-1α, IL-4, IP-10, MIP-1β, and ICAM-1, suggesting a specific role for Reelin in COVID-19 progression. Furthermore, Reelin and all of the inflammatory markers aforementioned returned to normal in a long COVID cohort, showing that the hyperinflammatory state was resolved. Finally, we tested Reelin inhibition with the anti-Reelin antibody CR-50 in hACE2 transgenic mice infected with SARS-CoV-2. CR-50 prophylactic treatment decreased mortality and disease severity in this model. These results demonstrate a direct proinflammatory function for Reelin in COVID-19 and identify it as a drug target. This work opens translational clinical applications in severe SARS-CoV-2 infection and beyond in auto-inflammatory diseases

Absence of cardiotrophin 1 is associated with decreased age-dependent arterial stiffness and increased longevity in mice

Cardiotrophin 1 (CT-1), an interleukin 6 family member, promotes fibrosis and arterial stiffness. We hypothesized that the absence of CT-1 influences arterial fibrosis and stiffness, senescence, and life span. In senescent 29-month- old mice, vascular function was analyzed by echotracking device. Arterial histomorphology, senescence, metabolic, inflammatory, and oxidative stress parameters were measured by immunohistochemistry, reverse transcription polymerase chain reaction, Western blot, and ELISA. Survival rate of wild-type and CT-1–null mice was studied. Vascular smooth muscle cells were treated with CT-1 (10 −9 mol/L) for 15 days to analyze senescence. The wall stress-incremental elastic modulus curve of old CT-1–null mice was shifted rightward as compared with wild-type mice, indicating decreased arterial stiffness. Media thickness and wall fibrosis were lower in CT-1–null mice. CT-1–null mice showed decreased levels of inflammatory, apoptotic, and senescence pathways, whereas telomere-linked proteins, DNA repair proteins, and antioxidant enzyme activities were increased. CT-1–null mice displayed a 5-month increased median longevity compared with wild-type mice. In vascular smooth muscle cells, chronic CT-1 stimulation upregulated apoptotic and senescence markers and downregulated telomere-linked proteins. The absence of CT-1 is associated with decreased arterial fibrosis, stiffness, and senescence and increased longevity in mice likely through downregulating apoptotic, senescence, and inflammatory pathways. CT-1 may be a major regulator of arterial stiffness with a major impact on the aging proces

CD11c+ CD88+ CD317+ myeloid cells are critical mediators of persistent CNS autoimmunity

Natalizumab, a humanized monoclonal antibody (mAb) against α4-integrin, reduces the number of dendritic cells (DC) in cerebral perivascular spaces in multiple sclerosis (MS). Selective deletion of α4-integrin in CD11c+ cells should curtail their migration to the central nervous system (CNS) and ameliorate experimental autoimmune encephalomyelitis (EAE). We generated CD11c.Cre+/−ITGA4fl/fl C57BL/6 mice to selectively delete α4-integrin in CD11c+ cells. Active immunization and adoptive transfer EAE models were employed and compared with WT controls. Multiparameter flow cytometry was utilized to immunophenotype leukocyte subsets. Single-cell RNA sequencing was used to profile individual cells. α4-Integrin expression by CD11c+ cells was significantly reduced in primary and secondary lymphoid organs in CD11c.Cre+/−ITGA4fl/fl mice. In active EAE, a delayed disease onset was observed in CD11c.Cre+/−ITGA4fl/fl mice, during which CD11c+CD88+ cells were sequestered in the blood. Upon clinical EAE onset, CD11c+CD88+ cells appeared in the CNS and expressed CD317+. In adoptive transfer experiments, CD11c.Cre+/−ITGA4fl/fl mice had ameliorated clinical disease phenotype associated with significantly diminished numbers of CNS CD11c+CD88+CD317+ cells. In human cerebrospinal fluid from subjects with neuroinflammation, microglia-like cells display coincident expression of ITGAX (CD11c), C5AR1 (CD88), and BST2 (CD317). In mice, we show that only activated, but not naïve microglia expressed CD11c, CD88, and CD317. Finally, anti-CD317 treatment prior to clinical EAE substantially enhanced recovery in mice

Galectin-3 is a Mediator of Aldosterone Effects on Cardiovascular Remodeling

Contexte : l'aldostérone (Aldo) est impliquée dans la rigidité artérielle et l'insuffisance cardiaque (IC), mais les mécanismes sous-jacents restent méconnus. La galectine-3 (Gal-3), une lectine se liant aux bêta-galactoside, joue un rôle important dans la fibrose et l'IC. Dans cette étude, nous avons recherché si la Gal-3 était impliquée dans la fibrose vasculaire induite par l'Aldo. Méthodes et résultats : Des cellules musculaires lisses vasculaires de rat (CMLVs) ont été stimulées avec de l'Aldo en combinaison avec des antagonistes du récepteur minéralocorticoïde (MR) ou des inhibiteurs de la Gal-3. L'Aldo régule l'expression de la Gal-3 via le MR dans les CMLVs. De plus, la surexpression de la Gal-3 augmente spécifiquement la synthèse de collagène de type I. Les inhibiteurs de la Gal-3 ou sa sous-expression (siRNA) bloquent la synthèse de collagène de type I induite par l'Aldo. Des rats ont été traités avec de l'Aldo + sel combiné avec du spironolactone ou de la pectine de citron modifiée (MCP) pendant 3 semaines. Les rats hypertensifs traités à l'Aldo ont présenté une hypertrophie vasculaire, une fibrose et une augmentation de l'expression aortique de Gal-3. Les traitements avec le spironolactone ou le MCP préviennent tous ces effets. Des souris sauvages (WT) et mutées pour la Gal-3 (KO) ont été traitées avec de l'Aldo pendant 6 heures. Le bolus d'Aldo augmente l'expression de la Gal-3 et du collagène de type I dans l'aorte des souris WT alors qu'aucun changement ne se produit dans les souris KO pour la Gal-3. Conclusions : Nos donnés indiquent que la Gal-3 est indispensable à la réponse fibrotique de l'Aldo dans les CMLVs in vitro et in vivo, suggérant un rôle clef pour la Gal-3 dans la fibrose vasculaireBackground. Aldosterone (Aldo) is involved in arterial stiffness and heart failure (HF), but the mechanisms have remained unclear. Galectin-3 (Gal-3), a beta-galactoside-binding lectin, plays an important role in fibrosis and HF. We here investigated whether Gal-3 is involved in Aldo-induced vascular fibrosis. Methods and Results. Rat vascular smooth muscle cells (VSMCs) were stimulated with Aldo combined with mineralocorticoid receptor (MR) antagonists and Gal-3 inhibitors. Aldo upregulated Gal-3 expression via MR in VSMCs. Moreover, Gal-3 over-expression specifically enhanced collagen type I synthesis. Gal-3 inhibitors or Gal-3 silencing (siRNA) blocked Aldo-induced collagen type I synthesis. Rats were treated with Aldo-salt combined with spironolactone or modified citrus pectin (MCP) for 3 weeks. Hypertensive Aldo-treated rats presented vascular hypertrophy, fibrosis and increased aortic Gal-3 expression. Spironolactone or MCP treatment reversed all the above effects. Wild type (WT) and Gal-3 knock-out (KO) mice were treated with Aldo for 6 hours. Aldo bolus increased aortic Gal-3 and collagen type I expression in WT mice whereas no changes occurred in Gal-3 KO mice. Conclusions. Our data indicate that Gal-3 is required for the fibrotic response to Aldo in VSMCs in vitro and in vivo, suggesting a key role for Gal-3 in vascular fibrosi

La Galectine-3, médiateur des effets de l'aldostérone sur le remodelage cardiovasculaire

Background. Aldosterone (Aldo) is involved in arterial stiffness and heart failure (HF), but the mechanisms have remained unclear. Galectin-3 (Gal-3), a beta-galactoside-binding lectin, plays an important role in fibrosis and HF. We here investigated whether Gal-3 is involved in Aldo-induced vascular fibrosis. Methods and Results. Rat vascular smooth muscle cells (VSMCs) were stimulated with Aldo combined with mineralocorticoid receptor (MR) antagonists and Gal-3 inhibitors. Aldo upregulated Gal-3 expression via MR in VSMCs. Moreover, Gal-3 over-expression specifically enhanced collagen type I synthesis. Gal-3 inhibitors or Gal-3 silencing (siRNA) blocked Aldo-induced collagen type I synthesis. Rats were treated with Aldo-salt combined with spironolactone or modified citrus pectin (MCP) for 3 weeks. Hypertensive Aldo-treated rats presented vascular hypertrophy, fibrosis and increased aortic Gal-3 expression. Spironolactone or MCP treatment reversed all the above effects. Wild type (WT) and Gal-3 knock-out (KO) mice were treated with Aldo for 6 hours. Aldo bolus increased aortic Gal-3 and collagen type I expression in WT mice whereas no changes occurred in Gal-3 KO mice. Conclusions. Our data indicate that Gal-3 is required for the fibrotic response to Aldo in VSMCs in vitro and in vivo, suggesting a key role for Gal-3 in vascular fibrosisContexte : l'aldostérone (Aldo) est impliquée dans la rigidité artérielle et l'insuffisance cardiaque (IC), mais les mécanismes sous-jacents restent méconnus. La galectine-3 (Gal-3), une lectine se liant aux bêta-galactoside, joue un rôle important dans la fibrose et l'IC. Dans cette étude, nous avons recherché si la Gal-3 était impliquée dans la fibrose vasculaire induite par l'Aldo. Méthodes et résultats : Des cellules musculaires lisses vasculaires de rat (CMLVs) ont été stimulées avec de l'Aldo en combinaison avec des antagonistes du récepteur minéralocorticoïde (MR) ou des inhibiteurs de la Gal-3. L'Aldo régule l'expression de la Gal-3 via le MR dans les CMLVs. De plus, la surexpression de la Gal-3 augmente spécifiquement la synthèse de collagène de type I. Les inhibiteurs de la Gal-3 ou sa sous-expression (siRNA) bloquent la synthèse de collagène de type I induite par l'Aldo. Des rats ont été traités avec de l'Aldo + sel combiné avec du spironolactone ou de la pectine de citron modifiée (MCP) pendant 3 semaines. Les rats hypertensifs traités à l'Aldo ont présenté une hypertrophie vasculaire, une fibrose et une augmentation de l'expression aortique de Gal-3. Les traitements avec le spironolactone ou le MCP préviennent tous ces effets. Des souris sauvages (WT) et mutées pour la Gal-3 (KO) ont été traitées avec de l'Aldo pendant 6 heures. Le bolus d'Aldo augmente l'expression de la Gal-3 et du collagène de type I dans l'aorte des souris WT alors qu'aucun changement ne se produit dans les souris KO pour la Gal-3. Conclusions : Nos donnés indiquent que la Gal-3 est indispensable à la réponse fibrotique de l'Aldo dans les CMLVs in vitro et in vivo, suggérant un rôle clef pour la Gal-3 dans la fibrose vasculair

PPARγ and TGFβ—Major Regulators of Metabolism, Inflammation, and Fibrosis in the Lungs and Kidneys

Peroxisome proliferator-activated receptor gamma (PPARγ) is a type II nuclear receptor, initially recognized in adipose tissue for its role in fatty acid storage and glucose metabolism. It promotes lipid uptake and adipogenesis by increasing insulin sensitivity and adiponectin release. Later, PPARγ was implicated in cardiac development and in critical conditions such as pulmonary arterial hypertension (PAH) and kidney failure. Recently, a cluster of different papers linked PPARγ signaling with another superfamily, the transforming growth factor beta (TGFβ), and its receptors, all of which play a major role in PAH and kidney failure. TGFβ is a multifunctional cytokine that drives inflammation, fibrosis, and cell differentiation while PPARγ activation reverses these adverse events in many models. Such opposite biological effects emphasize the delicate balance and complex crosstalk between PPARγ and TGFβ. Based on solid experimental and clinical evidence, the present review summarizes connections and their implications for PAH and kidney failure, highlighting the similarities and differences between lung and kidney mechanisms as well as discussing the therapeutic potential of PPARγ agonist pioglitazone

PPARγ and TGFβ—Major Regulators of Metabolism, Inflammation, and Fibrosis in the Lungs and Kidneys

Peroxisome proliferator-activated receptor gamma (PPARγ) is a type II nuclear receptor, initially recognized in adipose tissue for its role in fatty acid storage and glucose metabolism. It promotes lipid uptake and adipogenesis by increasing insulin sensitivity and adiponectin release. Later, PPARγ was implicated in cardiac development and in critical conditions such as pulmonary arterial hypertension (PAH) and kidney failure. Recently, a cluster of different papers linked PPARγ signaling with another superfamily, the transforming growth factor beta (TGFβ), and its receptors, all of which play a major role in PAH and kidney failure. TGFβ is a multifunctional cytokine that drives inflammation, fibrosis, and cell differentiation while PPARγ activation reverses these adverse events in many models. Such opposite biological effects emphasize the delicate balance and complex crosstalk between PPARγ and TGFβ. Based on solid experimental and clinical evidence, the present review summarizes connections and their implications for PAH and kidney failure, highlighting the similarities and differences between lung and kidney mechanisms as well as discussing the therapeutic potential of PPARγ agonist pioglitazone.</jats:p

Reelin through the years: From brain development to inflammation

Summary: Reelin was originally identified as a regulator of neuronal migration and synaptic function, but its non-neuronal functions have received far less attention. Reelin participates in organ development and physiological functions in various tissues, but it is also dysregulated in some diseases. In the cardiovascular system, Reelin is abundant in the blood, where it contributes to platelet adhesion and coagulation, as well as vascular adhesion and permeability of leukocytes. It is a pro-inflammatory and pro-thrombotic factor with important implications for autoinflammatory and autoimmune diseases such as multiple sclerosis, Alzheimer’s disease, arthritis, atherosclerosis, or cancer. Mechanistically, Reelin is a large secreted glycoprotein that binds to several membrane receptors, including ApoER2, VLDLR, integrins, and ephrins. Reelin signaling depends on the cell type but mostly involves phosphorylation of NF-κB, PI3K, AKT, or JAK/STAT. This review focuses on non-neuronal functions and the therapeutic potential of Reelin, while highlighting secretion, signaling, and functional similarities between cell types