Wnt signaling has diverse actions in cardiovascular development and disease processes. Secreted frizzled-related protein 5 (Sfrp5) has been shown to function as an extracellular inhibitor of ...non-canonical Wnt signaling that is expressed at relatively high levels in white adipose tissue. The aim of this study was to investigate the role of Sfrp5 in the heart under ischemic stress. Sfrp5 KO and WT mice were subjected to ischemia/reperfusion (I/R). Although Sfrp5-KO mice exhibited no detectable phenotype when compared with WT control at baseline, they displayed larger infarct sizes, enhanced cardiac myocyte apoptosis, and diminished cardiac function following I/R. The ischemic lesions of Sfrp5-KO mice had greater infiltration of Wnt5a-positive macrophages and greater inflammatory cytokine and chemokine gene expression when compared with WT mice. In bone marrow-derived macrophages, Wnt5a promoted JNK activation and increased inflammatory gene expression, whereas treatment with Sfrp5 blocked these effects. These results indicate that Sfrp5 functions to antagonize inflammatory responses after I/R in the heart, possibly through a mechanism involving non-canonical Wnt5a/JNK signaling.
Adipose tissue dysfunction plays a pivotal role in the development of insulin resistance in obese individuals. Cell culture studies and gain-of-function mouse models suggest that canonical Wnt ...proteins modulate adipose tissue expansion. However, no genetic evidence supports a role for endogenous Wnt proteins in adipose tissue dysfunction, and the role of noncanonical Wnt signaling remains largely unexplored. Here we provide evidence from human, mouse, and cell culture studies showing that Wnt5a-mediated, noncanonical Wnt signaling contributes to obesity-associated metabolic dysfunction by increasing adipose tissue inflammation. Wnt5a expression is significantly upregulated in human visceral fat compared with subcutaneous fat in obese individuals. In obese mice, Wnt5a ablation ameliorates insulin resistance, in parallel with reductions in adipose tissue inflammation. Conversely, Wnt5a overexpression in myeloid cells augments adipose tissue inflammation and leads to greater impairments in glucose homeostasis. Wnt5a ablation or overexpression did not affect fat mass or adipocyte size. Mechanistically, Wnt5a promotes the expression of proinflammatory cytokines by macrophages in a Jun NH2-terminal kinase-dependent manner, leading to defective insulin signaling in adipocytes. Exogenous interleukin-6 administration restores insulin resistance in obese Wnt5a-deficient mice, suggesting a central role for this cytokine in Wnt5a-mediated metabolic dysfunction. Taken together, these results demonstrate that noncanonical Wnt signaling contributes to obesity-induced insulin resistance independent of adipose tissue expansion.
The management of schizophrenia is evolving towards a more comprehensive model based on functional recovery. The concept of functional recovery goes beyond clinical remission and encompasses multiple ...aspects of the patient's life, making it difficult to settle on a definition and to develop reliable assessment criteria. In this consensus process based on a panel of experts in schizophrenia, we aimed to provide useful insights on functional recovery and its involvement in clinical practice and clinical research.
After a literature review of functional recovery in schizophrenia, a scientific committee of 8 members prepared a 75-item questionnaire, including 6 sections: (I) the concept of functional recovery (9 items), (II) assessment of functional recovery (23 items), (III) factors influencing functional recovery (16 items), (IV) psychosocial interventions and functional recovery (8 items), (V) pharmacological treatment and functional recovery (14 items), and (VI) the perspective of patients and their relatives on functional recovery (5 items). The questionnaire was sent to a panel of 53 experts, who rated each item on a 9-point Likert scale. Consensus was achieved in a 2-round Delphi dynamics, using the median (interquartile range) scores to consider consensus in either agreement (scores 7-9) or disagreement (scores 1-3). Items not achieving consensus in the first round were sent back to the experts for a second consideration.
After the two recursive rounds, consensus was achieved in 64 items (85.3%): 61 items (81.3%) in agreement and 3 (4.0%) in disagreement, all of them from section II (assessment of functional recovery). Items not reaching consensus were related to the concepts of functional recovery (1 item, 1.3%), functional assessment (5 items, 6.7%), factors influencing functional recovery (3 items, 4.0%), and psychosocial interventions (2 items, 5.6%).
Despite the lack of a well-defined concept of functional recovery, we identified a trend towards a common archetype of the definition and factors associated with functional recovery, as well as its applicability in clinical practice and clinical research.
The accumulation of acquired mutations is an inevitable consequence of the aging process, but its pathophysiological relevance has remained largely unexplored beyond cancer. Most of these mutations ...have little or no functional consequences, but in a few rare instances, a mutation may arise that confers a competitive advantage to a stem cell, leading to its clonal expansion. When such a mutation occurs in hematopoietic stem cells, it leads to a situation of clonal hematopoiesis, which has the potential to affect multiple tissues beyond the bone marrow, as the clonal expansion of the mutant stem cell is extended to circulating blood cells and tissue-infiltrating immune cells. Recent genomics and experimental studies have provided support to the notion that this somatic mutation-driven clonal hematopoiesis contributes to vascular inflammation and the development of atherosclerosis and related cardiovascular and cerebrovascular ischemic events. Here, we review our current understanding of this emerging cardiovascular risk modifier and the mechanisms underlying its connection to atherosclerosis development.
•Somatic mutation-driven clonal hematopoiesis has emerged as an independent risk factor forcardiovascular disease.•Experimental studies are testing the hypothesis that clonal hematopoiesis promotes inflammation and atherosclerosis.•Mechanistic studies may provide rationale for the development of personalized preventive care strategies or therapies.•Further research is required to understand this new cardiovascular risk factor and its clinical management.
Clonal hematopoiesis driven by somatic mutations in hematopoietic cells, frequently called clonal hematopoiesis of indeterminate potential (CHIP), has been associated with adverse cardiovascular ...outcomes in population-based studies and in patients with ischemic heart failure (HF) and reduced left ventricular ejection fraction (LVEF). Yet, the impact of CHIP on HF progression, including nonischemic etiology, is unknown.
The purpose of this study was to assess the clinical impact of clonal hematopoiesis on HF progression irrespective of its etiology.
The study cohort comprised 62 patients with HF and LVEF <45% (age 74 ± 7 years, 74% men, 52% nonischemic, and LVEF 30 ± 8%). Deep sequencing was used to detect CHIP mutations with a variant allelic fraction >2% in 54 genes. Patients were followed for at least 3.5 years for various adverse events including death, HF-related death, and HF hospitalization.
CHIP mutations were detected in 24 (38.7%) patients, without significant differences in all-cause mortality (p = 0.151). After adjusting for risk factors, patients with mutations in either DNA methyltransferase 3 alpha (DNMT3A) or Tet methylcytosine dioxygenase 2 (TET2) exhibited accelerated HF progression in terms of death (hazard ratio HR: 2.79; 95% confidence interval CI: 1.31 to 5.92; p = 0.008), death or HF hospitalization (HR: 3.84; 95% CI: 1.84 to 8.04; p < 0.001) and HF-related death or HF hospitalization (HR: 4.41; 95% CI: 2.15 to 9.03; p < 0.001). In single gene-specific analyses, somatic mutations in DNMT3A or TET2 retained prognostic significance with regard to HF-related death or HF hospitalization (HR: 4.50; 95% CI: 2.07 to 9.74; p < 0.001, for DNMT3A mutations; HR: 3.18; 95% CI: 1.52 to 6.66; p = 0.002, for TET2 mutations). This association remained significant irrespective of ischemic/nonischemic etiology.
Somatic mutations that drive clonal hematopoiesis are common among HF patients with reduced LVEF and are associated with accelerated HF progression regardless of etiology.
Rheumatoid arthritis (RA) is a common autoimmune disease characterized by chronic inflammation of the joints, leading to bone erosion and joint dysfunction. Despite the recent successes of ...disease-modifying anti-rheumatic drugs (DMARDs), there is still clinical need for understanding the development and molecular etiology of RA. Wnts are developmental morphogens whose roles in adult pathology are poorly characterized. Wnt5a is a member of the non-canonical family of Wnts that modulates a wide range of cell processes, including differentiation, migration, and inflammation. Wnt5a has been implicated as a possible contributor to arthritis and it is upregulated in synovial fibroblasts from RA patients.
We investigated the role of endogenous Wnt5a in RA. Tamoxifen-inducible, Wnt5a knockout (Wnt5a cKO) mice and littermate controls were monitored for arthritis development and joint pathology using the K/BxN serum transfer-induced arthritis (STIA) model. To explore a role of Wnt5a in osteoclast fusion, bone marrow-derived monocytes (BMDMs) were differentiated in vitro.
Wnt5a cKO mice were resistant to arthritis development compared to control littermates as assessed by ankle thickness and histologic measurements. Some parameters of inflammation were reduced in the Wnt5a cKO mice, including the extent of polymononuclear cell infiltration and extra-articular inflammation. Wnt5a cKO mice also exhibited less cartilage destruction and a reduction in osteoclast activity with concomitant reduction in tartrate-resistant acid phosphatase (TRAP), cathepsin K (CTSK), macrophage colony-stimulating factor (MCSF), matrix metalloproteinase (MMP)2 and MMP9 in the arthritic joints. Treatment of BMDMs with Wnt5a enhanced osteoclast fusion and increased the expression of dendrocyte-expressed seven transmembrane protein (DCSTAMP) and MMP9, that are necessary for osteoclast formation and activity.
These data suggest that Wnt5a modulates the development of arthritis by promoting inflammation and osteoclast fusion, and provide the first mouse genetic evidence of a role for endogenous Wnt5a in autoimmune disease.
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