Comprehensive Physiology最新文献

Adipose tissue ATGL has emerged as an important player in cardiovascular disease. Myocardial infarction is accompanied by sympathetic stimulation and activation of white adipose tissue and peripheral lipolysis. We therefore investigate here the role of adipocyte ATGL in a murine model of cardiac ischemia and reperfusion (I/R) by using an inducible, adipocyte specific KO of ATGL (iatATGL-KO). Notably this led to successfully inhibited lipolysis during cardiac ischemia, and KO mice exhibited aggravated cardiac dysfunction and enhanced scar formation after 28 days I/R. This phenotype went along with multiple structural and molecular alterations mainly in the subcutaneous white adipose tissue depot (iWAT) and brown adipose tissue (BAT). The iatATGL-KO mainly reduced BAT activation as well as adiponectin-secretion. In the heart spatial transcriptomic analysis suggested higher mechanical stress in the remote myocardium, which went along with higher oxygen consumption rates (OCR) and higher dependency on glucose as substrate after 24 h I/R. Taken together, iatATGL-KO hearts after I/R seem to be affected in multiple ways, such as a reduction in cardioprotective factors from iWAT and BAT as well as an oxygen wasting effect in the remote zone of the heart, which contribute to the worse outcome. This indicates a time and depot-specific role of adipocyte ATGL in cardiac ischemia and reperfusion injury.

Introduction: Pulmonary hypertension (PH) is a severe cardiovascular disorder characterized by elevated pulmonary artery pressure caused by remodeling of the pulmonary circulation. This study aimed to investigate the role of the soluble epoxide hydrolase phosphatase domain (sEH-P) in PH pathogenesis.

Methods: The effects of sEH-P genetic inactivation were evaluated in vivo using a CRISPR/Cas9-mediated approach in two rat modes of PH: the monocrotaline and the Sugen/hypoxia model. To further explore the underlying mechanisms, complementary in vitro experiments were conducted in cultured human pulmonary artery smooth muscle cells (PA-SMCs), where sEH expression was modulated.

Results: sEH-P inactivation attenuated experimental PH in both rat models, as demonstrated by reductions in mean pulmonary artery pressure and total pulmonary vascular resistance. Histological analysis showed decreased pulmonary artery muscularization and reduced collagen deposition in the right ventricle. Moreover, sEH-P inactivation reduced sEH protein levels and enhanced SIRT3 expression in the lungs. Two-hybrid interaction assays suggested that sEH indirectly regulates SIRT3 expression. In cultured human PA-SMCs, altering sEH levels influenced SIRT3 expression, cell proliferation, and the levels of FoxO1, BCL2, and Bax proteins. In sEH-P KI rat lungs, FoxO1 levels increased, while anti-apoptotic BCL2 protein decreased.

Conclusions: Our findings underscore the role of sEH-P in the development and progression of PH, partly through its regulation of SIRT3 expression, cell proliferation, and apoptosis-related proteins. Targeting sEH-P emerges as a promising therapeutic strategy for PH.

The DJ-1 protein was initially identified as an oncogene, but subsequent studies revealed its crucial protective role in neurodegenerative diseases. Increasing evidence indicates that DJ-1 possesses critical physiological functions in skeletal muscle, but the underlying mechanisms remain to be systematically elucidated. Existing research has conclusively demonstrated that DJ-1 is widely expressed in skeletal muscle and functions as a central hub integrating multiple pathways to establish a multi-level cellular protection network: it safeguards energy metabolism by maintaining mitochondrial structure and function; enhances antioxidant capacity by directly scavenging ROS and regulating Nrf2/ARE signaling; and delays muscle aging by inhibiting protein aggregation and preserving protein homeostasis. Under pathological conditions, DJ-1 dysfunction is closely associated with muscular dystrophy, inflammatory myopathy, metabolic myopathy, and muscle atrophy. Its abnormalities lead to mitochondrial damage, exacerbated oxidative stress, and disrupted protein homeostasis, ultimately triggering muscle structural deterioration. Based on these insights, researchers have developed various DJ-1 regulatory strategies, including small-molecule activators, transcriptional modulators, and functional peptide compounds, which show promising therapeutic potential. This review represents the first systematic, cross-disease integration of DJ-1's role in aging-related sarcopenia, diabetic myopathy, inflammatory myopathies, and neuromuscular degenerative diseases. It elucidates DJ-1's core function as a central integrator coordinating antioxidant defense, mitochondrial homeostasis, metabolic regulation, and protein homeostasis. A deeper understanding of DJ-1's mechanisms will provide critical theoretical foundations for elucidating the common pathological basis of skeletal muscle diseases and developing novel therapeutic strategies.

Purpose: Pulmonary hypertension (PH) is a heterogeneous disease with patient-specific variability and vessel-specific remodeling, which eventually lead to right ventricular (RV) failure. The gold standard for RV assessment-pressure-volume (PV) loop acquisition-is invasive and limited to specialized settings. This study aims to develop a patient-specific lumped-parameter model that quantifies vessel-specific remodeling and simulates RV PV loops across PH phenotypes using routine clinical data.

Methods: A lumped-parameter model was calibrated using right heart catheterization and echocardiography data. Model agreement was assessed by R² values for pressure and flow goodness-of-fit, and model-derived hemodynamic metrics were compared with clinical values. A dimensionality reduction approach was applied to investigate how well different PH phenotypes could be separated.

Results: Across the cohort, the lumped-parameter model showed good agreement with clinical data. Model-derived vessel-specific (pulmonary arterial, capillary, venular) parameters highlighted physiological distinctions among phenotypes. Predicted RV PV loops revealed phenotype-specific differences in right ventricular volumes, pressures, and stroke work. The linear discriminant analysis (LDA) demonstrated qualitative separability, indicating that model-derived, nonmeasurable features offer additional discriminatory information.

Conclusion: Our results demonstrate that lumped-parameter models can be calibrated to clinical data to quantify vessel-specific remodeling and simulate RV pressure-volume dynamics to provide useful information for distinguishing among different PH phenotypes. This underscores the potential of computational models as noninvasive, clinically feasible tools for assessing in-depth pulmonary vascular and RV function in PH.

Preeclampsia (PE) is a complex hypertensive disorder of pregnancy characterized by placental dysfunction, systemic inflammation, oxidative stress, and widespread maternal endothelial injury. Although multiple molecular pathways have been implicated in its pathogenesis, the regulatory mechanisms that integrate placental stress with vascular and immune maladaptation remain incompletely understood. Post-translational modifications (PTMs) have emerged as critical regulators of protein function, stability, localization, and signaling, positioning them as key molecular integrators of the pathological processes underlying PE. In this review, we synthesize current evidence linking PTM dysregulation to the major biological processes disrupted in PE, with a particular focus on SUMOylation, ubiquitination, S-nitrosylation, acetylation, and glycosylation. These modifications modulate trophoblast invasion, angiogenic balance, redox homeostasis, immune tolerance, and endothelial signaling across placental, and maternal vascular compartments. We highlight how hypoxia, inflammation, and metabolic stress converge to disrupt PTM-regulating enzyme systems, thereby amplifying placental dysfunction and maternal vascular injury. Emerging evidence supporting PTM crosstalk further underscores the existence of coordinated regulatory networks rather than isolated molecular events. Advances in proteomics, systems biology, and extracellular vesicle profiling have revealed PTM-enriched molecular signatures in maternal circulation that precede clinical disease onset, offering opportunities for early diagnosis and risk stratification. We critically address current limitations in the field, including the predominance of cross-sectional studies, challenges in cell type-specific and temporal resolution, and barriers to clinical implementation. This review positions PTMs as central molecular hubs linking placental stress to systemic vascular dysfunction and highlights their potential to inform future precision medicine approaches in PE.

Understanding communication between various organ systems is vital to understanding the pathophysiology of disease, and this assists in tailoring appropriate therapies. Pulmonary vein stenosis is an example of a multi-organ disease process that occurs in infancy and later throughout life. The organs involved may be at a distance from the heart and lungs or from within the thoracic cavity. In former preterm infants with bronchopulmonary dysplasia (BPD), this condition is associated with ongoing inflammation in other organ systems, including lung parenchyma as well as the gut. It is also associated with perturbation in blood flow due to intracardiac shunt lesions or external pressure from intrathoracic structures. In patients with congenital heart disease (CHD) associated with PVS at baseline or after surgery involving pulmonary veins, there may be a genetic component to the development of PVS as well as factors like flow and shear stress and other less understood instigators of tissue proliferation within the veins. Understanding these interactions has led to improved surveillance as well as the development of protocols for the evaluation of pulmonary veins in the setting of infection or inflammation of the other organs and in patients otherwise predisposed to developing PVS. This early surveillance has resulted in prompt diagnosis, targeted drug development tailored to the disease process, appropriate and timely intervention with improved outcomes.

The greater omentum, often described as a "plaster" of the abdominal cavity, exhibits remarkable regenerative and immunological properties. Its unique morphology-rich vasculature and a diverse cellular composition comprising adipocytes, endothelial cells, and leukocyte aggregates known as milky spots (MS)-facilitates immune surveillance, fluid uptake, and the secretion of neurotransmitters. Additionally, MS contribute to peritoneal immunity by capturing pathogens, promoting lymphocyte proliferation, and releasing cytokines and chemokines that recruit effector immune cells while limiting local inflammation. Structurally, this peritoneal extension shields visceral organs, prevents adhesions, and absorbs tumor secretions, yet paradoxically also provides a niche for metastatic spread. Moreover, the greater omentum is susceptible to various pathologies-vascular steal can deprive organs of blood, torsion and herniation threaten tissue viability, and ossification can transform the greater omentum into a rigid structure lacking protective properties. Notably, omentectomy has been associated with weakened antibacterial defense, underscoring its protective role. This review aims to explore the multifaceted nature of the greater omentum, emphasizing both its physiological benefits and the potential disadvantages associated with its alteration or removal.

Objectives: This study aimed to identify metabolites and metabolic pathways associated with blood-brain barrier (BBB) dysfunction in human and animal metabolomic research.

Methods: PubMed, Scopus, Web of Science, and Embase were searched (last search: 24 November 2025) without date limits. Original studies applying metabolomic techniques (¹H-NMR, LC-MS, GC-MS) to CSF, serum, or plasma and reporting metabolites linked to BBB damage were included. Study selection, full-text assessment, and data extraction were performed independently by two reviewers, with disagreements resolved by a third. Risk of bias was evaluated using SYRCLE and ROBINS-I tools. Metabolites reported in ≥ 2 studies were mapped to metabolic pathways using MetaboAnalyst with hypergeometric testing and Holm-Bonferroni and FDR corrections.

Results: Of 12,182 records identified, eight studies (four human, four animal) met the inclusion criteria. Across these, 157 metabolites were identified, 25 of which were reported in more than one study. Frequently observed metabolites included glutamate, glutamine, alanine, choline, creatine, and branched-chain amino acids (valine, leucine, isoleucine). Pathway analysis revealed significant enrichment of alanine, aspartate and glutamate metabolism, nitrogen metabolism, and BCAA biosynthesis (FDR = 0.01). Glutamate and glutamine most consistently correlated with BBB dysfunction and neuroinflammatory processes. Substantial heterogeneity was observed, partly due to differences in analytical platforms, sample types, and reporting standards.

Conclusions: Metabolites and pathways related to glutamate, nitrogen metabolism, and BCAA may play key roles in BBB impairment. Metabolomics shows promise for identifying BBB biomarkers, but larger, methodologically standardized studies are required.

Trial registration: OSF identifier: dapu9.

Background: Chronic kidney disease and cognitive impairment are common in heart failure, but how changes in microcirculatory perfusion and oxygenation contribute to these complications remains unclear. We investigated how heart failure with mildly reduced ejection fraction (HFmrEF) affects renal and cerebral perfusion and oxygenation, renal blood flow (RBF), and renal function in adult female sheep (Ovis aries, Linnaeus 1758).

Methods: HFmrEF was induced in Merino ewes (n = 10) via progressive ligation of coronary artery branches. Sham-operated controls (n = 10) underwent thoracotomy without ligation. Three weeks later, fiber-optic probes were implanted in the renal cortex, renal medulla, and frontal cerebral cortex to measure tissue perfusion and oxygenation. Transit-time flow probes and vascular catheters enabled continuous assessment of systemic hemodynamics, left atrial pressure, and RBF. Bladder catheterization allowed urine output measurement, and plasma and urine samples were collected to calculate creatinine clearance. Systolic function was assessed by two-dimensional echocardiography.

Results: Animals with HFmrEF exhibited reduced left ventricular ejection fraction (50.6% ± 1.4% vs. 77.8% ± 0.9%; p < 0.0001), elevated left atrial pressure (7.5 ± 0.9 vs. 3.3 ± 0.8 mmHg; p = 0.003), and clinical signs of heart failure. Renal medullary oxygenation was significantly reduced (41.4 ± 4.3 vs. 54.7 ± 2.7 mmHg; p = 0.02), while renal cortical and cerebral oxygenation were preserved. Systemic hemodynamics, RBF, and creatinine clearance were similar between groups.

Conclusions: In this large mammalian model of HFmrEF, selective renal medullary hypoxia occurred despite preserved renal function and systemic hemodynamics. These findings underscore the vulnerability of the renal medulla and support the need for early markers and interventions targeting renal microcirculation in heart failure.