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Remodeling (re-engineering) of a tumor's stroma has been shown to improve the efficacy of anti-tumor therapies, without destroying the stroma. Even though it still remains unclear which stromal component/-s and what characteristics hinder the reach of nanoparticles deep into cancer cells, we hypothesis that mechanisms behind stroma's resistance to the penetration of nanoparticles rely heavily on extrinsic mechanical forces on stromal cells and cancer cells. Our hypothesis has been formulated on the basis of our previous study which has shown that changes in extracellular matrix (ECM) stiffness with tumor growth influence stresses exerted on fibroblasts and cancer cells, and that malignant cancer cells generate higher stresses on their stroma. This study attempts to establish a distinct identification of the components' remodeling on the distribution and magnitude of stress within a tumor tissue which ultimately will impact the resistance of stroma to treatment. In this study, our objective is to construct a three-dimensional in silico model of a pancreas tumor tissue consisting of cancer cells, stromal cells, and ECM to determine how stromal remodeling alters the stresses distribution and magnitude within the pancreas tumor tissue. Our results show that changes in mechanical properties of ECM significantly alter the magnitude and distribution of stresses within the pancreas tumor tissue. Our results revealed that these stresses are more sensitive to ECM properties as we see the stresses reaching to a maximum of 22,000 Pa for softer ECM with Young's modulus of 250 Pa. The stress distribution and magnitude within the pancreas tumor tissue does not show high sensitivity to the changes in mechanical properties of stromal cells surrounding stiffer cancer cells (PANC-1 with Young's modulus of 2400 Pa). However, softer cancer cells (MIA-PaCa-2 with (Young's modulus of 500 Pa) increase the stresses experienced by stiffer stromal cells and for stiffer ECM. By providing a unique platform to dissect and quantify the impact of individual stromal components on the stress distribution within a tumor tissue, this study serves as an important first step in understanding of which stromal components are vital for an efficient remodeling. This knowledge will be leveraged to overcome a tumor's resistance against the penetration of nanoparticles on a per-patient basis. [ABSTRACT FROM AUTHOR]

Pulmonary hypertension (PH) arises from increased pulmonary vascular resistance due to contraction and remodeling of the pulmonary arteries. The structural changes include thickening of the smooth muscle layer from increased proliferation and resistance to apoptosis. The mechanisms underlying apoptosis resistance in PH are not fully understood. In cancer cells, high expression of aquaporin 1 (AQP1), a water channel, is associated with apoptosis resistance. We showed AQP1 protein was expressed in pulmonary arterial smooth muscle cells (PASMCs) and upregulated in preclinical PH models. In this study, we used PASMCs isolated from control male rats and the SU5416 plus hypoxia (SuHx) model to test the role of AQP1 in modulating susceptibility to apoptosis. We found the elevated level of AQP1 in PASMCs from SuHx rats was necessary for resistance to apoptosis and that apoptosis resistance could be conferred by increasing AQP1 in control PASMCs. In exploring the downstream pathways involved, we found AQP1 levels influence the expression of Bcl‐2, with enhanced AQP1 levels corresponding to increased Bcl‐2 expression, reducing the ratio of BAX to Bcl‐2, consistent with apoptosis resistance. These results provide a mechanism by which AQP1 can regulate PASMC fate. [ABSTRACT FROM AUTHOR]

The hierarchic assembly of fibrillar collagen into an extensive and ordered supramolecular protein fibril is critical for extracellular matrix function and tissue mechanics. Despite decades of study, we still know very little about the complex process of fibrillogenesis, particularly at the earliest stages where observation of rapidly forming, nanoscale intermediates challenges the spatial and temporal resolution of most existing microscopy methods. Using video rate scanning atomic force microscopy (VRS-AFM), we can observe details of the first few minutes of collagen fibril formation and growth on a mica surface in solution. A defining feature of fibrillar collagens is a 67-nm periodic banding along the fibril driven by the organized assembly of individual monomers over multiple length scales. VRS-AFM videos show the concurrent growth and maturation of small fibrils from an initial uniform height to structures that display the canonical banding within seconds. Fibrils grow in a primarily unidirectional manner, with frayed ends of the growing tip latching onto adjacent fibrils. We find that, even at extremely early time points, remodeling of growing fibrils proceeds through bird-caging intermediates and propose that these dynamics may provide a pathway to mature hierarchic assembly. VRS-AFM provides a unique glimpse into the early emergence of banding and pathways for remodeling of the supramolecular assembly of collagen during the inception of fibrillogenesis. [ABSTRACT FROM AUTHOR]

Aneurysmal rupture is associated with wall thinning, but the mechanism is poorly understood. This study aimed to characterize the three-dimensional wall-thickness distributions of unruptured intracranial aneurysms. Five aneurysmal tissues were investigated using micro-computed tomography. First, the wall thickness was related to the aneurysmal wall appearances during surgery. The median wall thicknesses of the translucent and non-translucent walls were 50.56 and 155.93 µm, respectively (p < 0.05) with significant variation in the non-translucent wall thicknesses (p < 0.05). The three-dimensional observations characterized the spatial variation of wall thicknesses. Thin walls showed a uniform thickness profile ranging from 10 to 40 µm, whereas thick walls presented a peaked thickness profile ranging from 300 to 500 µm. In transition walls, the profile undulated due to the formation of focal thin/thick spots. Overall, the aneurysmal wall thicknesses were strongly site-dependent and spatially varied by 10 to 40 times within individual cases. Aneurysmal walls are exposed to wall stress driven by blood pressure. In theory, the magnitude of wall stress is inversely proportional to wall thickness. Thus, the observed spatial variation of wall thickness may increase the spatial variation of wall stress to a similar extent. The irregular wall thickness may yield stress concentration. The observed thin walls and focal thin spots may be caused by excessive wall stresses at the range of mechanical failure inducing wall injuries, such as microscopic tears, during aneurysmal enlargement. The present results suggested that blood pressure (wall stress) may have a potential of acting as a trigger of aneurysmal wall injury. [ABSTRACT FROM AUTHOR]

Perivascular adipose tissue (PVAT) regulates vascular function due to its capacity to synthesize vasoactive products and its mechanical properties. PVATs most abundant cells are adipocytes, and their populations are maintained by the maturation of adipocyte progenitor cells (APC), which may play a pivotal role in the pathogenesis of cardiovascular diseases. However, the distribution of APC within PVAT depots, their potential variation in spatial location, and the influence of sex and age on their abundance remain unknown. We hypothesize that APC abundance in PVAT is affected by location, age, sex and that APC subtypes have specific spatial distributions. PVAT from thoracic and abdominal aorta, and mesenteric arteries, and AT from interscapular, gonadal, and subcutaneous depots from 13-week and 30-week-old females and males Pdgfrα-CreERT2 x LSLtdTomato mice (n = 28) were analyzed. Abdominal aorta PVAT had fewer progenitors than mesenteric PVAT and gonadal AT. Aging reduced the abundance of APC in the thoracic aorta but increased their numbers in mesenteric PVAT. Females had more APC than males in mesenteric PVAT and gonadal AT depots. APC exhibited unique spatial distribution in the aorta and mesenteric PVAT where they localized neighboring vasa vasorum and arteries. APC subtypes (APC1, APC2, APC3, diff APC) were identified in all PVAT depots. Thoracic aorta PVAT APC3 were located in the adventitia while diff APC were in the parenchyma. This study identified variability in APC populations based on depot, age, and sex. The distinctive spatial distribution and the presence of diverse APC subtypes suggest that they may contribute differently to cardiovascular diseases-induced PVAT remodeling. [ABSTRACT FROM AUTHOR]

Musculoskeletal injuries, including tendinopathies, present a significant clinical burden for aging populations. While the biological drivers of age‐related declines in tendon function are poorly understood, it is well accepted that dysregulation of extracellular matrix (ECM) remodeling plays a role in chronic tendon degeneration. Senescent cells, which have been associated with multiple degenerative pathologies in musculoskeletal tissues, secrete a highly pro‐inflammatory senescence‐associated secretory phenotype (SASP) that has potential to promote ECM breakdown. However, the role of senescent cells in the dysregulation of tendon ECM homeostasis is largely unknown. To assess this directly, we developed an in vitro model of induced cellular senescence in murine tendon explants. This novel technique enables us to study the isolated interactions of senescent cells and their native ECM without interference from age‐related systemic changes. We document multiple biomarkers of cellular senescence in induced tendon explants including cell cycle arrest, apoptosis resistance, and sustained inflammatory responses. We then utilize this in vitro senescence model to compare the ECM remodeling response of young, naturally aged, and induced‐senescent tendons to an altered mechanical stimulus. We found that both senescence and aging independently led to alterations in ECM‐related gene expression, reductions in protein synthesis, and tissue compositional changes. Furthermore, MMP activity was sustained, thus shifting the remodeling balance of aged and induced‐senescent tissues towards degradation over production. Together, this demonstrates that cellular senescence plays a role in the altered mechano‐response of aged tendons and likely contributes to poor clinical outcomes in aging populations. [ABSTRACT FROM AUTHOR]

Background: Fibroblast differentiation to a myofibroblast phenotype is a feature of airway remodeling in asthma. Lung fibroblasts express the integrin receptor α4β7 and fibronectin induces myofibroblast differentiation via this receptor. Objectives: To investigate the role of the β7 integrin receptor subunit and α4β7 integrin complex in airway remodeling and airway hyperresponsiveness (AHR) in a murine model of chronic allergen exposure. Methods: C57BL/6 wild type (WT) and β7 integrin null mice (β7 -/-) were sensitized (days 1,10) and challenged with ovalbumin (OVA) three times a week for one or 4 weeks. Similar experiments were performed with WT mice in the presence or absence of α4β7 blocking antibodies. Bronchoalveolar (BAL) cell counts, AHR, histological evaluation, soluble collagen content, Transforming growth factor-β (TGFβ) and Interleukin-13 (IL13) were measured. Phenotype of fibroblasts cultured from WT and β7 -/- saline (SAL) and OVA treated mice was evaluated. Results: Eosinophil numbers were similar in WT vs β7-/- mice. Prolonged OVA exposure in β7-/- mice was associated with reduced AHR, lung collagen content, peribronchial smooth muscle, lung tissue TGFβ and IL13 expression as compared to WT. Similar findings were observed in WT mice treated with α4β7 blocking antibodies. Fibroblast migration was enhanced in response to OVA in WT but not β7 -/- fibroblasts. α-SMA and fibronectin expression were reduced in β7-/- fibroblasts relative to WT. Conclusions: The β7 integrin subunit and the α4β7 integrin complex modulate AHR and airway remodeling in a murine model of allergen exposure. This effect is, at least in part, explained by inhibition of fibroblast activation and is independent of eosinophilic inflammation. [ABSTRACT FROM AUTHOR]

In patients with end-stage chronic obstructive pulmonary disease (COPD), severe pulmonary hypertension (PH) is frequently associated with less severe airway obstruction as compared to mild or no PH. However, the histologic correlate of this finding is not clear. We aimed to quantify remodeling of pulmonary arteries, airways, and parenchyma in random samples of explanted end-stage COPD lungs. We quantified remodeling of small pulmonary arteries, small airways, and the degree of emphysema (mean interseptal distance [MID]) with dedicated software. As primary objective, we compared COPD patients with severe PH (SevPH-COPD) with age- and sex-matched MildPH-COPD. For comparison, we also investigated COPD lungs with no PH (NoPH-COPD), idiopathic PAH (IPAH), and healthy donors. We included n = 17 SevPH-COPD (mPAP = 43 [39-45]mm Hg), n = 17 MildPH-COPD (mPAP = 28 [24-31]mm Hg), n = 5 NoPH-COPD (mPAP = 18 [16-19]mm Hg), n = 10 IPAH (mPAP = 72 [65-91]mm Hg), and n = 10 healthy donor lungs. SevPH-COPD versus MildPH-COPD was characterized by better preserved forced vital capacity (51% vs 40% predicted, p < 0.05), less emphysema (MID 169 µm vs 279 µm, p < 0.001), and less PAS-positive and CD45-positive mucosa cells (15% vs 22%, p = 0.063% and 5% vs 7%, p = 0.058) suggesting less airway inflammation. In COPD patients, intimal and medial thickening were strongly correlated with mPAP (r = 0.676, p < 0.001 and r = 0.595, p < 0.001). MID was negatively correlated with mPAP (r = −0.556, p < 0.001) and was highest in NoPH-COPD (mean 281 µm), suggesting that emphysema per se is not associated with PH. End-stage COPD with severe PH is characterized by pronounced pulmonary vascular remodeling, less inflammation of small airways, and less emphysema as compared to COPD with mild PH or no PH, suggesting that COPD with severe PH may represent a unique phenotype of COPD. [ABSTRACT FROM AUTHOR]

Background: Rate control (RC; meanHRHolter ≤ 125 bpm) increases survival in dogs with atrial fibrillation (AF). The mechanisms remain unclear. Hypothesis/Objectives: Investigate echocardiographic and biomarker differences between RC and non‐RC (NRC) dogs. Determine if changes post‐anti‐arrhythmic drugs (AAD) predict successful RC in subsequent Holter monitoring. Evaluate if early vs late RC affects survival. Animals: Fifty‐two dogs with AF. Methods: Holter‐derived mean heart rate, echocardiographic and biomarker variables from dogs receiving AAD were analyzed prospectively at each re‐evaluation and grouped into RC or NRC. The primary endpoint was successful RC. Between group comparisons of absolute values, magnitude of change from admission to re‐evaluations and end of study were performed using Mann‐Whitney tests or unpaired t‐tests. Logistic regression explored variables associated with inability to achieve RC at subsequent visits. Kaplan‐Meier survival analysis was used to compare survival time of early vs late RC. Results: At visit 2, 11/52 dogs were RC; at visit 3, 14/52 were RC; and at visit 4, 4/52 were RC. At the end of study, 25/52 remained NRC. At visit 2, both groups had increased cardiac dimensions, but NRC dogs had larger dimensions; biomarkers did not differ. At the end of study, RC showed decreased cardiac dimensions and end‐terminal pro‐brain natriuretic peptide (NT‐proBNP) compared with NRC. No variables were useful at predicting RC success in subsequent visits. Survival analysis found no differences between early vs late RC. Conclusions and Clinical Importance: The RC dogs had decreased cardiac dimensions and NT‐proBNP, suggesting HR‐mediated reverse‐remodeling might benefit survival, even with delayed RC achievement. Pursuit of RC is crucial despite initial failures. [ABSTRACT FROM AUTHOR]

Loss of proteostasis and cellular senescence have been previously established as characteristics of aging; however, their interaction in the context of lung aging and potential contributions to aging-associated lung remodeling remains understudied. In this study, we aimed to characterize endoplasmic reticulum (ER) stress response, cellular senescence, and their interaction in relation to extracellular matrix (ECM) production in lung fibroblasts from young (25–45 yr) and old (>60 yr) humans. Fibroblasts from young and old patients without significant preexisting lung disease were exposed to vehicle, MG132, etoposide, or salubrinal. Afterward, cells and cell lysates or supernatants were analyzed for ER stress, cellular senescence, and ECM changes using protein analysis, proliferation assay, and senescence-associated beta-galactosidase (SA-b-Gal) staining. At baseline, fibroblasts from aging individuals showed increased levels of ER stress (ATF6 and PERK), senescence (p21 and McL-1), and ECM marker (COL1A1) compared to those from young individuals. Upon ER stress induction and etoposide exposure, fibroblasts showed an increase in senescence (SA-b-Gal, p21, and Cav-1), ER stress (PERK), and ECM markers (COL1A1 and LUM) compared to vehicle. Additionally, IL-6 and IL-8 levels were increased in the supernatants of MG132- and etoposide-treated fibroblasts, respectively. Finally, the ER stress inhibitor salubrinal decreased the expression of p21 compared to vehicle and MG132 treatments; however, salubrinal inhibited COL1A1 but not p21 expression in MG132-treated fibroblasts. Our study suggests that ER stress response plays an important role in establishment and maintenance of a senescence phenotype in lung fibroblasts and therefore contributes to altered remodeling in the aging lung. NEW & NOTEWORTHY The current study establishes functional links between endoplasmic reticulum (ER) stress and cellular senescence per se in the specific context of aging human lung fibroblasts. Recognizing that the process of aging per se is complex, modulated by the myriad of lifelong and environmental exposures, it is striking to note that chronic ER stress may play a crucial role in the establishment and maintenance of cellular senescence in lung fibroblasts. [ABSTRACT FROM AUTHOR]

Signal transduction by G protein-coupled receptors (GPCRs), receptor tyrosine kinases (RTKs) and immunoreceptors converge at the activation of phospholipase C (PLC) for the hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP2) into inositol 1,4,5- trisphosphate (IP3) and diacylglycerol (DAG). This is a point for second-messenger bifurcation where DAG via protein kinase C (PKC) and IP3 via calcium activate distinct protein targets and regulate cellular functions. IP3 signaling is regulated by multiple calcium influx and efflux proteins involved in calcium homeostasis. A family of lipid kinases belonging to DAG kinases (DGKs) converts DAG to phosphatidic acid (PA), negatively regulating DAG signaling and pathophysiological functions. PA, through a series of biochemical reactions, is recycled to produce new molecules of PIP2. Therefore, DGKs act as a central switch in terminating DAG signaling and resynthesis of membrane phospholipids precursor. Interestingly, calcium and PKC regulate the activation of α and ζ isoforms of DGK that are predominantly expressed in airway and immune cells. Thus, DGK forms a feedback and feedforward control point and plays a crucial role in fine-tuning phospholipid stoichiometry, signaling, and functions. In this review, we discuss the previously underappreciated complex and intriguing DAG/DGK-driven mechanisms in regulating cellular functions associated with asthma, such as contraction and proliferation of airway smooth muscle (ASM) cells and inflammatory activation of immune cells. We highlight the benefits of manipulating DGK activity in mitigating salient features of asthma pathophysiology and shed light on DGK as a molecule of interest for heterogeneous diseases such as asthma. [ABSTRACT FROM AUTHOR]

A major hurdle to therapeutic development in cerebral small vessel diseases is the lack of in-vivo method that can be used repeatedly for evaluating directly cerebral microvessels. We hypothesised that Adaptive Optics (AO), which allows resolution images up to 1–2 μm/pixel at retinal level, could provide a biomarker for monitoring vascular changes in CADASIL, a genetic form of such condition. In 98 patients and 35 healthy individuals, the wall to lumen ratio (WLR), outer and inner diameter, wall thickness and wall cross-sectional area were measured in a parapapillary and/or paramacular retinal artery. The ratio of vessel diameters before and after light flicker stimulations was also calculated to measure vasoreactivity (VR). Multivariate mixed-model analysis showed that WLR was increased and associated with a larger wall thickness and smaller internal diameter of retinal arteries in patients. The difference was maximal at the youngest age and gradually reduced with aging. Average VR in patients was less than half of that of controls since the youngest age. Any robust association was found with clinical or imaging manifestations of the disease. Thus, AO enables the detection of early functional or structural vascular alterations in CADASIL but with no obvious link to the clinical or imaging severity. [ABSTRACT FROM AUTHOR]

Remodeling aging structures is common to enhance their structural, economic, and functional performance. However, the exceeding of bearing capacity of existing piles caused by increased upper loads due to vertical expansion frequently hinders their revitalization. In this paper, a methodology is proposed to control the demand-tocapacity ratio of existing piles without retrofitting the foundation, which is often accompanied by technical limitations and safety issues. A total of 12 tests were performed on four full-scale specimens, with tendon shape, wall thickness, boundary condition, and construction sequence as variables. Factors affecting load-transfer performance were identified based on test results. The target loadtransfer pattern implemented in accordance with the tendon shape was confirmed. To verify the validity of the method, tests using tendon shape and wall thickness as variables were compared with results from finite element analysis. [ABSTRACT FROM AUTHOR]

Abstract Remodeling (re-engineering) of a tumor’s stroma has been shown to improve the efficacy of anti-tumor therapies, without destroying the stroma. Even though it still remains unclear which stromal component/-s and what characteristics hinder the reach of nanoparticles deep into cancer cells, we hypothesis that mechanisms behind stroma’s resistance to the penetration of nanoparticles rely heavily on extrinsic mechanical forces on stromal cells and cancer cells. Our hypothesis has been formulated on the basis of our previous study which has shown that changes in extracellular matrix (ECM) stiffness with tumor growth influence stresses exerted on fibroblasts and cancer cells, and that malignant cancer cells generate higher stresses on their stroma. This study attempts to establish a distinct identification of the components’ remodeling on the distribution and magnitude of stress within a tumor tissue which ultimately will impact the resistance of stroma to treatment. In this study, our objective is to construct a three-dimensional in silico model of a pancreas tumor tissue consisting of cancer cells, stromal cells, and ECM to determine how stromal remodeling alters the stresses distribution and magnitude within the pancreas tumor tissue. Our results show that changes in mechanical properties of ECM significantly alter the magnitude and distribution of stresses within the pancreas tumor tissue. Our results revealed that these stresses are more sensitive to ECM properties as we see the stresses reaching to a maximum of 22,000 Pa for softer ECM with Young’s modulus of 250 Pa. The stress distribution and magnitude within the pancreas tumor tissue does not show high sensitivity to the changes in mechanical properties of stromal cells surrounding stiffer cancer cells (PANC-1 with Young’s modulus of 2400 Pa). However, softer cancer cells (MIA-PaCa-2 with (Young’s modulus of 500 Pa) increase the stresses experienced by stiffer stromal cells and for stiffer ECM. By providing a unique platform to dissect and quantify the impact of individual stromal components on the stress distribution within a tumor tissue, this study serves as an important first step in understanding of which stromal components are vital for an efficient remodeling. This knowledge will be leveraged to overcome a tumor’s resistance against the penetration of nanoparticles on a per-patient basis.

Rationale: Surgical interventions have been recognized as the main method to repair of valvular disorders. Percutaneous transcatheter intervention with a clipping system is being actively introduced into the treatment of chronic heart failure (CHF) patients and mitral valve insufficiency (MVI) for correction of mitral regurgitation (MR), along with drug therapy. Aim: To establish the effect of the mitral valve leaflet clipping in the combination treatment of CHF patients on the clinical course of heart failure and the remodeling process. Methods: This single center prospective comparative study included 80 patients with CHF NYHA class II–IV and secondary MR grade 3–4. The patients were on optimal medical treatment (OMT) for CHF for at least 3 months before inclusion into the study. The main group included 55 patients who underwent transcatheter mitral valve repair with the use of MitraClip system, and the control group consisted of 25 patients in whom the surgery for MR was waived for various reasons (refusal of the surgery by the patient, some valve characteristics), and only OMT for CHF was used. At baseline, main clinical and demographic characteristics of the patients in the both groups were comparable. The duration of the follow-up was 6 months. Echocardiography (echoCG), a 6-minute walk test, and measurements of the brain natriuretic propeptide level were performed in all patients at baseline and at 6 months of the follow-up. Results: At 6 months, there was a significant reduction in CHF NYHA class and an increase in the 6-minute walk test distance and a decrease in diuretic requirements (converted to furosemide, from 58.4 ± 17.2 to 38.1 ± 20.7 mg daily, р = 0.02) in the group with the MitraClip implant, but not in the control group. In the OMT only group, there were no changes over 6 months in the diuretic requirements (48.1 ± 6.68 and 43.8 ± 27.15 mg daily, respectively, р = 0.8). The number of hospital readmissions due to CHF decompensation was 7 (12.7%) in the implanted MitraClip group and 4 (16%) in the OMT group (р = 0.69). EchoCG performed at 6 months after the surgical intervention identified no cases of MR grade 2. In the MitraClip implant group, there was a decrease in the size and volumes of the left atrium (р = 0.02 and р = 0.05, respectively), left ventricle (for end-diastolic diameter p = 0.002, end-diastolic volume p = 0.03), mean pulmonary artery pressure (p = 0.03), as well as an increase in cardiac output (р = 0.04). In the patients receiving OMT only, there were no significant changes in EchoCG parameters over time. Conclusion: Our study has shown benefits of the implantation of the mitral valve leaflet clipping system, compared to OMT only, in CHF. The clipping procedure promotes a significant improvement in clinical course of CHF, reverse myocardial remodeling, and reduction in diuretic requirements.

Abstract Background Rate control (RC; meanHRHolter ≤ 125 bpm) increases survival in dogs with atrial fibrillation (AF). The mechanisms remain unclear. Hypothesis/Objectives Investigate echocardiographic and biomarker differences between RC and non‐RC (NRC) dogs. Determine if changes post‐anti‐arrhythmic drugs (AAD) predict successful RC in subsequent Holter monitoring. Evaluate if early vs late RC affects survival. Animals Fifty‐two dogs with AF. Methods Holter‐derived mean heart rate, echocardiographic and biomarker variables from dogs receiving AAD were analyzed prospectively at each re‐evaluation and grouped into RC or NRC. The primary endpoint was successful RC. Between group comparisons of absolute values, magnitude of change from admission to re‐evaluations and end of study were performed using Mann‐Whitney tests or unpaired t‐tests. Logistic regression explored variables associated with inability to achieve RC at subsequent visits. Kaplan‐Meier survival analysis was used to compare survival time of early vs late RC. Results At visit 2, 11/52 dogs were RC; at visit 3, 14/52 were RC; and at visit 4, 4/52 were RC. At the end of study, 25/52 remained NRC. At visit 2, both groups had increased cardiac dimensions, but NRC dogs had larger dimensions; biomarkers did not differ. At the end of study, RC showed decreased cardiac dimensions and end‐terminal pro‐brain natriuretic peptide (NT‐proBNP) compared with NRC. No variables were useful at predicting RC success in subsequent visits. Survival analysis found no differences between early vs late RC. Conclusions and Clinical Importance The RC dogs had decreased cardiac dimensions and NT‐proBNP, suggesting HR‐mediated reverse‐remodeling might benefit survival, even with delayed RC achievement. Pursuit of RC is crucial despite initial failures.

Abstract Background Fibroblast differentiation to a myofibroblast phenotype is a feature of airway remodeling in asthma. Lung fibroblasts express the integrin receptor α4β7 and fibronectin induces myofibroblast differentiation via this receptor. Objectives To investigate the role of the β7 integrin receptor subunit and α4β7 integrin complex in airway remodeling and airway hyperresponsiveness (AHR) in a murine model of chronic allergen exposure. Methods C57BL/6 wild type (WT) and β7 integrin null mice (β7 -/-) were sensitized (days 1,10) and challenged with ovalbumin (OVA) three times a week for one or 4 weeks. Similar experiments were performed with WT mice in the presence or absence of α4β7 blocking antibodies. Bronchoalveolar (BAL) cell counts, AHR, histological evaluation, soluble collagen content, Transforming growth factor-β (TGFβ) and Interleukin-13 (IL13) were measured. Phenotype of fibroblasts cultured from WT and β7 -/- saline (SAL) and OVA treated mice was evaluated. Results Eosinophil numbers were similar in WT vs β7-/- mice. Prolonged OVA exposure in β7-/- mice was associated with reduced AHR, lung collagen content, peribronchial smooth muscle, lung tissue TGFβ and IL13 expression as compared to WT. Similar findings were observed in WT mice treated with α4β7 blocking antibodies. Fibroblast migration was enhanced in response to OVA in WT but not β7 -/- fibroblasts. α-SMA and fibronectin expression were reduced in β7-/- fibroblasts relative to WT. Conclusions The β7 integrin subunit and the α4β7 integrin complex modulate AHR and airway remodeling in a murine model of allergen exposure. This effect is, at least in part, explained by inhibition of fibroblast activation and is independent of eosinophilic inflammation.

Background Studies in mice and small patient subsets implicate metabolic dysfunction in cardiac remodeling in aortic stenosis, but no large comprehensive studies of human metabolism in aortic stenosis with long-term follow-up and characterization currently exist. Methods and Results Within a multicenter prospective cohort study, we used principal components analysis to summarize 12 echocardiographic measures of left ventricular structure and function pre-transcatheter aortic valve implantation in 519 subjects (derivation). We used least absolute shrinkage and selection operator regression across 221 metabolites to define metabolic signatures for each structural pattern and measured their relation to death and multimorbidity in the original cohort and up to 2 validation cohorts (N=543 for overall validation). In the derivation cohort (519 individuals; median age, 84 years, 45% women, 95% White individuals), we identified 3 axes of left ventricular remodeling, broadly specifying systolic function, diastolic function, and chamber volumes. Metabolite signatures of each axis specified both known and novel pathways in hypertrophy and cardiac dysfunction. Over a median of 3.1 years (205 deaths), a metabolite score for diastolic function was independently associated with post-transcatheter aortic valve implantation death (adjusted hazard ratio per 1 SD increase in score, 1.54 [95% CI, 1.25-1.90]; P

Thoracic endovascular aortic repair (TEVAR) represents optimal therapy for complicated acute type B aortic dissection (aTBAD). Persistent knowledge gaps remain, including the optimal length of aortic coverage, impact on distal aortic remodeling, and fate of the dissected abdominal aorta. Review of the Emory Aortic Database identified 92 patients who underwent TEVAR for complicated aTBAD from 2012 to 2018. Standard TEVAR covered aortic zones 3 and 4 (from the left subclavian to the mid-descending thoracic aorta). Extended TEVAR fully covered aortic zones 3 though 5 (from the left subclavian to the celiac artery). Long-term imaging, clinical follow-up, and overall and aortic-specific mortality were reviewed. Extended TEVAR (n = 52) required a greater length of coverage vs standard TEVAR (n = 40) (240 ± 32 mm vs 183 ± 23 mm; P <.01). In-hospital mortality occurred in 5.4% of patients (7.7% vs 2.5%; P =.27) owing to mesenteric malperfusion (n = 3) or rupture (n = 2). The overall incidences of postoperative stroke, transient paraparesis, paraplegia, and dialysis were 5.4% (3.9% vs 7.5%; P =.38), 3.2% (5.8% vs 0%; P =.18), 0%, and 0% respectively, equivalent between groups. Follow-up was 96.6% complete to a mean of 6.1 years (interquartile range, 3.5-8.6 years). There were significantly higher rates of complete thrombosis or obliteration of the entire thoracic false lumen after Extended TEVAR (82.2% vs 51.5%; P =.04). Distal aortic reinterventions were less frequent after extended TEVAR (5.8% vs 20%; P =.04). Late aorta-specific survival was 98.1% after extended TEVAR vs 92.3% for standard TEVAR (P =.32). Extended TEVAR for complicated aTBAD is safe, results in a high rate of total thoracic false lumen thrombosis/obliteration, and reduces distal reinterventions. Longer-term follow-up will be needed to demonstrate a survival benefit compared to limited aortic coverage. [ABSTRACT FROM AUTHOR]

Background: Aortico right atrial tunnel (ARAT) is a rare extracardiac communication between the aorta and the right atrium with two anatomical types. A recent global review identified 59 patients. Methods: Patients with ARAT from two centers were analyzed for their demographics, symptoms, morphology, management, and follow-up thromboprophylaxis. Results: Among 21 patients including 8 males with a median age of 3 years (18 days–72 years) diagnosed as ARAT, 12 (57%) had posterior tunnels and 9 had anterior tunnels. Four patients had multiple exits. Eighteen tunnels were closed after arteriovenous circuit formation. Six patients (29%) weighing

Myocardial infarction (MI) is a leading cause of death worldwide. Few drugs hold the ability to depress cardiac electrical and structural remodeling simultaneously after MI, which is crucial for the treatment of MI. The aim of this study is to investigate an effective therapy to improve both electrical and structural remodeling of the heart caused by MI. Here, an "ion cocktail therapy" is proposed to simultaneously reverse cardiac structural and electrical remodeling post‐MI in rats and minipigs by applying a unique combination of silicate, strontium (Sr) and copper (Cu) ions due to their specific regulatory effects on the behavior of the key cells involved in MI including angiogenesis of endothelial cells, M2 polarization of macrophages and apoptosis of cardiomyocyte. The results demonstrate that ion cocktail treatment attenuates structural remodeling post‐MI by ameliorating infarct size, promoting angiogenesis in both peri‐infarct and infarct areas. Meantime, to some extent, ion cocktail treatment reverses the deteriorative electrical remodeling by reducing the incidence rate of early/delayed afterdepolarizations and minimizing the heterogeneity of cardiac electrophysiology. This ion cocktail therapy reveals a new strategy to effectively treat MI with great clinical translation potential due to the high effectiveness and safety of the ion cocktail combination. [ABSTRACT FROM AUTHOR]

Objectives: The aim of this study was to report the long-term outcomes of proximal thoracic endovascular aortic repair (TEVAR) for chronic Stanford type B aortic dissection (cTBAD). Methods: We retrospectively analyzed the clinical data of 48 cases of patients with cTBAD who underwent proximal TEVAR in Zhongshan Hospital Fudan University from January 2010 to September 2013. The preoperative and postoperative imaging examinations, overall survival rate, aortic-related survival rate, and freedom from reintervention rate data were collected to evaluate aortic remodeling and clinical outcomes. The enrolled patients received follow-up at 1, 3, 6, and 12 months following treatment and annually thereafter. Results: A total of 48 patients (mean age, 58.3 ± 10.6 years; men:women, 40:8) were included, of which 38 cases (79.2%) were uncomplicated dissection and 10 cases (20.8%) were complicated. The mean follow-up time was 48.7 ± 40 months (1–120 months). The mean time interval from the initial procedure to reintervention was 50.6 ± 32.7 months (11–98 months). The following changes were observed at preoperative versus last follow-up timepoints. Descending aortic level: true lumen, 19.2 ± 7.01 mm vs. 36.9 ± 9.53 mm (p < 0.001); false lumen, 30.47 ± 15.89 mm vs. 19.16 ± 15.33 mm (p < 0.001); maximum diameter, 49.67 ± 13.96 mm vs. 56.66 ± 14.95 mm (p = 0.018). Diaphragm level: true lumen, 16.24 ± 5.41 mm vs. 24.41 ± 8.04 mm (p < 0.001); false lumen, 12.37 ± 11.49 mm vs. 14.92 ± 12.25 mm (p = 0.196); and maximum diameter, 34 ± 7.81 mm vs. 38.04 ± 7.7 mm (p < 0.001). The freedom from reintervention rate was 81% in 5 years and 50.6% in 10 years. The overall 10-years survival rate was 83% (6 of 48), and the aortic-related survival rate was 92.3% (3 of 48). Conclusions: TEVAR is a safe and effective proximal repair intervention for cTBAD that can reliably induce the positive remodeling of the descending aorta. [ABSTRACT FROM AUTHOR]

For orthopedic implants, biocompatibility is essential to ensure that they integrate with biological systems without causing negative reactions or impairing tissue function. Orthopedic implants must be cellularly acceptable to interact with neighboring tissues, including muscle, cartilage, and bone. Implant materials should not cause cytotoxic reactions or inflammatory responses that might hinder healing or result in long-term inflammation. Progress in surface engineering and biomaterials science is discovering implants that work well with the body, benefiting patients in the long run. The biocompatibility of orthopedic implants, their interaction with surrounding tissues, and the potential for biological problems are all important aspects of their design and operation. Orthopedic implants must be successful and long-lasting to ensure biocompatibility, promote osseointegration (osteointegration), avoid biofilm development, and consider the patient's biological environment. This paper discusses biocompatibility in orthopedic implants, its advancements, and challenges. [ABSTRACT FROM AUTHOR]

Arteries and veins develop different types of occlusive diseases and respond differently to injury. The biological reasons for this discrepancy are not well understood, which is a limiting factor for the development of vein-targeted therapies. This study contrasts human peripheral arteries and veins at the single-cell level, with a focus on cell populations with remodeling potential. Upper arm arteries (brachial) and veins (basilic/cephalic) from 30 organ donors were compared using a combination of bulk and single-cell RNA sequencing, proteomics, flow cytometry, and histology. The cellular atlases of six arteries and veins demonstrated a 7.8× higher proportion of contractile smooth muscle cells (SMCs) in arteries and a trend toward more modulated SMCs. In contrast, veins showed a higher abundance of endothelial cells, pericytes, and macrophages, as well as an increasing trend in fibroblasts. Activated fibroblasts had similar proportions in both types of vessels but with significant differences in gene expression. Modulated SMCs and activated fibroblasts were characterized by the upregulation of MYH10, FN1, COL8A1, and ITGA10. Activated fibroblasts also expressed F2R, POSTN, and COMP and were confirmed by F2R/CD90 flow cytometry. Activated fibroblasts from veins were the top producers of collagens among all fibroblast populations from both types of vessels. Venous fibroblasts were also highly angiogenic, proinflammatory, and hyper-responders to reactive oxygen species. Differences in wall structure further explain the significant contribution of fibroblast populations to remodeling in veins. Fibroblasts are almost exclusively located outside the external elastic lamina in arteries, while widely distributed throughout the venous wall. In line with the above, ECM-targeted proteomics confirmed a higher abundance of fibrillar collagens in veins vs. more basement ECM components in arteries. The distinct cellular compositions and transcriptional programs of reparative populations in arteries and veins may explain differences in acute and chronic wall remodeling between vessels. This information may be relevant for the development of antistenotic therapies. [ABSTRACT FROM AUTHOR]

In the Latin-American context, public spaces have been conceptualized and intervened upon using approaches strongly inspired by the reality of the global North. These approaches, insofar as they align with a normative ideal of public space, are not well-suited to analyze the situated and conflictive reality of different Latin American public spaces. Furthermore, they are characterized by a dualistic perspective where public space is understood as the physical stage that hosts urban life. Given these conceptions, in this article we generate a dual proposal to understand the production of public space. Firstly, from an axiological dimension, we propose a perspective focused on conflict; then, from the ontoepistemic dimension we propose an assamblage analysis. To test the extent of the reach allowed by the proposed analytical coordinates, we studied the remodeling of an urban park in Valparaíso through the production of different kind of data (geo-spatialized interviews, photographs, documentary review and walking interviews). In the light of the results, we reflect on how socio-spatial conflict articulates the production of space through the assembled hybridization of aspects of different natures, and how the place is more than a mere scenario of conflict. [ABSTRACT FROM AUTHOR]

Introduction: The management of aortic dissection has evolved significantly over the decades, with the frozen elephant trunk (FET) procedure emerging as a key technique for treating complex aortic pathologies. Recent practices involve deploying the FET prosthesis more proximally in the aorta (Zone 0) to reduce complications, leading to questions about its impact on long-term aortic remodeling compared to traditional Zone 2 deployment. Methods: This retrospective analysis utilized 3D segmentation software to assess the volumetric changes in aortic remodeling after acute Type A aortic dissections, comparing FET stent graft deployment in Zone 0 and Zone 2. The study included 27 patients operated on between 2020 and 2022, with volumetric measurements taken from postoperative and 6-month follow-up CT scans. Statistical analyses were performed to evaluate the differences in the aortic true lumen (TL) and the perfused false lumen (PFL) between the two groups. Results: Both Zone 0 and Zone 2 deployments resulted in significant true lumen (TL) increases (Z0 p = 0.001, Z2 p < 0.001) and perfused false lumen (PFL) decreases (Z0 p = 0.02, Z2 p = 0.04), with no significant differences in volumetric changes between the groups (p = 0.7 post op and p = 0.9 after 6 months). The distal anastomosis in Zone 0 did not compromise the aortic remodeling outcomes and was associated with reduced distal ischemia and cerebral perfusion times (p = 0.041). The angle measurements in Zone 0 did not show any significant changes after the 6-month control (p = 0.2). However, in Zone 2, a significant change was detected. (p = 0.022). The part comparison analyses did not indicate significant differences in aortic deviation between the groups (p = 0.62), suggesting comparable effectiveness in aortic remodeling. Conclusions: Performing the distal anastomosis more proximally in Zone 0 offers technical advantages without compromising the effectiveness of aortic remodeling compared to the traditional Zone 2 deployment. This finding supports the continued recommendation of Zone 0 deployment in the management of acute Type A aortic dissections, with ongoing studies being needed to confirm the long-term outcomes and survival benefits. [ABSTRACT FROM AUTHOR]

The adipose organ adapts and responds to internal and environmental stimuli by remodeling both its cellular and extracellular components. Under conditions of energy surplus, the subcutaneous white adipose tissue (WAT) is capable of expanding through the enlargement of existing adipocytes (hypertrophy), followed by de novo adipogenesis (hyperplasia), which is impaired in hypertrophic obesity. However, an impaired hyperplastic response may result from various defects in adipogenesis, leading to different WAT features and metabolic consequences, as discussed here by reviewing the results of the studies in animal models with either overexpression or knockdown of the main molecular regulators of the two steps of the adipogenesis process. Moreover, impaired WAT remodeling with aging has been associated with various age-related conditions and reduced lifespan expectancy. Here, we delve into the latest advancements in comprehending the molecular and cellular processes underlying age-related changes in WAT function, their involvement in common aging pathologies, and their potential as therapeutic targets to influence both the health of elderly people and longevity. Overall, this review aims to encourage research on the mechanisms of WAT maladaptation common to conditions of both excessive and insufficient fat tissue. The goal is to devise adipocyte-targeted therapies that are effective against both obesity- and age-related disorders. [ABSTRACT FROM AUTHOR]

Numerous studies have shown that a low level of high-density lipoprotein cholesterol (HDL-C) is an independent biomarker of cardiovascular disease. High-density lipoprotein (HDL) is considered to be a protective factor for atherosclerosis (AS). Therefore, raising HDL-C has been widely recognized as a promising strategy to treat atherosclerotic cardiovascular diseases (ASCVD). However, several studies have found that increasing HDL-C levels does not necessarily reduce the risk of ASCVD. HDL particles are highly heterogeneous in structure, composition, and biological function. Moreover, HDL particles from atherosclerotic patients exhibit impaired anti-atherogenic functions and these dysfunctional HDL particles might even promote ASCVD. This makes it uncertain that HDL-raising therapy will prevent and treat ASCVD. It is necessary to comprehensively analyze the structure and function of HDL subfractions. We review current advances related to HDL subfractions remodeling and highlight how current lipid-modifying drugs such as niacin, statins, fibrates, and cholesteryl ester transfer protein inhibitors regulate cholesterol concentration of HDL and specific HDL subfractions. [ABSTRACT FROM AUTHOR]

Healthy aortic heart valves are essential to the regulation of unidirectional blood flow. Calcific aortic valve disease (CAVD) is an actively progressive disease that involves the disorganization of valve cells and accumulation of calcium deposits on the aortic valve leaflets. CAVD involves disruption of cell environment homeostasis that prior cell culture models have found difficult to portray and model. As it is still poorly understood how tissue stiffening associates with lesion formation, here, we implement a novel 3D culture platform to characterize the relationship between mechanical stress and tissue remodeling and analyze how the application of pro-osteogenic stimulation dysregulates the native ability of valve cells to organize its matrix. Through a temporal study of macroscopic remodeling, we determine that aortic valve interstitial neo-tissues undergo varying stiffness and mechanical stress, demonstrate greater myofibroblastic gene expression, and show greater remodeling activity in the outer surface of the neo-tissue in a banding pattern when cultured in osteogenic growth medium. In human aortic valve interstitial cells cultured in osteogenic growth medium, we observed an increase in stress but significant decreases in myofibroblastic gene expression with the addition of growth factors. In summary, we are able to see the interplay of biochemical and biomechanical stimuli in valvular remodeling by using our platform to model dynamic stiffening of valve interstitial neo-tissues under different biochemical conditions. [ABSTRACT FROM AUTHOR]

Matrix metalloproteinases (MMPs) are a group of enzymes that are essential in maintaining extracellular matrix (ECM) homeostasis, regulating inflammation and tissue remodeling. In chronic rhinosinusitis (CRS), the overexpression of certain MMPs can contribute to chronic nasal tissue inflammation, ECM remodeling, and tissue repair. This review provides a comprehensive overview of the biological characteristics and functions of the MMP family, particularly focusing on the expression and activity of MMPs in patients with CRS, and delves into their role in the pathogenesis of CRS and their potential as therapeutic targets. MMPs are important in tissue remodeling and have been implicated in the pathophysiology of CRS. Previous studies have shown that the expression of MMPs is upregulated in the nasal mucosa of patients with CRS and positively correlates with the severity of CRS. However, there is still a large gap in the research content of MMP in CRS, and the specific expression and pathogenic mechanism of MMP still need to be clarified. The significance and value of the ratio of MMP to tissue inhibitors of metalloproteinase (TIMP) in diseases still need to be demonstrated. Moreover, further studies are needed to assess the efficacy and safety of biologics that target MMPs in patients with CRS. [ABSTRACT FROM AUTHOR]

This review examines the impact of obesity on the pathophysiology of heart failure with preserved ejection fraction (HFpEF) and focuses on novel mechanisms for HFpEF prevention using a glucagon-like peptide-1 receptor agonism (GLP-1 RA). Obesity can lead to HFpEF through various mechanisms, including low-grade systemic inflammation, adipocyte dysfunction, accumulation of visceral adipose tissue, and increased pericardial/epicardial adipose tissue (contributing to an increase in myocardial fat content and interstitial fibrosis). Glucagon-like peptide 1 (GLP-1) is an incretin hormone that is released from the enteroendocrine L-cells in the gut. GLP-1 reduces blood glucose levels by stimulating insulin synthesis, suppressing islet α-cell function, and promoting the proliferation and differentiation of β-cells. GLP-1 regulates gastric emptying and appetite, and GLP-1 RA is currently indicated for treating type 2 diabetes (T2D), obesity, and metabolic syndrome (MS). Recent evidence indicates that GLP-1 RA may play a significant role in preventing HFpEF in patients with obesity, MS, or obese T2D. This effect may be due to activating cardioprotective mechanisms (the endogenous counter-regulatory renin angiotensin system and the AMPK/mTOR pathway) and by inhibiting deleterious remodeling mechanisms (the PKA/RhoA/ROCK pathway, aldosterone levels, and microinflammation). However, there is still a need for further research to validate the impact of these mechanisms on humans. [ABSTRACT FROM AUTHOR]

Succinate dehydrogenase inhibition with malonate during initial reperfusion reduces myocardial infarct size in both isolated mouse hearts subjected to global ischemia and in in situ pig hearts subjected to transient coronary ligature. However, the long-term effects of acute malonate treatment are unknown. Here, we investigated whether the protective effects of succinate dehydrogenase inhibition extend to a reduction in scar size and adverse left ventricular remodeling 28 days after myocardial infarction. Initially, ten wild-type mice were subjected to 45 min of left anterior descending coronary artery (LAD) occlusion, followed by 24 h of reperfusion, and were infused during the first 15 min of reperfusion with saline with or without disodium malonate (10 mg/kg/min, 120 μL/kg/min). Malonate-treated mice depicted a significant reduction in infarct size (15.47 ± 3.40% of area at risk vs. 29.34 ± 4.44% in control animals, p < 0.05), assessed using triphenyltetrazolium chloride. Additional animals were then subjected to a 45 min LAD ligature, followed by 28 days of reperfusion. Treatment with a single dose of malonate during the first 15 min of reperfusion induced a significant reduction in scar area, measured using Picrosirius Red staining (11.94 ± 1.70% of left ventricular area (n = 5) vs. 23.25 ± 2.67% (n = 9), p < 0.05), an effect associated with improved ejection fraction 28 days after infarction, as determined using echocardiography, and an attenuated enhancement in expression of the pro-inflammatory and fibrotic markers NF-κB and Smad2/3 in remote myocardium. In conclusion, a reversible inhibition of succinate dehydrogenase with a single dose of malonate at the onset of reperfusion has long-term protective effects in mice subjected to transient coronary occlusion. [ABSTRACT FROM AUTHOR]

Background: Dupilumab is used for the treatment of atopic dermatitis (AD). Approximately one third of AD patients develop a dupilumab‐associated ocular surface disease (DAOSD), of which the pathomechanism is poorly understood. This study aimed at investigating inflammatory markers in tear fluids of patients on dupilumab therapy. Methods: Tear fluids were collected from AD patients with DAOSD (ADwDAOSD), AD patients without DAOSD (ADw/oDAOSD), and non‐AD patients before and during dupilumab therapy, and analyzed using a specialized proteomic approach quantifying inflammatory markers. The ocular surface microbiome was determined by next generation sequencing technology. Results: Upon dupilumab therapy, an upregulation of 31 inflammatory markers was observed in DAOSD tear fluids compared to baseline in AD patients. While IL‐12B was upregulated in both ADwDAOSD and ADw/oDAOSD groups, the pattern of inflammatory markers significantly differed between groups and over time. In the ADwDAOSD group, a shift from a mixed Th2/Th17 pattern at baseline toward a Th1/Th17 profile under dupilumab was observed. Furthermore, an upregulation of remodeling and fibrosis markers was seen in DAOSD. Semantic map and hierarchical cluster analyses of baseline marker expression revealed four clusters distinguishing between AD and non‐AD as well as ADwDAOSD and ADw/oDAOSD patient groups. In a pilot study, dupilumab therapy was associated with a decrease in richness of the ocular surface microbiome. Conclusions: DAOSD is characterized by a Th1/Th17 cytokine profile and an upregulation of markers known to promote remodeling and fibrosis. The expression pattern of inflammatory markers in tear fluids at baseline might serve as a prognostic factor for DAOSD. [ABSTRACT FROM AUTHOR]

Atrial myopathy is a condition that consists of electrical, structural, contractile, and autonomic remodeling of the atria and is the substrate for development of atrial fibrillation, the most common arrhythmia. Pathophysiologic mechanisms driving atrial myopathy are inflammation, oxidative stress, atrial stretch, and neurohormonal signals, e.g., angiotensin-II and aldosterone. These mechanisms initiate the structural and functional remodeling of the atrial myocardium. Novel therapeutic strategies are being developed that target the pathophysiologic mechanisms of atrial myopathy. In this review, we will discuss the pathophysiology of atrial myopathy, as well as diagnostic and therapeutic strategies. [ABSTRACT FROM AUTHOR]

Adverse cardiac remodeling contributes to heart failure development and progression, partly due to inappropriate sympathetic nervous system activation. Although b-adrenergic receptor (β-AR) blockade is a common heart failure therapy, not all patients respond, prompting exploration of alternative treatments. Minocycline, an FDA-approved antibiotic, has pleiotropic properties beyond antimicrobial action. Recent evidence suggests it may alter gene expression via changes in miRNA expression. Thus, we hypothesized that minocycline could prevent adverse cardiac remodeling induced by the β-AR agonist isoproterenol, involving miRNA-mRNA transcriptome alterations. Male C57BL/6J mice received isoproterenol (30 mg/kg/day sc) or vehicle via osmotic minipump for 21 days, along with daily minocycline (50 mg/kg ip) or sterile saline. Isoproterenol induced cardiac hypertrophy without altering cardiac function, which minocycline prevented. Total mRNA sequencing revealed isoproterenol altering gene networks associated with inflammation and metabolism, with fibrosis activation predicted by integrated miRNA-mRNA sequencing, involving miR-21, miR-30a, miR-34a, miR-92a, and miR-150, among others. Conversely, the cardiac miRNA-mRNA transcriptome predicted fibrosis inhibition in minocycline-treated mice, involving antifibrotic shifts in Atf3 and Itgb6 gene expression associated with miR-194 upregulation. Picrosirius red staining confirmed isoproterenol-induced cardiac fibrosis, prevented by minocycline. These results demonstrate minocycline's therapeutic potential in attenuating adverse cardiac remodeling through miRNA-mRNA-dependent mechanisms, especially in reducing cardiac fibrosis. NEW & NOTEWORTHY: We demonstrate that minocycline treatment prevents cardiac hypertrophy and fibrotic remodeling induced by chronic b-adrenergic stimulation by inducing antifibrotic shifts in the cardiac miRNA-mRNA transcriptome. [ABSTRACT FROM AUTHOR]

The extracellular matrix (ECM) is not just a three-dimensional scaffold that provides stable support for all cells in the lungs, but also an important component of chronic fibrotic airway, vascular, and interstitial diseases. It is a bioactive entity that is dynamically modulated during tissue homeostasis and disease, that controls structural and immune cell functions and drug responses, and that can release fragments that have biological activity and that can be used to monitor disease activity. There is a growing recognition of the importance of considering ECM changes in chronic airway, vascular, and interstitial diseases, including 1) compositional changes, 2) structural and organizational changes, and 3) mechanical changes and how these affect disease pathogenesis. As altered ECM biology is an important component of many lung diseases, disease models must incorporate this factor to fully recapitulate disease-driver pathways and to study potential novel therapeutic interventions. Although novel models are evolving that capture some or all of the elements of the altered ECM microenvironment in lung diseases, opportunities exist to more fully understand cell–ECM interactions that will help devise future therapeutic targets to restore function in chronic lung diseases. In this perspective article, we review evolving knowledge about the ECM's role in homeostasis and disease in the lung. [ABSTRACT FROM AUTHOR]

Introduction: Asthma is a heterogeneous chronic inflammatory disease of the airways. Chronic inflammation leads to changes in the structure and stiffening of the bronchial wall, and irreversible disruption of airflow through the airways. One of the factors researchers consider important in the process of inflammation and fibrosis is the transforming growth factor β (TGF-β). Overexpression of TGF-β in the structural cells of the bronchial tree is thought to translate into excessive secretion of type I and III collagen, fibronectin, tenascin and proteoglycans, as well as inhibition of matrix metalloproteinases and collagenases, promoting the phenomenon of remodeling. Aim: To evaluate serum levels of all the TGF-β (TGF-β 1-3) isoforms in asthmatic patients, compare the obtained results with those of non-asthmatic subjects, and analyze potential correlations between particular isoforms. Material and methods: The study included 69 individuals, 41 asthmatic patients and 28 non-asthmatic volunteers recruited from the Department of Allergology and the Allergy and Pulmonology Outpatient Clinic of N. Barlicki University Teaching Hospital No. 1 in Lodz. The participants underwent a full medical examination and spirometry, and blood samples were collected from them for serum TGF-β levels. Individual isoforms, i.e., TGF-β1, TGF-β2 and TGF-β3, were determined by ELISA. The data obtained were then subjected to statistical analysis using Student's t-test, the Mann-Whitney U-test, Fisher's t-test and Pearson's correlation method. Results: The obtained results show a significant increase in TGF-β1 and TGF-β2 levels, as well as a slight increase in TGF-β3 concentration among asthmatic patients compared to the general population. Additionally, there occurred a significant association between TGF-β1 and TGF-β2. TGF-β1 and TGF-β2 isoforms were found to be associated with the pathogenesis of asthma. Among the patients, serum TGF-β levels were significantly higher compared to the control group. Conclusions: The TGF-β1 and TGF-β2 isoforms appear to have a cumulative effect on remodeling processes in the airways. [ABSTRACT FROM AUTHOR]

Background: Tyrosine kinase inhibitors (TKIs) targeting fms-like tyrosine kinase 3 (Flt3) such as quizartinib were specifically designed for acute myeloid leukemia treatment, but also multi-targeting TKIs applied to solid tumor patients inhibit Flt3. Flt3 is expressed in the heart and its activation is cytoprotective in myocardial infarction (MI) in mice. Objectives: We sought to test whether Flt3-targeting TKI treatment aggravates cardiac injury after MI. Methods and results: Compared to vehicle, quizartinib (10 mg/kg/day, gavage) did not alter cardiac dimensions or function in healthy mice after four weeks of therapy. Pretreated mice were randomly assigned to MI or sham surgery while receiving quizartinib or vehicle for one more week. Quizartinib did not aggravate the decline in ejection fraction, but significantly enhanced ventricular dilatation one week after infarction. In addition, apoptotic cell death was significantly increased in the myocardium of quizartinib-treated compared to vehicle-treated mice. In vitro, quizartinib dose-dependently decreased cell viability in neonatal rat ventricular myocytes and in H9c2 cells, and increased apoptosis as assessed in the latter. Together with H2O2, quizartinib potentiated the phosphorylation of the pro-apoptotic mitogen activated protein kinase p38 and augmented H2O2-induced cell death and apoptosis beyond additive degree. Pretreatment with a p38 inhibitor abolished apoptosis under quizartinib and H2O2. Conclusion: Quizartinib potentiates apoptosis and promotes maladaptive remodeling after MI in mice at least in part via a p38-dependent mechanism. These findings are consistent with the multi-hit hypothesis of cardiotoxicity and make cardiac monitoring in patients with ischemic heart disease under Flt3- or multi-targeting TKIs advisable. [ABSTRACT FROM AUTHOR]

Rationale: Severe pulmonary hypertension (PH) in chronic obstructive pulmonary disease (COPD) is currently defined by an elevated mean pulmonary arterial pressure and strongly elevated pulmonary vascular resistance >5 wood units. Clinically, these patients show a male predominance, and usually present with very severe dyspnea, severe hypoxemia, strongly decreased exercise capacity and poor prognosis, even though the clinical picture is frequently associated with less severe airflow obstruction. Explanted lung samples of patients with COPD and severe PH show severe remodeling of small pulmonary arterioles, predominantly in the intima and media of the vessels. In this concise review, we discuss the clinical and histopathological evidence of severe PH in COPD.

Abstract Pulmonary hypertension (PH) arises from increased pulmonary vascular resistance due to contraction and remodeling of the pulmonary arteries. The structural changes include thickening of the smooth muscle layer from increased proliferation and resistance to apoptosis. The mechanisms underlying apoptosis resistance in PH are not fully understood. In cancer cells, high expression of aquaporin 1 (AQP1), a water channel, is associated with apoptosis resistance. We showed AQP1 protein was expressed in pulmonary arterial smooth muscle cells (PASMCs) and upregulated in preclinical PH models. In this study, we used PASMCs isolated from control male rats and the SU5416 plus hypoxia (SuHx) model to test the role of AQP1 in modulating susceptibility to apoptosis. We found the elevated level of AQP1 in PASMCs from SuHx rats was necessary for resistance to apoptosis and that apoptosis resistance could be conferred by increasing AQP1 in control PASMCs. In exploring the downstream pathways involved, we found AQP1 levels influence the expression of Bcl‐2, with enhanced AQP1 levels corresponding to increased Bcl‐2 expression, reducing the ratio of BAX to Bcl‐2, consistent with apoptosis resistance. These results provide a mechanism by which AQP1 can regulate PASMC fate.

Skeletal muscle has a unique ability to remodel in response to stimuli such as contraction and aerobic exercise training. Phenotypic changes in muscle that occur with training such as a switch to a more oxidative fiber type, and increased capillary density contribute to the well-known health benefits of aerobic exercise. The muscle matrisome likely plays an important role in muscle remodeling with exercise. However, due to technical limitations in studying muscle ECM proteins, which are highly insoluble, little is known about the muscle matrisome and how it contributes to muscle remodeling. Here, we utilized two-fraction methodology to extract muscle proteins, combined with multiplexed tandem mass tag proteomic technology to identify 161 unique ECM proteins in mouse skeletal muscle. In addition, we demonstrate that aerobic exercise training induces remodeling of a significant proportion of the muscle matrisome. We performed follow-up experiments to validate exercise-regulated ECM targets in a separate cohort of mice using Western blotting and immunofluorescence imaging. Our data demonstrate that changes in several key ECM targets are strongly associated with muscle remodeling processes such as increased capillary density in mice. We also identify LOXL1 as a novel muscle ECM target associated with aerobic capacity in humans. In addition, publically available data and databases were used for in silico modeling to determine the likely cellular sources of exercise-induced ECM remodeling targets and identify ECM interaction networks. This work greatly enhances our understanding of ECM content and function in skeletal muscle and demonstrates an important role for ECM remodeling in the adaptive response to exercise. The raw MS data have been deposited to the ProteomeXchange with identifier PXD053003.

Host remodeling of decellularized extracellular matrix (dECM) material through the appropriate involvement of immune cells is essential for achieving functional organ/tissue regeneration. As many studies have focused on the role of macrophages, only few have evaluated the role of regulatory T cells (Tregs) in dECM remodeling. In this study, we used a mouse model of traumatic muscle injury to determine the role of Tregs in the constructive remodeling of vascular-derived dECM. According to the results, a certain number of Tregs could be recruited after dECM implantation. Notably, using anti-CD25 to reduce the number of Tregs recruited by the dECM was significantly detrimental to material remodeling based on a significant reduction in the number of M2 macrophages. In addition, collagen and elastic fibers, which maintain the integrity and mechanical properties of the material, rapidly degraded during the early stages of implantation. In contrast, the use of CD28-SA antibodies to increase the number of Tregs recruited by dECM promoted constructive remodeling, resulting in a decreased inflammatory response at the material edge, thinning of the surrounding fibrous connective tissue, uniform infiltration of host cells, and significantly improved tissue remodeling scores. The number of M2 macrophages increased whereas that of M1 macrophages decreased. Moreover, Treg-conditioned medium further enhanced material-induced M2 macrophage polarization in vitro. Overall, Treg is an important cell type that influences constructive remodeling of the dECM. Such findings contribute to the design of next-generation biomaterials to optimize the remodeling and regeneration of dECM materials.

Perivascular adipose tissue (PVAT) regulates vascular function due to its capacity to synthesize vasoactive products and its mechanical properties. PVATs most abundant cells are adipocytes, and their populations are maintained by the maturation of adipocyte progenitor cells (APC), which may play a pivotal role in the pathogenesis of cardiovascular diseases. However, the distribution of APC within PVAT depots, their potential variation in spatial location, and the influence of sex and age on their abundance remain unknown. We hypothesize that APC abundance in PVAT is affected by location, age, sex and that APC subtypes have specific spatial distributions. PVAT from thoracic and abdominal aorta, and mesenteric arteries, and AT from interscapular, gonadal, and subcutaneous depots from 13-week and 30-week-old females and males Pdgfrα-CreERT2 x LSL-tdTomato mice (n = 28) were analyzed. Abdominal aorta PVAT had fewer progenitors than mesenteric PVAT and gonadal AT. Aging reduced the abundance of APC in the thoracic aorta but increased their numbers in mesenteric PVAT. Females had more APC than males in mesenteric PVAT and gonadal AT depots. APC exhibited unique spatial distribution in the aorta and mesenteric PVAT where they localized neighboring vasa vasorum and arteries. APC subtypes (APC1, APC2, APC3, diff APC) were identified in all PVAT depots. Thoracic aorta PVAT APC3 were located in the adventitia while diff APC were in the parenchyma. This study identified variability in APC populations based on depot, age, and sex. The distinctive spatial distribution and the presence of diverse APC subtypes suggest that they may contribute differently to cardiovascular diseases-induced PVAT remodeling.

Spontaneous repair and remodeling of the mandibular head of the condylar process is a rarely reported outcome following condylectomy. This clinical report describes the spontaneous repair and subsequent remodeling of the mandibular head of the condylar process in four immature dogs that sustained traumatic injuries, necessitating surgical intervention through arthroplasty via partial or complete condylectomy, or caudal mandibulectomy. In subsequent evaluations, it was observed that all dogs exhibited clinically functional TMJs, as evidenced by an appropriate range of motion. These findings were corroborated by the owners reports of the patients normal eating and drinking abilities. Conventional and cone-beam computed tomography studies demonstrated the repair and remodeling of the osseous tissues of the mandibular head of the condylar process. Histopathology was unavailable to assess the novel tissues. No evidence of intraarticular or extraarticular ankylosis or osteoarthritic changes was observed.