Biology subjects

Bhattarai, U.

Publications and source records attributed to Bhattarai, U..

4 recordsLinked to original sources

bioRxiv2026

IL27 exerts a powerful effect on systolic overload-induced cardiac inflammation, fibrosis, and heart failure development

BACKGROUNDInterleukin-27 (IL-27) is a heterodimeric cytokine that serves as a bifunctional rheostat rather than an inherently pro- or anti-inflammatory signaling protein. However, the specific role of IL-27 in regulating systolic overload-induced cardiac inflammation and heart failure (HF) pathogenesis remains unknown. METHODSWe investigated the effects of genetic IL-27 receptor deficiency (IL-27R knockout), pharmacological IL-27 blockade, and recombinant IL-27 administration on transverse aortic constriction (TAC)-induced HF in mice. RESULTSCardiac IL-27 expression was significantly elevated in both murine and human HF tissues. The global genetic ablation of the IL-27 receptor (IL-27R) significantly suppressed TAC-induced cardiac inflammation, fibrosis, hypertrophy, HF progression, and mortality. Corroborating these protective effects, transcriptomic analysis (RNA-seq) revealed that IL-27R deficiency drastically suppressed pathways driving immune responses and antigen presentation, alongside the significant downregulation of networks governing systemic inflammation, pathogen infection, and extracellular matrix remodeling. Furthermore, pharmacological neutralization of IL-27 effectively attenuated TAC-induced left ventricular dysfunction, chamber dilation, myocardial hypertrophy, fibrosis, and leukocyte infiltration. Conversely, the administration of recombinant mouse IL-27 exacerbated the TAC-induced cardiac accumulation of multiple immune cell subsets, resulting in worsened cardiac fibrosis, cardiomyocyte hypertrophy, and overall HF progression. CONCLUSIONSOur findings demonstrate that IL-27 acts as a critical pathogenic driver of cardiac inflammation and HF development by modulating both cardiac immune cells (predominantly T cells) and non-immune cells, highlighting the IL-27 signaling axis as a promising therapeutic target.

physiology↗

bioRxiv2025

Genetic inhibition of IL-12β suppresses systolic overload-induced cardiac inflammation and heart failure development

Inflammation promotes heart failure (HF) development, and inhibition of IL-12{beta} simultaneously attenuates interleukin-12 (IL-12) and interleukin-23 (IL-23), two important proinflammatory cytokines. In this study, we used IL-12{beta} knockout (KO) mice to test the hypothesis that genetic inhibition of IL-12{beta} would attenuate transverse aortic constriction (TAC)-induced cardiac inflammation, hypertrophy, and dysfunction, as well as the consequent lung remodeling. IL-12{beta} KO in male and female mice significantly attenuated TAC-induced cardiac dysfunction as evidenced by improved left ventricular (LV) ejection fraction and fractional shortening. IL-12{beta} KO also significantly ameliorated the TAC-induced increase of LV weight, left atrial weight, lung weight, right ventricular (RV) weight, and their ratios to body weight or tibial length in male and female mice. In addition, IL-12{beta} KO significantly attenuated TAC-induced LV leukocyte infiltration, cardiomyocyte hypertrophy, fibrosis, and the consequent lung inflammation and remodeling. Moreover, IL-12{beta} KO reduced TAC-induced alterations of LV gene profile associated with inflammation and fibrosis, as shown by bulk LV RNA sequencing. Furthermore, we found that IL-12{beta} KO significantly attenuated TAC-induced LV accumulation of multiple immune cell subsets, activation of CD4+ and CD8+ T cells, and the percentage of central memory CD4+ and CD8+ T cells in the cardiac drainage lymph nodes. Finally, IL-12{beta} KO mice showed significantly reduced IFN{gamma}+CD8+ and CXCR3+CD8+ T cells in the drainage lymph nodes as compared with WT after TAC. These findings collectively demonstrate that IL-12{beta} plays a critical role in systolic overload-induced LV inflammation, remodeling, and dysfunction, likely through cardiac immune cell infiltration.

physiology↗

bioRxiv2020

Integrin Affinity Modulation Critically Regulates Atherogenic Endothelial Activation in vitro and in vivo

While vital to platelet and leukocyte adhesion, the role of integrin affinity modulation in adherent cells remains controversial. In endothelial cells, atheroprone hemodynamics and oxidized lipoproteins drive an increase in the high affinity conformation of 5{beta}1 integrins in endothelial cells in vitro, and 5{beta}1 integrin inhibitors reduce proinflammatory endothelial activation to these stimuli in vitro and in vivo. However, the importance of 5{beta}1 integrin affinity modulation to endothelial phenotype remains unknown. We now show that endothelial cells (talin1 L325R) unable to induce high affinity integrins initially adhere and spread, but show significant defects in nascent adhesion formation. In contrast, overall focal adhesion number, area, and composition in stably adherent cells are similar between talin1 wildtype and talin1 L325R endothelial cells. However, talin1 L325R endothelial cells fail to induce high affinity 5{beta}1 integrins, fibronectin deposition, and proinflammatory responses to atheroprone hemodynamics and oxidized lipoproteins. Inducing the high affinity conformation of 5{beta}1 integrins in talin1 L325R cells partially restores fibronectin deposition, whereas NF-{kappa}B activation and maximal fibronectin deposition require both integrin activation and other integrin-independent signaling. In endothelial-specific talin1 L325R mice, atheroprone hemodynamics fail to promote inflammation and macrophage recruitment, demonstrating a vital role for integrin activation in regulating endothelial phenotype.

cell biology↗

bioRxiv2019

The Adaptor Protein Nck1, but not Nck2, Mediates Shear Stress-Induced Endothelial Permeability.

Alteration in hemodynamic shear stress at atheroprone sites promotes endothelial paracellular pore formation and permeability. Previously, we have reported that a peptide inhibitor to Nck prevented shear stress-induced p21 activated kinase (PAK) activation and endothelial permeability. However, the specificity of this peptide is unclear, and the role of individual Nck isoforms remain unknown. Here, we show that genetic deletion of Nck1/2 adaptor proteins significantly ameliorates shear stress induced permeability, and selective isoform depletion suggests distinct signaling mechanisms. Only Nck1 deletion significantly reduces flow-induced paracellular pore formation and permeability, whereas Nck2 depletion has no significant effects. Additionally, Nck1 reexpression, but not Nck2, restores shear stress-induced permeability in Nck1/2 knockout cells, confirming the non-compensating roles. In vivo, using the partial carotid ligation model of disturbed flow, Nck1 knockout prevented the increase in vascular permeability, as assessed by both Evans blue extravasation and leakage of plasma fibrinogen into the vessel wall. Domain swap experiments mixing SH2 (phosphotyrosine binding) and SH3 (proline rich binding) domains between Nck1 and Nck2 showed a dispensable role for SH2 domains but a critical role for the Nck1 SH3 domains in rescuing shear stress-induced endothelial permeability. Consistent with this, both Nck1 and Nck2 bind to PECAM-1 (SH2 dependent) in response to shear stress, but only Nck1 ablation interferes with shear stress-induced PAK2 activation (SH3 dependent). This work provides the first evidence that Nck1 and Nck2 play distinct roles in flow-induced vascular permeability.\n\nNew and NoteworthyThe present study shows a specific role for Nck1 in endothelial permeability in response to shear stress. Using in vitro and in vivo models, we demonstrate improvement in endothelial barrier integrity in cells subjected to disturbed flow only following Nck1 but not Nck2 deletion. Selective Nck1 inhibition may limit endothelial permeability at sites of disturbed flow to reduce atherosclerosis without affecting angiogenesis, which requires both Nck1 and Nck2 inhibition.

molecular biology↗