Elizabeth D Cockerham

Louisiana State University Health Sciences Center Shreveport

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Arif Yurdagul

Louisiana State University Health Sciences Center Shreveport

Oren Rom

Louisiana State University Health Sciences Center Shreveport

Christopher B. Pattillo

Louisiana State University Health Sciences Center Shreveport

Alexandra C Finney

Louisiana State University Health Sciences Center Shreveport

A. Wayne Orr

Louisiana State University Health Sciences Center Shreveport

Sandeep Das

Louisiana State University Health Sciences Center Shreveport

Nabil A. Rashdan

Louisiana State University Health Sciences Center Shreveport

Babak Razani

Washington University in St. Louis

Wanqing Liu

Shanghai University of Traditional Chinese Medicine

Dhananjay Kumar

Louisiana State University Health Sciences Center Shreveport

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Louisiana State University Health Sciences Center Shreveport

Louisiana State University Health Sciences Center New Orleans

Louisiana State University

Louisiana State University in Shreveport

University of Michigan–Ann Arbor

VA Tennessee Valley Healthcare System

The University of Texas MD Anderson Cancer Center

Michigan Medicine

Ochsner Health System

Michigan United

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

bioRxiv (Cold Spring Harbor Laboratory) (2019)

Mabruka Alfaidi Umesh Bhattarai Elizabeth D Cockerham A. Wayne Orr

Abstract 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. New and Noteworthy The 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.

Paracellular transport

Evans Blue

Vascular permeability

10.1101/651687

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Inhibition of hepatic oxalate overproduction ameliorates metabolic dysfunction-associated steatohepatitis

Nature Metabolism (2024)

Sandeep Das Alexandra C Finney Sumit Kumar Anand Sumati Rohilla Yuhao Liu

Overproduction

Steatohepatitis

Steatosis

10.1038/s42255-024-01134-4

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Abstract 684: Hepatic Oxalate Overproduction As A Driver And Therapeutic Target In NASH And Atherosclerosis

Arteriosclerosis Thrombosis and Vascular Biology (2023)

Sandeep R. Das Alexandra C Finney Dhananjay kumar Yuhao Liu Sumati Rohilla

Affecting one third of the global population, with no pharmacotherapy available, nonalcoholic fatty liver disease (NAFLD) has become the leading cause of chronic liver disease. Surprisingly, the major cause of death in patients with NAFLD, particularly in those with the more severe nonalcoholic steatohepatitis (NASH), is atherosclerotic cardiovascular disease (CVD). Thus, there is a critical need to identify targetable pathways for concurrent treatment of NASH and atherosclerotic CVD, which has been hampered by limited understanding of the pathophysiology and metabolic pathways linking these two diseases. Recently, we and others uncovered oxalate metabolism commonly dysregulated in NAFLD and CVD. Using unbiased transcriptomics, we identified suppression of genes that limit oxalate production in livers from humans and mice with NASH. Alanine-glyoxylate aminotransferase (AGXT), a liver-specific enzyme that detoxifies glyoxylate, the oxalate precursor, was reduced and oxalate was markedly increased in correlation with NASH severity. Remarkably, oxalate was also increased both in patients and mice with atherosclerosis. In our mouse models of hepatic oxalate overproduction ( Agxt -/- and Agxt -/- / Apoe -/- ), both NASH and atherosclerosis were increased with suppressed hepatic fatty acid β-oxidation (FAO) and induction of proinflammatory pathways. In hepatocytes, oxalate induced mitochondrial dysfunction and lipid accumulation while downregulating peroxisome proliferator-activated receptor α (PPARα), inhibiting FAO and upregulating C-C motif chemokine ligand 5 (CCL5). Importantly, limiting hepatic oxalate production via hepatocyte-specific overexpression of AGXT (AAV8-TBG-AGXT) reduced NASH and atherosclerosis in mice by stimulating FAO and attenuating proinflammatory responses. Together, our findings uncover hepatic oxalate overproduction as a dysregulated metabolic pathway linking NASH and atherosclerotic CVD, highlighting the potential of oxalate reduction for concurrent treatment of these two prominent diseases.

Proinflammatory cytokine

10.1161/atvb.43.suppl_1.684

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