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American Heart Association

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Final ID: Tu043

Gut Microbial Metabolite Phenylacetylglutamine Leads to Cardiomyocyte Hypercontractility and Vascular Endothelial Cell Activation

Abstract Body: Background: Numerous gut microbial metabolites including phenylacetylglutamine (PAGln) are associated with increased cardiovascular disease risk and mortality. However, little is known about the cellular-specific perturbations by which PAGln may drive cardiovascular dysfunction.

Aims: To understand if elevated PAGln leads to cardiovascular dysfunction and what direct cardiac- and vascular-specific pathophysiology is occurring.

Methods: Herein, we subject C57Bl/6N male mice to pharmacological increases in circulating PAGln (50mg/kg) or vehicle twice daily for 20 days. We performed echocardiography, invasive hemodynamics, and vascular reactivity assays. We also performed ex vivo cardiomyocyte cell physiology experiments in the presence or absence of PAGln. Moreover, to understand vascular effects we subjected endothelial cells to PAGln and looked at expression of proinflammatory and cell adhesion molecules.

Results: We first performed LC-MS/MS analysis demonstrating significant elevation in PAGln levels in multiple tissues compared to vehicle. There was no significant alteration in cardiac structure and function through echocardiographic analysis. Invasive hemodynamic assessment of systemic blood pressure showed no change, however left ventricular filling pressures were significantly elevated in PAGln group. Aortic rings subjected to varying concentrations of acetylcholine in the PAGln-treated animals were significantly impaired compared to vehicle controls. Given the elevated filling pressures and aberrant vascular endothelial relaxation we measured nitrite levels. Nitrite was significantly reduced in the plasma, cardiac, and liver tissue in PAGln group. Cardiomyocyte fractional shortening was significantly increased compared to baseline and equivalent to b-adrenergic agonism. PAGln hypercontractility was not inhibited with adrenergic antagonism. Vascular endothelial cells which were exposed to PAGln had an increase in expression of proinflammatory and cell adhesion molecules versus vehicle.

Conclusion: Our data demonstrates that PAGln drives cardiovascular dysfunction through cardiomyocyte hypercontractility and inducing vascular coronary endothelial cell activation in vitro.
  • Li, Zhen  ( Cedars-Sinai Medical Center , Los Angeles , California , United States )
  • Zaparte, Aline  ( LSUHSC-NO , New Orleans , Louisiana , United States )
  • Fu, Xiaoming  ( Cleveland Clinic , Cleveland , Ohio , United States )
  • Li, Xinmin  ( Cleveland Clinic , Cleveland , Ohio , United States )
  • Wong, David  ( UCLA , Los Angeles , California , United States )
  • Gibson, Aaron  ( CINCINNATI CHILDRENS HOSPITAL , Cincinnati , Ohio , United States )
  • Gorse, Kiersten  ( University of South Florida , Tampa , Florida , United States )
  • Wong, Zeneng  ( CLEVELAND CLINIC FOUNDATION , Cleveland , Ohio , United States )
  • Hazen, Stanley  ( CLEVELAND CLINIC FOUNDATION , Cleveland , Ohio , United States )
  • Lefer, David  ( Cedars-Sinai Medical Center , Los Angeles , California , United States )
  • Quijada, Pearl  ( UCLA , Los Angeles , California , United States )
  • Makarewich, Cat  ( CINCINNATI CHILDRENS HOSPITAL , Cincinnati , Ohio , United States )
  • Sharp, Thomas  ( University of South Florida , Tampa , Florida , United States )
  • Author Disclosures:
    Zhen Li: No Answer | David Lefer: DO NOT have relevant financial relationships | Pearl Quijada: DO NOT have relevant financial relationships | Cat Makarewich: DO NOT have relevant financial relationships | Thomas Sharp: DO NOT have relevant financial relationships | Aline Zaparte: DO NOT have relevant financial relationships | Xiaoming Fu: No Answer | Xinmin Li: No Answer | David Wong: No Answer | aaron gibson: No Answer | Kiersten Gorse: No Answer | Zeneng Wong: No Answer | Stanley Hazen: DO have relevant financial relationships ; Royalties/Patent Beneficiary:Cleveland Clinic:Active (exists now) ; Research Funding (PI or named investigator):Procter & Gamble:Past (completed) ; Research Funding (PI or named investigator):Zehna Therapeutics:Active (exists now) ; Consultant:Procter & Gamble:Active (exists now) ; Consultant:Zehna Therapeutics:Active (exists now) ; Royalties/Patent Beneficiary:Procter & Gamble:Active (exists now) ; Royalties/Patent Beneficiary:Quest Diagnostics:Active (exists now)
Meeting Info:

Basic Cardiovascular Sciences

2024

Chicago, Illinois

Session Info:

Poster Session and Reception 2

Tuesday, 07/23/2024 , 04:30PM - 07:00PM

Poster Session and Reception

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