Astrocytic glutamate transporter loss drives chemoreflex hyperactivity and cardiorespiratory dysfunction in a heart failure model

Esteban Diaz-Jara; Sinay C. Vicencio; Katherin V. Pereyra; Karla G. Schwarz; Fernando C. Ortiz; Camilo Toledo; Ignacio Bernal-Santander; Sandeep Kaur; Bisan El Dakkak; Rodrigo Del Rio

doi:10.1172/JCI203834

Astrocytic glutamate transporter loss drives chemoreflex hyperactivity and cardiorespiratory dysfunction in a heart failure model

Esteban Diaz-Jara,¹ Sinay C. Vicencio,¹ Katherin V. Pereyra,¹ Karla G. Schwarz,¹ Fernando C. Ortiz,² Camilo Toledo,³ Ignacio Bernal-Santander,¹ Sandeep Kaur,³ Bisan El Dakkak,³ and Rodrigo Del Rio¹

Published October 20, 2026 - More info

View PDF

Abstract

Heart failure (HF) is a leading cause of morbidity and mortality worldwide. Breathing instability and exaggerated chemoreflex activation contribute to adverse HF outcomes, yet the central mechanisms linking respiratory control to cardiac dysfunction remain poorly defined. The retrotrapezoid nucleus (RTN) is a key brainstem chemosensory region regulating ventilatory and autonomic output, but whether glial dysfunction within this circuit contributes to HF pathophysiology is unknown. We hypothesized that loss of astrocytic glutamate transporter 1 (GLT-1) in the RTN disrupts glutamate homeostasis, producing chemoreflex hyperactivity and cardiorespiratory dysfunction in HF. In a rat model of nonischemic HF, reduced astrocytic GLT-1 expression in the RTN was accompanied by extracellular glutamate accumulation and heightened excitability of chemosensitive neurons. These changes were associated with exaggerated central chemoreflex responses, breathing instability, autonomic imbalance, and impaired cardiac function. Astrocyte-specific GLT-1 restoration normalized RTN glutamate levels, reduced central chemoreceptor neuron hyperexcitability, stabilized breathing, and improved cardiac performance. Systemic riluzole, an FDA-approved glutamate-modulating drug, similarly reduced RTN glutamate accumulation and attenuated chemoreflex-driven respiratory instability. These findings identify loss of astrocytic GLT-1-mediated glutamate homeostasis in the RTN as a mechanism contributing to cardiorespiratory dysfunction in HF and support pharmacological targeting of brainstem glutamate homeostasis as a therapeutic strategy requiring further investigation.

Astrocytic glutamate transporter loss drives chemoreflex hyperactivity and cardiorespiratory dysfunction in a heart failure model

Esteban Diaz-Jara,¹ Sinay C. Vicencio,¹ Katherin V. Pereyra,¹ Karla G. Schwarz,¹ Fernando C. Ortiz,² Camilo Toledo,³ Ignacio Bernal-Santander,¹ Sandeep Kaur,³ Bisan El Dakkak,³ and Rodrigo Del Rio¹

Article tools

Metrics

Go to

Astrocytic glutamate transporter loss drives chemoreflex hyperactivity and cardiorespiratory dysfunction in a heart failure model

Esteban Diaz-Jara,1 Sinay C. Vicencio,1 Katherin V. Pereyra,1 Karla G. Schwarz,1 Fernando C. Ortiz,2 Camilo Toledo,3 Ignacio Bernal-Santander,1 Sandeep Kaur,3 Bisan El Dakkak,3 and Rodrigo Del Rio1

Article tools

Metrics

Go to

Sign up for email alerts

Esteban Diaz-Jara,¹ Sinay C. Vicencio,¹ Katherin V. Pereyra,¹ Karla G. Schwarz,¹ Fernando C. Ortiz,² Camilo Toledo,³ Ignacio Bernal-Santander,¹ Sandeep Kaur,³ Bisan El Dakkak,³ and Rodrigo Del Rio¹