1. Impaired T cell IRE1a/XBP1 signaling directs inflammation in experimental heart failure with preserved ejection fraction.
- Author
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Smolgovsky, Sasha, Bayer, Abraham L., Kaur, Kuljeet, Sanders, Erin, Aronovitz, Mark, Filipp, Mallory E., Thorp, Edward B., Schiattarella, Gabriele G., Hill, Joseph A., Blanton, Robert M., Cubillos-Ruiz, Juan R., and Alcaide, Pilar
- Subjects
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T cells , *HEART failure , *VENTRICULAR ejection fraction , *UNFOLDED protein response , *CELL communication - Abstract
Heart failure with preserved ejection fraction (HFpEF) is a widespread syndrome with limited therapeutic options and poorly understood immune pathophysiology. Using a 2-hit preclinical model of cardiometabolic HFpEF that induces obesity and hypertension, we found that cardiac T cell infiltration and lymphoid expansion occurred concomitantly with cardiac pathology and that diastolic dysfunction, cardiomyocyte hypertrophy, and cardiac phospholamban phosphorylation were T cell dependent. Heart-infiltrating T cells were not restricted to cardiac antigens and were uniquely characterized by impaired activation of the inositol-requiring enzyme 1a/X-box-binding protein 1 (IRE1a/XBP1) arm of the unfolded protein response. Notably, selective ablation of XBP1 in T cells enhanced their persistence in the heart and lymphoid organs of mice with preclinical HFpEF. Furthermore, T cell IRE1a/XBP1 activation was restored after withdrawal of the 2 comorbidities inducing HFpEF, resulting in partial improvement of cardiac pathology. Our results demonstrated that diastolic dysfunction and cardiomyocyte hypertrophy in preclinical HFpEF were T cell dependent and that reversible dysregulation of the T cell IRE1a/XBP1 axis was a T cell signature of HFpEF. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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