1. Impaired T cell IRE1α/XBP1 signaling directs inflammation in experimental heart failure with preserved ejection fraction.
- Author
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Smolgovsky S, Bayer AL, Kaur K, Sanders E, Aronovitz M, Filipp ME, Thorp EB, Schiattarella GG, Hill JA, Blanton RM, Cubillos-Ruiz JR, and Alcaide P
- Subjects
- Animals, Mice, Endoribonucleases genetics, Endoribonucleases metabolism, Hypertrophy, Inflammation, Protein Serine-Threonine Kinases genetics, Protein Serine-Threonine Kinases metabolism, Stroke Volume physiology, T-Lymphocytes pathology, X-Box Binding Protein 1 genetics, X-Box Binding Protein 1 metabolism, Cardiomyopathies genetics, Cardiomyopathies metabolism, Heart Failure metabolism
- 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 1α/X-box-binding protein 1 (IRE1α/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 IRE1α/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 IRE1α/XBP1 axis was a T cell signature of HFpEF.
- Published
- 2023
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