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Impaired T cell IRE1α/XBP1 signaling directs inflammation in experimental heart failure with preserved ejection fraction.
- Source :
-
The Journal of clinical investigation [J Clin Invest] 2023 Dec 15; Vol. 133 (24). Date of Electronic Publication: 2023 Dec 15. - Publication Year :
- 2023
-
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.
- 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
Subjects
Details
- Language :
- English
- ISSN :
- 1558-8238
- Volume :
- 133
- Issue :
- 24
- Database :
- MEDLINE
- Journal :
- The Journal of clinical investigation
- Publication Type :
- Academic Journal
- Accession number :
- 37874641
- Full Text :
- https://doi.org/10.1172/JCI171874