| First Author | Smolgovsky S | Year | 2023 |
| Journal | J Clin Invest | Volume | 133 |
| Issue | 24 | PubMed ID | 37874641 |
| Mgi Jnum | J:343503 | Mgi Id | MGI:7567318 |
| Doi | 10.1172/JCI171874 | Citation | Smolgovsky S, et al. (2023) Impaired T cell IRE1alpha/XBP1 signaling directs inflammation in experimental heart failure with preserved ejection fraction. J Clin Invest 133(24) |
| abstractText | 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 1alpha/X-box-binding protein 1 (IRE1alpha/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 IRE1alpha/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 IRE1alpha/XBP1 axis was a T cell signature of HFpEF. |
