1. Impaired T cell IRE1[alpha]/XBP1 signaling directs inflammation in experimental heart failure with preserved ejection fraction
- Author
-
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
Cardiac output -- Measurement -- Health aspects ,Antigens -- Testing ,Heart failure -- Risk factors -- Prevention ,Physiology, Pathological -- Analysis ,Health care industry - 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 1[alpha]/X-box-binding protein 1 (IRE1[alpha]/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 IRE1[alpha]/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 IRE1[alpha]/ XBP1 axis was a T cell signature of HFpEF., Introduction Widely regarded as the greatest unmet need in cardiovascular medicine, heart failure with preserved ejection fraction (HFpEF) is a complex and heterogeneous syndrome accounting for roughly 50% of HF [...]
- Published
- 2023
- Full Text
- View/download PDF