Proinflammatory T Cells with Downregulated Unfolded Protein Response Genes Contribute to Experimental Heart Failure with Preserved Ejection Fraction (HFpEF)

Introduction Heart Failure with Preserved Ejection Fraction (HFpEF) is an uncurable widespread syndrome characterized by impaired cardiac relaxation (diastolic function), preserved cardiac contractility (systolic function), and the concordance of several comorbidities, such as obesity and hypertension. While T cell inflammation is known to contribute to HF with reduced cardiac contractility (HF with reduced EF), whether T cell inflammation occurs in HFpEF remains elusive. Recently, downregulation of the unfolded protein response (UPR) in cardiomyocytes was identified as a cardiometabolic HFpEF-unique molecular signature. Interestingly, downregulation of the UPR has been reported to improve T cell anti-tumor inflammatory responses. We hypothesized T cells contribute to diastolic dysfunction in HFpEF following T cell UPR downregulation in response to metabolic and nitrosative stress. Methods We modeled cardiometabolic HFpEF in male C57/Bl6 (WT), Nur77-GFP mice, reporter mice for T cell antigen engagement, and T cell receptor-a (Tcra−/−) mice using high-fat diet (HFD) and L-NAME-supplemented drinking water to mimic obesity and hypertension, respectively. Mice fed standard chow (STD) were used as controls. Invasive hemodynamic analyses were used to measure cardiac function. Immune populations in the heart, mediastinal lymph nodes (MdLN), and spleen were characterized using flow cytometry. CD4+ T cells from MdLN and spleen were isolated using magnetic-assisted cell sorting, and UPR gene expression was assessed using qPCR. Results We observed significant increases in cardiac CD4+ T cells in WT mice fed HFD/L-NAME, concordant with diastolic dysfunction and preserved EF, compared to STD mice. We found increased effector CD4+CD62LloCD44hiIFNγ+ T cells in spleens and MdLN isolated from WT HFD/L-NAME mice compared to STD controls. Nur77-GFP mice revealed no antigen recognition by CD4+ T cells in the heart following HFD/L-NAME. Tcra−/−mice fed HFD/L-NAME did not develop diastolic dysfunction or cardiomyocyte hypertrophy. Strikingly, qPCR analysis of splenic T cells of WT HFD/L-NAME mice revealed significantly decreased expression of spliced X box-binding protein 1 (XBP1s), compared to controls, with no significant changes in unspliced XBP1 or activating transcription factor 4 (ATF4). ATF6 and C/EBP homologous protein (CHOP) gene expression was also reduced compared to T cells from control mice. Conclusion Our data demonstrate that diastolic dysfunction and cardiomyocyte hypertrophy are T cell dependent in preclinical cardiometabolic HFpEF and reveal downregulation of two branches of the T cell UPR as a potential novel mechanism that contributes to T cell inflammation in HFpEF.