Akash Gupta, Nahla Zaghloul, Senthil Kumar Thulasingam, Ian Richard Robbins, Geetanjali Gupta, Jad Bader, Joe Gn Garcia, Mohamed Ahmed
University of Arizona. University of Florida.
United States
Translational Research
Transl Res 2025;
DOI: 10.1016/j.trsl.2025.02.001
Abstract
ChAT-expressing T cells represent ∼0.01% of total circulating T lymphocytes in adult wild-type mice. However, we previously reported that systemic infusion of ChAT+ve Jurkat T cells into adult mice elicits vasodilation and instantaneous decline in the mean systolic blood pressure, suggesting potential as a biologic therapeutic to attenuate pathologic increases in pulmonary arterial pressures. We now report that ChAT gene-expressing Jurkat cells dose-dependently decrease right ventricular systolic pressures (RVSP) in hypoxic mice and that transgenic mice with ChAT KO restricted to endothelial cells (KO END/ChAT-/-) exhibit significantly elevated pulmonary arterial pressure and peripheral systemic resistance (compared to WT mice). To rigorously characterize the role of CD4 ChAT+ T cells in regulating pulmonary arterial hypertension (PAH) hemodynamics and molecular signatures, we infused CD4+ ChAT+ve cells (0.5 to 2.0 million cells/animal) into adult PAH mice and noted significant reductions in RVSP within 2-3 minutes post injection (∼ 50% reduction). The tailored tail vein injection effect was sustained until the animal was euthanized (30-40 min). Mice KO END/ChAT-/-showed a significant and severe hypoxia-induced PAH phenotype compared to WT adult mice. Tail vein injection of biologically active CD4 ChAT+ve cells into either KO END/ChAT-/-mice with hypoxia-induced PAH or into adult rats with hypoxia/Sugen-induced PAH resulted in significant attenuation of RVP elevations. RNA seq data analysis of human pulmonary endothelial cells (HPAECs) incubated with CD4 ChAT+ve T cells showed significant differential regulation of pathways involved in systemic and pulmonary pressure regulation, NO synthesis/regulation, antioxidant expression, and vasodilation. In conclusion, CD4 ChAT+ve T cells have a unique, vasodilating innate immunity mechanism to augment nitric oxide release and potentially mitigate molecular and genetic pathways involved in PAH pathogenesis.
Category
Animal Models of Pulmonary Vascular Disease and Therapy
Class III. Pulmonary Hypertension Associated with Alveolar Hypoxia
Class I. Drug-induced and Toxin-induced Pulmonary Hypertension
Medical Therapy. Efficacy or Lack of Efficacy
Age Focus: No Age-Related Focus
Fresh or Filed Publication: Fresh (PHresh). Less than 1-2 years since publication
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