Colten Rowan

Introduction. Hypertension is defined as blood pressure greater than or equal to 140/90 mmHg and occurs in 25-43% of the global population older than 18 yr¹. In the vast majority of patients, the explicit etiology is unknown and is defined as primary or essential hypertension¹. Despite advances in medical therapy, primary hypertension remains uncontrolled in 8-12% of patients and remains a major risk factor for stroke, heart failure, renal failure, and atherosclerosis^1,2. Persistent immune system activation has been established as an important factor in the pathogenesis of primary hypertension³. T Regulatory cells (Tregs) suppress the innate and adaptive immune response through the secretion of the suppressive cytokine IL-10^4,5. Naïve CD4+ T cells can be induced into T regulatory cells through the presence of H₂S, which has been shown to have antihypertensive effects⁵. Cystathionine Gamma Lyase (CSE) is a H₂S-generating enzyme expressed basally in naïve CD4+ T-Cells⁵. As such, CSE may be a viable target in the treatment of hypertension through the proliferation and differentiation of Tregs⁵. Methods. CD4+ T cells were isolated from spleens of mice, then Tregs were differentiated with or without TGF-β comparing the application of a CSE inhibitor with the overexpression of CSE⁵. H₂S release from isolated lymphocytes of NTN and patients with untreated hypertension or with treated HTN was measured by methylene blue assay⁵. H₂S production changes were measured across heart, aorta, kidney and liver tissue homogenates upon administration of a CSE small molecule agonist, Norswertianolin⁶. Blood pressure changes were tracked over 8 weeks in spontaneously hypertensive rats following IV administration of Norswertianolin⁶. T Regulatory cells were adoptively transferred into CSE knockout mice and blood pressure changes were compared against T Effector Cell adoptive transfer⁵. Results. CSE inhibition reduced Treg differentiation in the presence of TGF-β, while CSE overexpression enhanced Treg differentiation with or without TGF-β⁵. H₂S production from lymphocytes was decreased in untreated patients, but recovered in patients with BP control⁵. Norswertianolin increased H₂S production in the heart, aorta, and kidney⁶. Norswertianolin administration decreased systolic BP of spontaneously hypertensive rats at 2 weeks, continuous to 8 weeks as measured by tail artery BP⁶. Adoptive transfer of Tregs to CSE knockout mice lowered sBP (10 mm Hg) and dBP (9 mm Hg) under physiological conditions and reduced sBP (20 mm Hg) and dBP (16 mm Hg) induced by AngII as compared with T effector cell transfer⁵. Conclusion. CSE generates H₂S endogenously in naïve CD4+ T Cells, which can induce T Regulatory Cell differentiation and proliferation. Small molecule CSE agonists such as Norswertianolin can induce CSE activity, which may be a potential therapeutic target in the treatment of hypertension.

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