Increased Levels of Plasma Soluble Sema4D in Patients with Heart Failure

Abstract

Semaphorin 4D (Sema4D/CD100) is a 150-kDa transmembrane glycoprotein expressed by platelets and T-cells. When these cells are activated, Sema4D is cleaved proteolytically, generating a biologically active 120-kDa fragment (soluble Sema4D) capable of targeting receptors on platelets, B-cells, endothelial cells and tumor cells. However, its plasma levels and significance in heart failure (HF) have not been reported. In this study, we established an ELISA and detected soluble Sema4D in human plasma. In healthy controls, plasma Sema4D levels were higher in men than women (5.15±3.30 ng/mL, n = 63, vs. 4.19±2.39 ng/mL, n = 63, P<0.05). In HF patients, plasma Sema4D levels were significantly higher than those in healthy controls (8.94±5.89 ng/mL, n = 157 vs. 4.67±2.99 ng/mL, n = 126, P<0.0001) with the highest levels being in HF patients with diabetes mellitus (DM) (10.45±5.76 ng/mL, n = 40). We also found that there was a higher percentage of Sema4Dhigh CD3+ (P<0.01), CD4+ (P<0.001), and CD8+ (P<0.01) T-cells in samples from HF patients, but no changes in Sema4D expression levels in B cells and platelets. Therefore, our investigation shows that plasma Sema4D levels are increased in HF patients, especially in those who also have diabetes. There was an accompanying increase in the Sema4Dhigh population of T-cells, suggesting a potential role of these T-cells in heart failure.

Netrins & Semaphorins: Novel regulators of the immune response

“…In addition to regulating the B cell response by mitigating CD72 inhibitory signals allowing downstream BCR signaling to proceed [38, 45, 46], these mice manifested improved T-cell responses [47]. Consistent with these observations, serum levels of soluble Sema4D positively correlated with increased CD3+, CD4+ and CD8+ cells in a clinical cohort of patients suffering from heart failure [48]. These sets of data were compelling as they further evidenced the similarity between the highly patterned and circulating signaling mediators in both the nervous and immune systems.…”

Semaphorin 4D levels in heart failure patients: a potential novel biomarker of acute heart failure?

“…To the best of our knowledge, the only previous study that addressed the issue of Sema4D and HF is that of Lu et al . The researchers demonstrated elevated plasma levels of Sema4D in HF patients compared with healthy controls.…”

“…Second, in our study, diabetes mellitus was not found to influence Sema4D levels. Third, Lu et al . gave no details regarding patients' kidney function, while according to our study, Sema4D is highly dependent on creatinine levels.…”

“…The pathogenesis of the disease involves inflammatory aspects, neuro‐hormonal changes, and biomechanical alterations . Lu et al . showed that in HF patients, plasma Sema4D levels were significantly higher than those in healthy controls, with the highest levels being in HF patients with diabetes mellitus.…”

“…Activated Sema4D influences immune system cells' migration, B-cell (CD40) proliferation, and cytokine and immunoglobulin production. 6 Elevated serum levels of Sema4D are related to chronic inflammatory diseases, 7,8 malignancy, 9,10 and arrhythmias (i.e. atrial fibrillation).…”