Monoclonal Antibody to Marinobufagenin Downregulates TGFβ Profibrotic Signaling in Left Ventricle and Kidney and Reduces Tissue Remodeling in Salt‐Sensitive Hypertension

Abstract

Background Elevated levels of an endogenous Na/K‐ ATP ase inhibitor marinobufagenin accompany salt‐sensitive hypertension and are implicated in cardiac fibrosis. Immunoneutralization of marinobufagenin reduces blood pressure in Dahl salt‐sensitive (Dahl‐S) rats. The effect of the anti‐marinobufagenin monoclonal antibody on blood pressure, left ventricular ( LV ) and renal remodeling, and gene expression were investigated in hypertensive Dahl‐S rats. Methods and Results Dahl‐S rats were fed high NaCl (8%, HS ; n=14) or low NaCl (0.1%, LS ; n=14) diets for 8 weeks. Animals were administered control antibody (LS control antibody, LSC; HS control antibody, HSC; n=7 per group) or anti‐marinobufagenin antibody once on week 7 of diet intervention (n=7 per group). Levels of marinobufagenin, LV, and kidney mRNAs and proteins implicated in profibrotic signaling were assessed. Systolic blood pressure was elevated (211±8 versus 133±3 mm Hg, P <0.01), marinobufagenin increased 2‐fold in plasma ( P <0.05) and 5‐fold in urine ( P <0.01), LV and kidney weights increased, and levels of LV collagen‐1 rose 3.5‐fold in HSC versus LSC. Anti‐marinobufagenin antibody treatment decreased systolic blood pressure by 24 mm Hg ( P <0.01) and reduced organ weights and level of LV collagen‐1 ( P <0.01) in hypertensive Dahl salt‐sensitive rats with anti‐marinobufagenin antibody versus HSC. The expression of genes related to transforming growth factor‐β–dependent signaling was upregulated in the left ventricles and kidneys in HSC versus LSC groups and became downregulated following administration of anti‐marinobufagenin antibody to hypertensive Dahl‐S rats. Marinobufagenin also activated transforming growth factor‐β signaling in cultured ventricular myocytes from Dahl‐S rats. Conclusions Immunoneutralization of heightened marinobufagenin levels in hypertensive Dahl‐S rats resulted in a downregulation of genes implicated in transforming growth factor‐β pathway, which indicates that marinobufagenin is an activator of profibrotic transforming growth factor‐β–dependent signaling in salt‐sensitive hypertension.