Abstract 1106: TNF-α Blockade Prevents Mitochondrial Dysfunction in the Heart and Attenuates Hypertensive Response in Salt Sensitive Hypertensive Rats
Recent studies suggest that the hypertension induced end organ damage is due to an imbalance in the reactive oxygen species production and antioxidant defense. In this study, we demonstrate that tumor necrosis factor-alpha modulates hypertensive response and contributes to mitochondrial damage in the heart of salt sensitive Dahl Rapp (SS+8% Nacl) rats. Method: The groups include:
normal salt (control)
SS+ Nacl +Apocyanin (APO) for 5 weeks.
Mean arterial pressure (MAP) was measured by tail cuff method. The left ventricular (LV) function was measured using echocardiography at baseline and at 5 week. Subsequently, rats sacrificed the LV tissue was removed for gene expression studies and mitochondrial structural integrity study using swelling assay and Western blot. The antioxidant status in the mitochondria and tissue were measured using enzymatic assay.
Results: Compared to control, in the SS+Nacl group there was a significant increase in MAP (118±9.4 vs 157± 12.8, 5th wk values), increased cardiac dysfunction, hypertrophy LV. It also showed increased mitochondrial damage, with a decrease in the mitochondrial membrane protein expression of adenine nucleotide translocase, VDAC and a depleted SOD2 activity. These rats also showed increased superoxide production (DHE staining) and an increase in NADPH oxidase subunits (gp91phox and its homologue, Nox1 and Nox4) in the LV tissue. In contrast, in the SS+Nacl+ETN, treatment decreased MAP (120± 9.8), attenuated cardiac dysfunction, prevented mitochondrial damage, restored mitochondrial membrane proteins, and decreased the NADPH oxidase subunits. In the SS+Nacl+APO group, there was similar decrease in MAP (106 ± 11.2), mitochondrial membrane restored, NADPH oxidase subunits decreased and SOD activity improved. These results suggests that in salt sensitive hypertension, there a induction of TNF-α and this causes an increase in the production of superoxide by NADPH oxidase and contributes to hypertension, and end organ damage.
Conclusion: Tumor necrosis factor-alpha contributes to salt sensitive hypertension by increasing blood pressure and inducing end organ damage by affecting the structural integrity of mitochondrial membrane and antioxidant status.