Tumor Necrosis Factor Alpha Deficiency Improves Endothelial Function and Cardiovascular Injury in Deoxycorticosterone Acetate/Salt-Hypertensive Mice

It has been shown that the inflammatory cytokine tumor necrosis factor alpha (TNF alpha) plays a role in the development of hypertension and end-stage renal diseases. We hypothesize that TNF alpha contributes to endothelial dysfunction and cardiac and vascular injury in deoxycorticosterone acetate (DOCA)/salt-hypertensive mice. The wild-type or TNF alpha-deficient mice were uninephrectomized and implanted with DOCA pellet treatment for 5 weeks; the mice were given either tap water or 1% NaCl drinking water. DOCA mice developed hypertension (systolic blood pressure (SBP): 167 +/- 5 vs. 110 +/- 4 mmHg in control group, p<0.05), cardiac and vascular hypertrophy, and the impairment of endothelium-dependent relaxation to acetylcholine (EDR). TNF alpha deficiency improved EDR and lowered cardiac and vascular hypertrophy with a mild reduction in SBP (152 +/- 4 vs. 167 +/- 5 mmHg in DOCA group, p<0.05) in DOCA mice. The mRNA expressions of the inflammatory cytokines, including TNF alpha, interleukin 1 beta (IL1 beta), monocyte chemotactic protein 1 (MCP1), and monocyte/macrophage marker F4/80 were significantly increased in the aorta of DOCA-hypertensive mice; TNF alpha deficiency reduced these inflammatory gene expressions. DOCA-hypertensive mice also exhibited an increase in the vascular oxidative fluorescence intensities, the protein expressions of gp91phox and p22phox, and the fibrotic factors transforming growth factor beta and fibronectin. TNF alpha deficiency reduced oxidative stress and fibrotic protein expressions. The DOCA mice also showed a decrease in the protein expression of eNOS associated with increased miR155 expression; TNF alpha deficiency prevented a decrease in eNOS expression and an increase in miR155 expression in DOCA mice. These results support the idea that TNF alpha significantly contributes to vascular inflammation, vascular dysfunction, and injury in hypertension.