TLR4 is a critical regulator of angiotensin II-induced vascular remodeling: the roles of extracellular SOD and NADPH oxidase

Abstract

Toll-like receptor 4 (TLR4) and angiotensin II (AngII) induce vascular remodeling through the production of reactive oxygen species (ROS). AngII has also been shown to increase antioxidant enzyme extracellular superoxide dismutase (ecSOD). However, the roles of TLR4 in Ang II-induced ROS production, vascular remodeling and hypertension remain unknown. Mice lacking TLR4 function showed significant inhibition of vascular remodeling in response to chronic AngII infusion, with no impact on blood pressure. The increases in ROS level and NADPH oxidase activity in response to AngII infusion were markedly blunted in TLR4-deficient mice. Similar effects were observed in wild-type (WT) mice treated with a sub-depressor dose of the AT1 receptor antagonist irbesartan, which had no effects on TLR4-deficient mice. Intriguingly, the AngII infusion-induced increases in ecSOD activity and expression were rather enhanced in TLR4-deficient mice compared with WT mice, whereas the expression of the proinflammatory chemokine MCP-1 was decreased. Importantly, AngII-induced vascular remodeling was positively correlated with NADPH oxidase activity, ROS levels and MCP-1 expression levels. Notably, chronic norepinephrine infusion, which elevates blood pressure without increasing ROS production, did not induce significant vascular remodeling in WT mice. Taken together, these findings suggest that ROS elevation is required for accelerating vascular remodeling but not for hypertensive effects in this model. We demonstrated that TLR4 plays a pivotal role in regulating AngII-induced vascular ROS levels by inhibiting the expression and activity of the antioxidant enzyme ecSOD, as well as by activating NADPH oxidase, which enhances inflammation to facilitate the progression of vascular remodeling.

Telmisartan improves vascular remodeling through ameliorating prooxidant and profibrotic mechanisms in hypertension via the involvement of transforming growth factor-β1

“…As reported previously, AT1 inhibitor notably attenuates aortic remodeling in diabetic rats with involvement of the TGF-β1/Smads-associated profibrotic pathway ( 33 ). In addition, inhibiting Ang II-induced vascular ROS effectively prevents vascular remodeling ( 34 , 35 ). Accordingly, drugs inhibiting AT1 or combined with antioxidant effects may have a higher capacity to decrease the expression of TGF-β1 and prevent vascular remodeling.…”

Coronary microvascular disease as an early culprit in the pathophysiology of diabetes and metabolic syndrome

“…Indeed, studies from our laboratory demonstrate that AngII/AT 1 R activation may contribute to the vascular remodeling observed in T2D (11). Additionally, this AT 1 R-mediated activation of the VSMC by pro-inflammatory signaling may contribute to remodeling present in metabolic diseases (75, 76). …”

MD2 Blockage Protects Obesity‐Induced Vascular Remodeling via Activating AMPK/Nrf2

“…Oxidative stress mediates diverse pathophysiological events in vascular cells and contributes to many of the abnormalities associated with vascular disease. It is now clear that reactive oxygen species (ROS) can be produced by all vascular cells with the stimulus of mechanical stress, angiotensin II, or FFAs , which in turn causes vascular cell injury, inflammation, and dysfunction. On the other hand, cells defend against oxidative stress and injury by activating antioxidation signaling proteins, including nuclear factor erythroid 2 (Nrf2) .…”