Nrf2 y KV1.3, nuevos mediadores de la inflamación y el daño cardiovascular asociado a hipertensión

Abstract

Hypertension is one of the main predisposing risk factors for various cardiovascular diseases, such as ischemic heart disease, stroke, and kidney failure, which are the main cause of death in the world. Hypertension is considered a chronic inflammatory disease with elevated levels of proinflammatory cytokines and enzymes, in addition to accumulation of inflammatory cells at vascular level and in other tissues, which induce the production of reactive oxygen species (ROS), leading to oxidative stress; these processes participate in the development of the functional and structural alterations of the heart and vasculature that characterize hypertension, among others endothelial dysfunction, vascular stiffness or vascular and cardiac remodeling. KV1.3 voltage-dependent potassium channels are involved in the regulation of immune and vascular smooth muscle cells (VSMC) function and proliferation, so they are postulated to account for the inflammation or oxidative stress associated with hypertension. Furthermore, their involvement in VSMC proliferation may play a role in vascular remodeling in the hypertensive pathology. Therefore, in the first chapter of this Doctoral Thesis we study the participation of KV1.3 channels in the development of hypertension and the associated inflammatory state and vascular alterations. As mentioned, oxidative stress is an important mediator of the cardiovascular alterations that occur in hypertension; therefore, the mechanisms involved in maintaining redox balance can contribute to reduce the deleterious effects caused by ROS. Among these mechanisms, highlights the nuclear factor Nrf2 (Nuclear Factor Erythroid 2-related factor-2), an oxidative stress sensitive transcription factor which activation induces antioxidant and anti-inflammatory effects, then improving the alterations observed in hypertension. The second chapter of this Doctoral Thesis evaluates the participation of Nrf2 in hypertension as well asin the inflammatory state, oxidative stress and cardiovascular alterations that occur in the hypertensive pathology. Hypertension is a high prevalence disease. Among diagnosed hypertensive patients under pharmacological treatment, only 30-35% of them have the blood pressure under control; then, development of new drugs for the treatment of hypertension and the reduction of end organ damage is necessary. ITH13001 is a new melatonin-derived compound with Nrf2-inducing activity, as well as antioxidant properties independent of this induction. In the third chapter of this Doctoral Thesis, the effect of ITH13001 on hypertension and the associated cardiovascular alterations is analyzed. The main objective of this work has been to study the involvement of KV1.3 and Nrf2 in the cardiovascular damage associated with hypertension and their contribution to the oxidative stress and inflammation that occur in this pathology. For this purpose, we performed experiments in C57BL/6J hypertensive mice by infusion with angiotensin II (Ang II, 1.44 mg/kg/day, 14 days). Specifically, three different models were used: 1) mice treated with the selective KV1.3 channel blocker HsTX[R14A] (100 µg/Kg/ every second day, sc), 2) Nrf2-deficient mice, and 3) mice treated with ITH13001 (1 mg/Kg/día, ip). Changes in vascular function and mechanical properties, vascular and cardiac structure, as well as the underlying molecular mechanisms were studied.