dc.description.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. | es |