Oxidative Stress: A Unifying Paradigm in Hypertension

Abstract

The etiology of hypertension involves complex interactions among genetic, environmental, and pathophysiologic factors that influence many regulatory systems. Hypertension is characteristically associated with vascular dysfunction, cardiovascular remodelling, renal dysfunction, and stimulation of the sympathetic nervous system. Emerging evidence indicates that the immune system is also important and that activated immune cells migrate and accumulate in tissues promoting inflammation, fibrosis, and target-organ damage. Common to these processes is oxidative stress, defined as an imbalance between oxidants and antioxidants in favour of the oxidants that leads to a disruption of oxidation-reduction (redox) signalling and control and molecular damage. Physiologically, reactive oxygen species (ROS) act as signalling molecules and influence cell function through highly regulated redox-sensitive signal transduction. In hypertension, oxidative stress promotes posttranslational modification (oxidation and phosphorylation) of proteins and aberrant signalling with consequent cell and tissue damage. Many enzymatic systems generate ROS, but NADPH oxidases (Nox) are the major sources in cells of the heart, vessels, kidneys, and immune system. Expression and activity of Nox are increased in hypertension and are the major systems responsible for oxidative stress in cardiovascular disease. Here we provide a unifying concept where oxidative stress is a common mediator underlying pathophysiologic processes in hypertension. We focus on some novel concepts whereby ROS influence vascular function, aldosterone/mineralocorticoid actions, and immunoinflammation, all important processes contributing to the development of hypertension.

Figure 1

Oxidative stress as a unifying factor in hypertension. Prohypertensive factors, eg, angiotensin II (Ang II), endothelin-1 (ET-1), aldosterone (Aldo), and salt (Na), induce activation of NADPH oxidases (Noxs) that generate reactive oxygen species (ROS), which influence multiple systems involved in the pathophysiology of hypertension. AT1R, angiotensin II type 1 receptor, ER, endoplasmic reticulum, ETAR, endothelin-1 type A receptor; MR, mineralocorticoid receptor; TNF, tumour necrosis factor; TNFR, tumour necrosis factor receptor.

Figure 2

Transactivation of growth factor receptors (GFRs) by angiotensin II (Ang II) and endothelin-1 (ET-1), through their G protein–coupled receptors (GPCRs), stimulate NADPH oxidase (Nox)–derived reactive oxygen species (ROS) production and activation of ROS-signalling pathways that influence cardiovascular processes leading to hypertension-associated target-organ damage.