Mitochondrial ROS in the prohypertensive immune response

Abstract

In the past decade, it has become clear that reactive oxygen species (ROS) and inflammation play an important role in the development of hypertension. Scavenging of mitochondrial superoxide and blocking either IL-17 or tumor necrosis factor-␣ (TNF-␣) attenuates hypertension. T-cells, critical for development of hypertension, once activated intensively produce cytokines, proliferate, and differentiate. Thus T-cell activation leads to expanded energy demand. To fulfill these needs, T-cells through tightly regulated mechanisms, supported by mitochondrial ROS (mtROS), alter their metabolic phenotype. In this review we summarize data and show evidence supporting new concept that mtROS directly contributes to prohypertensive response of immune cells.hypertension; mitochondrial ROS; T cells; immune cell activation; superoxide HYPERTENSION is a multifactorial pathological condition that includes genetic, environmental, neural, endocrine, and humoral causes. In the past decade it has become clear that reactive oxygen species (ROS) and the immune system contribute to all of these factors (4). Phagocytic NADPH oxidase (Nox2) and mitochondria are two key ROS sources in immune cells. Nox2 plays an important role in immune cell regulation, and blocking its expression or its activity reduces cytokine production and cell proliferation. Mitochondria contribute to Nox2 activation (2), regulation of cellular glycolysis, and antigen-specific expansion of T-cells (9). The underlining precise mechanisms, however, are not clear.T-cells are critical for hypertension (5); however, the exact mechanism of T-cell activation in hypertension has not been fully understand. Once activated, T-cells intensively proliferate, produce cytokines that further stimulate immune system, alter vascular function, and stimulate ROS production. Mitochondrial ROS (mtROS) regulates cellular signaling, cell functions, and metabolism. It controls major mitochondrial and cytoplasmic metabolic pathways, such as glycolysis and the citric acid cycle (Krebs cycle). Rapidly proliferating cells, including immune cells, may rely on glycolysis to fulfill growing energy needs. To trigger changes in metabolism, cells increase ROS and through tightly regulated mechanisms alter metabolic phenotype. Cellular sources of ROS are also required for immune cell activation and their responses. Knocking down in T-cells p47 phox, a NOX2 subunit, prevents tumor necrosis factor-␣ (TNF-␣) production, a cytokine that is critical for the development of hypertension (5). Inhibition of TNF-␣ mutes hypertension; thus, scavenging ROS in immune cells may attenuate their prohypertensive responses. Targeting ROS-sensitive signaling pathways could be a new strategy to treat hypertension. In fact, overexpression of mitochondrial SOD in mice prevents development of hypertension, or treatment mice with low doses of mitochondria-targeted SOD mimetic reverses fully developed hypertension (3). We and others (3, 12) have found that angiotensin II-induced hypertension leads to endothelial dysfunction de...

Mitochondrial Oxidative Stress, Mitochondrial DNA Damage and Their Role in Age-Related Vascular Dysfunction

“…This proposal is based on the finding that mtROS formation increases with age (and is higher in MnSOD +/− mice) and endothelial function is impaired with age (to a higher extent in MnSOD +/− mice) [ 23 ]. Of note, we and others also showed that mtROS participate in the activation of immune cells via stimulation of the phagocytic NADPH oxidase (Nox2) [ 97 , 174 ]. mtROS have also been reported to participate in the activation of the inflammasome and trigger the expression of proinflammatory cytokines [ 115 , 116 , 117 , 118 ].…”

“…Therefore, targeting of the chronic inflammatory phenotype in the elderly could represent a promising strategy to normalize the increased prevalence of comorbidities in the elderly and increase their healthspan [ 201 ]. mtROS formation is augmented with increasing age [ 28 ] and mtROS can lead to the activation of immune cells and their phagocytic NADPH oxidase, induce the inflammasome and trigger cytokine release [ 97 , 115 , 116 , 117 , 118 , 174 ]. Therefore, targeting mitochondrial oxidative stress in the elderly could represent another strategy to suppress the chronic inflammatory phenotype and adverse effects of the aging process.…”

Mechanisms of DNA repair in mitochondria

“…AFO are not only damaging agents, but also intermediates of numerous processes, including the cell adhesion, apoptosis, autophagy, immune response and cell differentiation, therefore control of the AFO level is absolutely necessary [38][39][40][41][42][43].…”

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“…AFO are not only damaging agents, but also intermediates of numerous processes, including the cell adhesion, apoptosis, autophagy, immune response and cell differentiation, therefore control of the AFO level is absolutely necessary [38][39][40][41][42][43].…”