Non-immune Pros of Reactive Oxygen Species

What Are the Non-immune Benefits of Reactive Oxygen Species?

Alexa Escobar Pastor

        According to our first page, reactive oxygen species (ROS) are molecules produced as byproducts during the mitochondrial electron transport chain or by oxidoreductases and metal catalyzed oxidation. Reactive oxygen species are known to be a deadly weapon against pathogens (Immune pros of Reactive Oxygen Species) and to play a major role in normal cell signal transduction and cell cycling. Therefore, a proper signaling of ROS is important because ROS’ actions cooperate with various hormones (growth factors and insulin) by modulating cellular responses to the respective hormone stimuli, and they serve as a sensor for the cell inner metabolic state and sensor for the extracellular ligand. (Bartosz, 2009) ROS may also be used to provide new therapies for different diseases; for example, ROS may be used to kill cancer cells and prevent aging and other neurological diseases. (Bartosz, 2009),(Uttara et al., 2009)  An overproduction of ROS leads to DNA damage, oxidation of polyunsaturated fatty acids and amino acids, and inactivation of some specific enzymes because ROS are highly reactive to most biological macromolecules (Cons of Reactive Oxygen Species). This ROS overproduction can also lead to different diseases such as cardiovascular and neurodegenerative diseases. (Bartosz, 2009) A lack of ROS can cause diseases such as chronic granulomatous disease (Brieger et al., 2012). There is not an exact biological concentration known for ROS. (Cardoso et al., 2012) According to Cardoso et al., O2− have a restricted diffusion limit of  10⁹–10¹⁰ mol L⁻¹ s⁻¹ , and there is a limitation in measuring intracellular concentrations of O2− . However, even if biological ROS concentrations are still undergoing research there is a hypothesis for the lifetimes of ROS which are shown in figure 1.  (Cardoso et al., 2012) ROS concentrations outside and inside the mitochondria are still in investigation. (Cardoso et al., 2012)

Figure 1.  ROS concentration evolutions based on their estimated lifetimes. (Cardoso et al., 2012)

Benefits of ROS in the Cardiovascular System

          Reactive oxygen species cooperate or intervene with many pathophysiological and physiological processes in the cardiovascular system mainly in the vascular smooth muscle cells. These processes include growth, migration, apoptosis, differentiation, and secretion of inflammatory cytokines. The overproduction of ROS can lead to numerous cardiovascular diseases such as  atherosclerosis, diabetes, hypercholesteremia, and hypertension; however, an appropriate balance of ROS can help maintain a healthy vascular smooth muscle. (Clempus and Griendling, 2006) 

         Reactive Oxygen Species and Vascular Cell Migration

          Vascular smooth muscle cells and endothelial cells (Figure 2) are the main cells for vessel development and repair. Nox (NADPH oxidase) proteins produce O2.- (A type of ROS as explained in page 1 of this website) in the cardiovascular tissue. (Figure 2) (Drummond and Sobey, 2014) Reactive oxygen species interact with the vascular smooth muscle and endothelial cells, and regulate integrin engagement, focal adhesion formation, and actin dynamics in the migratory process for red blood cells and white blood cells through the vascular system. (Figure 2) Cell migration is a multistep process that involves the creation and dissolving of focal adhesions to mediate movement.
           ROS is involved in the integrin binding and engagement pathway (Figure 3) The integrin binding and engagement pathway's primary function is to form the lamellipodia. The lamellipodia is a cellular extension that defines the front of migrating cells. (Wehrle-Haller, 2013) Integrins are αβ heterodimeric transmembrane receptors that link a cell’s dynamic interactions with the extracellular matrix (ECM) to the cytoskeletal rearrangements that are necessary to promote cell motility. (Koistinen and Heino, 2013) Integrins contain redox-sensitive cysteines in the α7 subunit that influences the binding of integrin to laminin. Laminin is an important extracellular matrix protein that forms the basal lamina (the part where the epithelium sits). Integrin binding and engagement pathways occur via a Rho-dependent pathway. Integrin binds and senses laminin in order to phosphorylate focal adhesion kinase (FAK). FAK recruits SH2- and SH3-domain containing proteins that will mature into stronger focal adhesions.  Focal adhesion turnover must be maintained in a balance in order for cell migration to occur. (Brown and Griendling, 2015) At the same time, downstream signaling leads to the production of ROS which causes the oxidation of β-actin Cys374, resulting in the union of β-actin with PDI (protein disulfide isomerase). This union is necessary for cell motility.(Figure 3) (Brown and Griendling, 2015) The binding of integrin and laminim is not well understood, but according to Brown and Griendling, in the absence of ROS, adhesion and spreading in the vascular smooth muscle cells would not occur. 

http://eurheartj.oxfordjournals.org/content/early/2015/07/28/eurheartj.ehv100

Figure 2. This image illustrates the modulation of vascular smooth muscle cell and endothelial cells. 

http://www.cytoskeleton.com/blog/integrin-mediated-redox-control-of-beta-actin-details

Figure 3.  This image shows the interaction of the integrin receptor and the extracellular matrix. 

           

 The following link would take you to a video that shows how ROS interacts with ventral    lamellipodia:

http://movie.rupress.org/video/10.1083/jcb.201209077/video-10

Another cell migration process that ROS interacts with is the process of coagulation. Coagulation is the cessation of blood loss and repair of a damaged vessel. Whenever there is a vascular injury, platelet-derived growth factor (PDGF) receptor dimerizes and autophosphorylates to provide binding sites for phospholipase C, Src, and phosphoinositidase 3-kinase (PI3K). PI3K promotes the formation of PIP3 which stimulates Rho-GTpase family members and activates Rac. Rac activates Nox1 and Nox2 which further increases ROS signaling. ROS signaling interrupts the cadherin-based cell-cell adhesion through either inhibition or activation of tyrosine phosphatases and kinases or activating IQGAP (Ras GTPase-activating-like protein) and/or small GTPases which leads to red blood cell migration and white blood cell proliferation. (Figure 4).(Brown and Griendling, 2015) 

http://www.hindawi.com/journals/jst/2012/807682/fig3

Figure 4.  The Diagram above shows the interaction of ROS and the different cell migration and adhesion molecules. 

The following video will give you a better understanding on how vessel repair occurs: 

https://www.youtube.com/watch?v=0pnpoEy0eYE

Angiotensin II and Reactive Oxygen Species Interaction

Another pathway that occurs in the cardiovascular system in which reactive oxygen species interact is through the Angiotensin II pathway. Angiotensin II is released by renin to promote high blood pressure. Angiotensin II also releases aldosterone that causes sodium retention, which also causes an increase in blood pressure.  (Brown and Griendling, 2015) 

The binding of Angiotensin II and AT1R (Angiotensin II receptor type 1) induces the activation of NADPH oxidase which results in intracellular generation of ROS. ROS send a signal to redox-sensitive signaling molecules (Mitogen activated protein kinases, transcription factors such as HIF-1, and matrix metalloproteins). These signaling events regulate vascular structural changes such as vascular remodeling. This pathway is mainly used when the cell is in hypoxia, because the vessels need to vasoconstrict because vasoconstriction will maintain a proper intrapulmonary blood flow distribution, provide gas exchange protection and keep the normal blood oxygen levels (~ 95% oxygen). (Figure 6) (Hummler et al., 2016; Brown and Griendling, 2015)

Figure 6. Angiotensin II  signaling that regulates vascular structural changes. (Schiffrin and Touyz, 2004)

Reactive Oxygen Species and the Prevention of Hypertrophy

Reactive oxygen species also protects from hypertrophy. Hypertrophy is the enlargement of the size of its cells causing an enlargement of an organ or tissue.This protection can be given by the induced preservation of capillary density during chronic pressure overload by Nox4 (Brown and Griendling 2015) or by ROS regulating cardiac calcium channels and transporters. Oxidative stress can cause a sustained release of calcium that contributes to cardiac remodeling. There are two main pathways in which ROS help with the conductance of Calcium. First, H₂O2 causes dimerization and activation of protein kinase G (PKG) which aids in muscle hyperpolarization which may counteract pulmonary hypertension in chronic hypoxia. (Figure 8) (Brown and Griendling, 2015) Hyperpolarization is a change in a cell's membrane potential that makes it more negative. Chronic hypoxia is a insidious diminution in the oxygenation of tissues resulting in chronic blood loss.

Figure 7.  ROS-induced ROS-release mechanism triggered by hypoxia.  (De Giusti et al., 2013)

          Reactive Oxygen Species effect in Ischemia Reperfusion

        Through potassium channels, ROS have been discovered to help as a pharmacological therapy to activate cell survival mechanisms that makes the organs and tissues more resistant to the deleterious effects of ischemia reperfusion. Ischemia reperfussion is the lack of blood flow to a tissue. Also it has been discovered that mitochondrial ROS could play a critical role in cell survival after postischemic tissue injury.  The cardioprotective mechanisms induced by preconditioning clearly involve activation of mitochondrial potassium ATP and BKCa channels, which produce membrane alkalinization and ROS.  ROS activate downstream signaling elements to induce expression of cardioprotective proteins that limit ischemia reperfusion injury and cell death. Thus, production of ROS by mitochondria can exert counterbalancing effects on tissue cells by regulating vascular caliber. Also ROS production could be beneficial for cell survival and enhance tolerance to ischemia. (Kalogeris, Bao, and Korthuis, 2014)

Conclusion 

      Reactive oxygen species are important for signaling in different cellular processes. Therefore, it is a challenge to separate the pathologies influenced by ROS production and the normal physiology of ROS production. Further investigations must be done to understand the ROS-signaling molecules.

The following video explains Reactive Oxygen signaling:

                                                 https://www.youtube.com/watch?v=F8rejf6cemA