Author and Reporter: Anamika Sarkar, Ph.D.
Nitric Oxide (NO) is highly regulated in the blood such that it can be released as vasodilator when needed. The importance and pathway of Nitric Oxide has been nicely reviewed by. “Discovery of NO and its effects of vascular biology”. Other articles which are good readings for the importance of NO are – a) regulation of glycolysis b) NO in cardiovascular disease c) NO and Immune responses Part I and Part II d) NO signaling pathways. The effects of NO in diseased states have been reviewed by the articles – “Crucial role of Nitric Oxide in Cancer”, “Nitric Oxide and Sepsis, Hemodynamic Collapse, and the Search for Therapeutic Options”.. (Also, please see Source for more articles on NO and its significance).
Computational models are very efficient tools to understand complex reactions like NO towards physiological conditions. Among them wall shear stress is one of the major factors which is reviewed in the article – “Differential Distribution of Nitric Oxide – A 3-D Mathematical Model”.
Moreover, decrease in availability of NO can lead to many complications like pulmonary hypertension. Some of the causes of decrease in NO have been identified as clinical hypertension, right ventricular overload which can lead to cardiac heart failure, low levels of zinc and high levels of cardiac necrosis.
Sickle Cell disease patients, a hereditary disease, are also known to have decreased levels of NO which can become physiologically challenging. In USA alone, there are 90,000 people who are affected by Sickle cell disease.
Sickle cell disease is breakage of red blood cells (RBC) membrane and resulting release of the hemoglobin (Hb) into blood plasma. This process is also known as Hemolysis. Sickle cell disease is caused by single mutation of Hb which changes RBC from round shape to sickle or crescent shapes (Figure 1).
Sickle Cell RBCs has much shorter life span of 10-20 days when compared with normal RBCs 100-120 days lifespan. Shorter life span of Sickle cell disease RBC’s are compensated by bone marrow generation of new RBCs. However, many times new blood generation cannot cope with the small life span of Sickle cell RBCs and causes pathological condition of Anemia.
RBCs generally breakdown and release Hbs in blood plasma after they reach their end of life span. Thus, in case of Sickle cell disease, there is more cell free Hb than normal. Furthermore, it is known that NO has a very high affinity towards Hbs, which is one of the ways free NO is regulated in blood. As a result presence of larger amounts of cell free Hb in Sickle cell disease lead to less availability of NO.
However, the question remained “what is the quantitative relationship between cell free Hb and depletion of NO”. Deonikar and Kavdia (J. Appl. Physiol., 2012) addressed this question by developing a 2 dimensional Mathematical Model of a single idealized arteriole, with different layers of blood vessels diffusing nutrients to tissue layers (Figure 2: Deonikar and Kavdia Figure 1).
cell free Hb in 2 dimensional representations of blood vessels.
The authors used steady state partial differential equation of circular geometry to represent diffusion of NO in blood and in tissues. They used first and second order biochemical reactions to represent the reactions between NO and RBC and NO autooxidation processes. Some of their reaction model parameters were obtained from literature, rest of them were fitted to experimental results from literature. The model and its parameters are explained in the previously published paper by same authors Deonikar and Kavdia, Annals of Biomed., 2010. The authors found that the reaction rate between NO and RBC is 0.2 x 105, M-1 s-1 than 1.4 x 105, M-1 s-1 as reported before by Butler et.al., Biochim. Biophys. Acta, 1998.
Their results show that even small increase in cell free Hb, 0.5uM, can decrease NO concentrations by 3-7 folds approximately (comparing Fig1(b) and 1(d) of Deonikar and Kavdia, 2012, as shown in Figure 2 of this article). Moreover, their mathematical analysis shows that the increase in diffusion resistance of NO from vascular lumen to cell free zone has no effect on NO distribution and concentration with available levels of cell free Hb.
Deonikar and Kavdia’s mathematical model is a simple representation of actual physiological scenario. However, their model results show that for Sickle cell disease patients, decrease in levels of bioavailable NO is an attribute to cell free Hb, which is in abundant for these patients. Their results show that small increase by 0.5 uM in cell free Hb can cause large decrease in NO concentrations.
These interesting insights from the model can help in further understanding in the context of physiological conditions, by replicating experiments in-vivo and then relating them to other known diseases of Sickle cell disease patients like Anemia, Pulmonary Hypertension. Further, drugs can be targeted towards decreasing free cell Hbs to keep balance in availability of NO, which in turn may help in other related disease like Pulmonary Hypertension of Sickle Cell disease patients.
Sources:
Deonikar and Kavdia (2012) :http://www.ncbi.nlm.nih.gov/pubmed/22223452
Previous model explaining mathematical representation and parameters used in the model :Deonikar and Kavdia, Annals of Biomed., 2010.
Previous paper stating reaction rate of Hb and NO: Butler et.al., Biochim. Biophys. Acta, 1998.
Causes of decrease in NO
Clinical Hypertension : http://www.ncbi.nlm.nih.gov/pubmed/11311074
Right ventricular overload : http://www.ncbi.nlm.nih.gov/pubmed/9559613
Low levels of zinc and high levels of cardiac necrosis : http://www.ncbi.nlm.nih.gov/pubmed/11243421
Sickle Cell Source:
http://en.wikipedia.org/wiki/Sickle-cell_disease
http://www.nhlbi.nih.gov/health/health-topics/topics/sca/
NO Source:
Differential Distribution of Nitric Oxide – A 3-D Mathematical Model:
Discovery of NO and its effects of vascular biology
Nitric oxide: role in Cardiovascular health and disease
Nitric Oxide and Immune Responses: Part 1
Nitric Oxide and Immune Responses: Part 2
Statins’ Nonlipid Effects on Vascular Endothelium through eNOS Activation
Nitric Oxide, Platelets, Endothelium and Hemostasis
Crucial role of Nitric Oxide in Cancer
The rationale and use of inhaled NO in Pulmonary Artery Hypertension and Right Sided Heart Failure
Nitric Oxide and Sepsis, Hemodynamic Collapse, and the Search for Therapeutic Options
Endothelial Function and Cardiovascular Disease
Interaction of Nitric Oxide and Prostacyclin in Vascular Endothelium
Endothelial Dysfunction, Diminished Availability of cEPCs, Increasing CVD Risk – Macrovascular Disease – Therapeutic Potential of cEPCs
This is very good. I covered NO and thalassemia minor a day ago. Thalassemia minor patients have a higher rate of thromboembolism than TM, but TM patients have frequent transfusions. This gets into the platelet and endothelium interaction, and of course, the NO reaction with Hb, as the RBC are removed by the spleen. Sickle cell is associated with thromboembolism as well.
Anamika,
Thank you for this interesting post.
Comments:
1. No live link to app physiology 2012, which I wish to read
2. I would have likes to have a description of the method used to obtain the result 0.5 uM.
3. I like posts to represent completeness, thus the burden on the reader is minimal, post as it, requires me to research to get to the original article, toil to find the methodology used, thus, sample size, methods and result must be ib the post.
4. Please contact a search on our web site for Vascular Biology, posts on this topic are relevant to this post, thus, please add them to the post.
5. Please add a general section on Causes for decrease bioavailability of NO, then explain the hemolysis specific to Sickle cell disorder
6. Please link the 3D model you posted in the past, with the 2D model you present here with the Med BIO ENG COMP, 2011
7. For Authorship on this post please address the points above
THANK YOU
Thanks Aviva for your detailed comments. I have addressed few. some requires more time. I will address them later today as I am extremely busy until late afternoon today.
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PUT IT IN CONTEXT OF CANCER CELL MOVEMENT
The contraction of skeletal muscle is triggered by nerve impulses, which stimulate the release of Ca2+ from the sarcoplasmic reticuluma specialized network of internal membranes, similar to the endoplasmic reticulum, that stores high concentrations of Ca2+ ions. The release of Ca2+ from the sarcoplasmic reticulum increases the concentration of Ca2+ in the cytosol from approximately 10-7 to 10-5 M. The increased Ca2+ concentration signals muscle contraction via the action of two accessory proteins bound to the actin filaments: tropomyosin and troponin (Figure 11.25). Tropomyosin is a fibrous protein that binds lengthwise along the groove of actin filaments. In striated muscle, each tropomyosin molecule is bound to troponin, which is a complex of three polypeptides: troponin C (Ca2+-binding), troponin I (inhibitory), and troponin T (tropomyosin-binding). When the concentration of Ca2+ is low, the complex of the troponins with tropomyosin blocks the interaction of actin and myosin, so the muscle does not contract. At high concentrations, Ca2+ binding to troponin C shifts the position of the complex, relieving this inhibition and allowing contraction to proceed.
Figure 11.25
Association of tropomyosin and troponins with actin filaments. (A) Tropomyosin binds lengthwise along actin filaments and, in striated muscle, is associated with a complex of three troponins: troponin I (TnI), troponin C (TnC), and troponin T (TnT). In (more ) Contractile Assemblies of Actin and Myosin in Nonmuscle Cells
Contractile assemblies of actin and myosin, resembling small-scale versions of muscle fibers, are present also in nonmuscle cells. As in muscle, the actin filaments in these contractile assemblies are interdigitated with bipolar filaments of myosin II, consisting of 15 to 20 myosin II molecules, which produce contraction by sliding the actin filaments relative to one another (Figure 11.26). The actin filaments in contractile bundles in nonmuscle cells are also associated with tropomyosin, which facilitates their interaction with myosin II, probably by competing with filamin for binding sites on actin.
Figure 11.26
Contractile assemblies in nonmuscle cells. Bipolar filaments of myosin II produce contraction by sliding actin filaments in opposite directions. Two examples of contractile assemblies in nonmuscle cells, stress fibers and adhesion belts, were discussed earlier with respect to attachment of the actin cytoskeleton to regions of cell-substrate and cell-cell contacts (see Figures 11.13 and 11.14). The contraction of stress fibers produces tension across the cell, allowing the cell to pull on a substrate (e.g., the extracellular matrix) to which it is anchored. The contraction of adhesion belts alters the shape of epithelial cell sheets: a process that is particularly important during embryonic development, when sheets of epithelial cells fold into structures such as tubes.
The most dramatic example of actin-myosin contraction in nonmuscle cells, however, is provided by cytokinesisthe division of a cell into two following mitosis (Figure 11.27). Toward the end of mitosis in animal cells, a contractile ring consisting of actin filaments and myosin II assembles just underneath the plasma membrane. Its contraction pulls the plasma membrane progressively inward, constricting the center of the cell and pinching it in two. Interestingly, the thickness of the contractile ring remains constant as it contracts, implying that actin filaments disassemble as contraction proceeds. The ring then disperses completely following cell division.
Figure 11.27
Cytokinesis. Following completion of mitosis (nuclear division), a contractile ring consisting of actin filaments and myosin II divides the cell in two.
http://www.ncbi.nlm.nih.gov/books/NBK9961/
This is good. I don’t recall seeing it in the original comment. I am very aware of the actin myosin troponin connection in heart and in skeletal muscle, and I did know about the nonmuscle work. I won’t deal with it now, and I have been working with Aviral now online for 2 hours.
I have had a considerable background from way back in atomic orbital theory, physical chemistry, organic chemistry, and the equilibrium necessary for cations and anions. Despite the calcium role in contraction, I would not discount hypomagnesemia in having a disease role because of the intracellular-extracellular connection. The description you pasted reminds me also of a lecture given a few years ago by the Nobel Laureate that year on the mechanism of cell division.
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Many thanks,Annette
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Open Journals vs. Subscription-based « Pharmaceutical Intelligenceâ, very compelling plus the blog post ended up being a good read.
Many thanks,Annette