Myocardial to Endocardial Commuication

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Endocardial cells combine to form endocardium tissues and are the inner-most layer of tissues that line the chambers of the heart. These tissues play a role in controlling myocardial contractions in mammals.

 

Endocardial notch signaling is one of several forms of communication utilized by endocardial cells to communicate with each other. It is a highly conserved cell signaling system meaning that the both the nucleic acid and protein sequences are similar and in some cases are even identical in different species of organisms.

There are four different notch receptors: NOTCH 1, NOTCH 2, NOTCH 3, and NOTCH 4. The notch signaling system also includes notch ligands that act as the receptors. These ligands are transmembrane receptor proteins that span the length of the membrane of the endocardial cell. The notch signaling receptor is a heterodimer transmembrane protein, meaning that the protein was formed from the combination of two normally non-covalently bonded macromolecules.

Notch signaling is activated by cell to cell contact causing the ligand to bind to the notch receptor. When this signal is activated it leads to three cleavages. The first cleavage is activated by an enzyme known as TACE/ADAM17 and this is responsible for the cleavage of the membrane. The other two cleavages are controlled by a mixture of enzyme (presenilin1, presenilin2, Pen-2, Aph-1, and nicastrin).

This form of signaling allows a group of cells to arrange themselves to form a large structure by influencing them to switch off certain traits in neighbouring cells.

 

Cell adhesion also occurs in endocardial cells.

The endocardial cell is structural made of 5-6 cubular cells along the AP axis of the endocardiaum (Westerfield et al 2009). The endocardial cell migrate mid-line before myocardial cells. Preceding myocardial cell bilateral migration, localized cardiomycytes change direction. This causes myocardial cells to alter direction and move inward to meet the endocardial cells thus establishing nascent heart circumference. Bilateral heart fields are formed as a result of fusion at the midline between the two forming cardiac tissue discs, which are located at the central circumference of the future ventricle (Bakkers 2011).

The physical proximity of the endocardial and myocardial cell suggests that the two may be influenced by each other or that they both respond to the similar environmental cues during their migration towards the midline. One such non-cardiac tissue to which both myocardial and endocardial cells are enar is the endoderm. The endoderm, which will later form the gut is shown to be an influencing factor in cardiac fusion.

1.Monte Westerfield, Leonard I. Zon, H. William Detrich, III ‘Essential Zebrafish Methods’. 2009.

1. Monte Westerfield, Leonard I. Zon, H. William Detrich, III ‘Essential Zebrafish Methods’. 2009.

References:

Monte Westerfield, Leonard I. Zon, H. William Detrich, III ‘Essential Zebrafish Methods’. 2009.

Jeroen Bakkers. ‘Zebrafish as a model to study cardiac development and human cardiac disease

Received January 18, 2011.

Revision received March 22, 2011.

Accepted April 1, 2011

http://cardiovascres.oxfordjournals.org/content/early/2011/05/19/cvr.cvr098.full

http://en.wikipedia.org/wiki/Receptors,_notch
http://circres.ahajournals.org/content/102/10/1169.full
http://edrv.endojournals.org/content/28/3/339.full
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3285259/

http://jcs.biologists.org/content/126/6/1381.full

Myocardial Communication at its Best!

Myocardial cells communicate using autocrine factors, cell to cell propagation of depolarization fronts, gap junctions and adhesion complexes. The autocrine communications involved an abundant array of secretions from leptin, FGF and TGFβ family members, midkine, hepatocyte growth factor, endothelin-1, and stromal cell–derived factor 1α, which causes the myocardial cell communications.

Adhesion complexes engage in cell to cell communication with intracellular signaling that are activated by cell to cell or cell to matrix action of specific protein in the complexes. This signal results in in the myocardial reactions to growth being changed to control cardiac development and hypertrophy.

Capture

Intercalated discs are made up of two types of cell junctions: desmosomes and gap junctions. Desmosomes comprises of strong protein fibers that are very tough and securely connects the myocardial cells together. This is a significant characteristic because of the continuous pumping of the heart results in an immense amount of pressure for the networks between the cells. Myocardial cells are stimulated to create electric current that can instigate and transmit action potentials. The transmission of action potential from one myocardial cell to another myocardial cell follows the transfer of sodium ions across the gap junction or can be referred to as an electric synapse.  Gap junctions connect the cytoplasm of a cell to bordering cells by small linking tubes called connexins, which allows miniature molecules and ions to easily move from one myocardial cell to another. Myocardial cells are branched and joined with other myocardial cells hence together with the gap junctions at the intercalated discs, an high intensity of correlations between the myocardial cells are produced. The myocardial cells linked to the gap junctions are all together known as a myocardium which functions as one. The entire myocardium contracts together when it is stimulated.

myocardial cell

“Cell Communications in the Heart .” Circulation . Accessed October 18, 2013.http://circ.ahajournals.org/content/122/9/928.full#sec-1

A myocardium is made up of two ventricles and another myocardium is from by two atria. The ventricles and the atria are dived by non-conducting fibrous skeleton. The simultaneous contraction of the myocardial cells which comprises the myocardium is essential to generate the force vital to allow pumping of blood.

References:

“Cell Communications in the Heart .” Circulation . Accessed October 18, 2013.http://circ.ahajournals.org/content/122/9/928.full#sec-1

Poon, Kar Lai , and Thomas Brand. “The zebrafish model system in cardiovascular research: A tiny fish with mighty prospects.” Global Cardiology Science & Practice 4 (2013).Accessed October 14, 2013 http://dx.doi.org/ 10.5339/gcsp.2013.4 .

Affairs of the Heart

I have chosen to reside in the heart of the zebrafish as a myocardial cell. I was born from a stem cell which added a special touch (specialization of cells). Stem cells are non-specialized cell that undergo complex processes, both during embryonic and adult life. Mitosis causes the segregation of cells followed by the specialization of the cells, i.e. the cells get assigned functional roles in the zebrafish.  

The heart is a vital organ in any organism as it works in a transport system, where blood is carried throughout the body providing oxygen and sustenance to other cells of the body as well as ridding the body of waste products such as carbon dioxide. The heart is the first organ to function during the embryo development.

Heart muscle cells (shown in green), regress to a more youthful state after injury, start dividing again (indicated by a red marker) to replenish lost cells and then mature a second time into cardiomyocytes.

Structure of myocardial cell in the zebrafish

I have one oval/circular shaped nucleus which is responsible for the controlling my every action, such as reproduction, metabolism and growth. Therefore you can say the nucleus is like my brain. I also have DNA which allows my offspring to function exactly like me. My nucleus is well protected as it is membrane bound, just as the brain is protected by the skull.

I also have lots of energy to perform all my duties, the contracting and relaxing is quite exhausting you know. And I would like to thank the mitochondria in me that provide me with lots of ATP that get me through this active life. This to, is well protected as it is membrane bound.

I have myofibrils which is just contractile protein fibers that are elongated and in abundance. Honestly I just think they are to make me look buffJ. Unlike my other organelles the myofibrils are not membrane bound.

I don’t have much organelles, you know, because of my duty, which just requires lots of energy. But a very cool thing is I can aid in the regeneration of the heart organ (I would tell u more about this a next time).

My main purpose in life is to work alongside my brothers and sisters (other myocardial cells) that make up the cardiac muscle. Together we are responsible for the heartbeat of the zebrafish and the functioning of the cardiovascular system.

Reference:

http://cardiovascres.oxfordjournals.org/content/early/2011/05/19/cvr.cvr098.full.pdf

http://www.alnmag.com/news/2013/07/atrium-cells-regenerate-ventricle-zebrafish-hearts

http://www.salk.edu/news/pressrelease_details.php?press_id=412

http://www.salk.edu/news/pressrelease_details.php?press_id=412

Zebrafish heart

 

I choose you!

An Adult Zebrafish

Danio rerio is a petite, fresh water fish commonly known as the zebrafish. The zebrafish gets its name from the stripes that run along the length of its body and fins and the adult fish is usually no more than 5cm long. This fish lives in rivers of northern India, Pakistan, northern Pakistan, Nepal, and Bhutan in South Asia.

The zebrafish is an idyllic model organism because of:

  • The petite size.

  • The short period of time required for reproduction.

  • The large number of offsprings.

  • Easy sustenance under laboratory conditions.

  • The translucence nature of the embryos.

 

The mutations that hamper the development of the embryo have been sequestered in the fish and will assist in interpreting the genetic control system in humans.

Reference:

The Zebrafish Model Organism Database.” ZFIN. Accessed September 25, 2013zfin.org/.

What are Model Organisms?

Model organisms are species which have limited complications in terms of breeding and sustaining under laboratory conditions. Model organisms are chosen based on their wide experimental characteristics.

Data is collected in abundance about the relative organisms and as such it is divided into three categories, genetic, experimental and genomic model organisms.

Genetic model organism is chosen based on their short life spans and their large reproducing numbers. Therefore genetic crosses can be set up on large scale over a number of generations which resulting in gene mapping and other phenomenon. An example is the mouse.

Experimental model organisms tend differ from the genetic model organism because of the extensive generation and insignificant genetic map details. However they tend to have other robust characteristics that can be of easy study and flexibility. An example is the African clawed frog.

Genomic model organisms are selected because of two reasons: their fundamental role in evolutionary equilibrium and/ or the superiority of their genome. An example is the puffer fish.

Reference:

What is a model organism? – Encyclopedia of Life.” Encyclopedia of Life – Animals – Plants – Pictures & Information. Accessed September 26, 2013 http://eol.org/info/466. 

Mitochondrial Complex I Inhibitor Rotenone Induces Apoptosis through Enhancing Mitochondrial Reactive Oxygen Species Production

References

Li, Nianyu , Kathy  Ragheb, and Gretchen  Lawler. “Mitochondrial Complex I Inhibitor Rotenone Induces Apoptosis through Enhancing Mitochondrial Reactive Oxygen Species Production.” The Journal Of Biological Chemistry 278, no. 10 (2003): 8516-8525. Accessed April 13, 2013. http://www.jbc.org/content/278/10/8516.full#sec-22

 PUBLISHED PAPER 2

Rotenone inhibits complex 1 in the electron transport chain (ETC) and has leads to the death of a number of cells. The reactive oxygen species (ROS) aids in apoptosis and the inhibiting of complex 1 by rotenone promotes the creation of ROS. Rotenone along with the increased ROS generates a similar substrate to complex 1 substrate. DNA fragmentation was able to determine that apoptosis, the release of cytochrome c and caspase is caused by rotenone. Apoptosis caused by rotenone can be stopped using antioxidants. In apoptosis, magnesium superoxide dismutase is resilient to rotenone-induced mitochondrial ROS.

 

Complex 1- 4 and ATP synthase in the ETC produces ATP as well as assist in apoptosis of the cell due to the ROS. Mitochondria discharge a number of proapoptotic regulators such as cytochrome c to the cytosol when the apoptosis process is stimulate. The regulators triggers the apoptotic process, as well as it is controlled by proteins and results in the mitochondria being the central path of apoptosis signal.

 

The significance of rotenone-induced apoptosis was determined with a tumor necrosis factor (TNF)-α which can disrupt complex 1 in ETC while other intelligences state that rotenone can inhibit cells outside the mitochondria.

 

ROS is suspected to be activated by several other molecules within the body including UV radiation. ETC produces the main supply of ROS under biological conditions and hence it is been thought that ROS formed from the mitochondria contributes to the apoptosis process. The ROS mitochondria manipulate the mitochondria functioning exclusive of the cytosol, two complexes in the ETC, complex 1 and 3 are also known to be contributors of ROS

 

From chemical determination superoxide and hydrogen peroxide was determined to be primary and secondary products and it has been noted that rotenone as well as complex b-c1 inhibitor antimycin can cause the formation of both oxides. The ROS made in the mitochondria can be altered when inhibition takes place.

Biochem crossword

K

 

ACROSS

1. A pocket or a cleft

2. Maximal velocity

3. Removal of water

4. S shaped curve

5. Covalent bond formed between the alpha amino group and the alpha carboxyl group

6. Smallest unit that is capable of performing life functions

7. Change in the optical rotation that occurs by epimerization

8. Two sugars that differ only in the configuration around one carbon atom

9. Common description of denaturation

10. Five membered ring

11. Each of two or more enzymes with identical function but different structure

12. Apoenzyme + cofactor

13. Has an aldehyde group

14. Reaction between a aldehyde and an alcohol

15. pH at which Amino acid would not move in an electric field

16. A substance that diminishes the velocity of an enzyme catalyzed reaction

DOWN

1. Inactive protein part

3. Have the same number of atoms arranged differently in space

6. Hydrates of carbon whose main role is to provide energy

12. When the substrate itself serves as an effector

14. Reaction between a ketone and an alcohol

17. Highest arrangement of atoms that is in the intermediate structure between reactants and product

18. A non-protein compound necessary for the functioning of an enzyme.

19. Enzymes that are composed of more than one sub-units

20. Has a keto group

21. One of two stereoisomers of a cyclic saccharide that differs only in its configuration at the hemiacetal or hemiketal carbon

22. Six membered ring

23. The amount of energy that is needed to convert all the molecules in one mole of a reacting substance from a ground state to the transition state.

24. A monosaccharide sugar that contains four carbons

25. Michaelis constant

26. Biological catalyst that speed up a chemical reaction by providing an alternate pathway with a lower activation energy

27. Vo = Vmax / Km + [S]

28. A molecule or ion having separate positively and negatively charged groups

29. A molecule that cannot be synthesized by the body and is obtained from the diet

30. Dynamic Equilibrum

31. A covalent bond that joins a sugar molecule to another sugar

32. 1 / micrometer per minute

 

Anticholinesterase Inhibition – Published Paper Review

Weinbroum, Avi A. “Pathophysiological and clinical aspects of combat anticholinesterase poisoning.” British Medical Bulletin 72, no. 1 (2004): 119-133. Accessed March 24, 2013.  http://bmb.oxfordjournals.org/content/72/

 

Anticholinesterase (AChE) is an enzyme and like all enzymes, their function is affected by several factors.

RECALL: Enzymes are affected by pH, temperature, substrate and enzyme concentration and inhibitors. These agents tend to disrupt the area of the enzyme called the active site by changing its conformation and hence hindering enzymatic activity.

INTRODUCTION

Organophosphate – like compounds are inhibitors of the enzyme acetylcholine esterase (AChE) and are referred to as nerve agents (NAs). It is related to those used in pesticides. The extremely lethal irreversibly AChE inhibitors results in an inoperative AChE causing a buildup of acetylcholine (ACh) affecting the entire cholinergic system.

DID YOU KNOW

In the 1854, Wurtz synthesized the first organophosphate compound, tetraethyl pyrophosphate.

Sad to say…. organophosphates were used as weapons of mass destruction

1980 Iraq – Iran war

1994-95 – Terrorist attacks in Japan

CLINICAL ASPECTS

The extent of absorption and contact with NA are vital issues in verifying biochemical intoxication route for the NA. NA can either be absorbed by the skin and mucous membrane or inhaled. The inhalation of the vapor results in instantaneous absorption due to the alveoli in the lungs causing respiratory ailments ranging from short breath to cardiovascular and respiratory failure and eventually death. Exposure to the skin has a nicotine-like effect causing muscle paralysis and continued developing respiratory indications and ultimately death.

BIOCHEMISTRY OF NAs

They are chemically obtained from phosphoric acids. They tend to differ slightly by substituting the -OH radical and the acid-base form but are still efficient of being both reversible and irreversible inhibitors to AChE. NAs chemical properties are such that it is both colorless and odorless in its volatile liquid state and denser that air in its gaseous state.

AChE enzyme is categorized as class three, Hydrolase and sub-class as esterase and therefore from the class it is determined that the enzyme hydrolyses esters, especially choline esters, ACh, a neurotransmitter for the cholinergic part of the nervous system.

AChE hydrolyses ACh swiftly and is located in the receptors sites of the nerves by the cholinergic nervous system. Reversible anticholinesterases are not lethal as compared to the irreversible anticholinesterases. Carbamates bind to anionic and the ester of the enzyme resulting in the separation of part of the carbamate and the formation at the location of the ester, an enzyme-cabamylated complex. Hence hydrolysis of ACh is no longer a rapid process. The most attractive binding sites for organophosphate compounds are the ester sites however the stability of the bonds depend on the correct orientation of the enzyme and inhibitor as well as other compounds are prevented from binding with the active site. They interfere with the cleft leaving the enzyme dysfunctional.

With irreversibly inhibition the NAs covalently binds (strongest bond formation) to the active site so therefore it is known as a completive inhibitor. This result in a buildup of the ACh in the neuro-effector junction hindering the synapse process in peripheral and the central cholinergic system causing toxic contamination to the nicotinic (CNS) and muscarinic cleft (muscle system). The covalent bond partakes in an instantaneous chemical reaction which stabilizes the molecule due to the surge in the thermodynamic stabilization resulting in the production of more hydrogen bridges between the phosphate and organic groups.

The skeletel muscles, the pre-ganglionic autonomic nerves and the post-ganglionic parasympathetic nerves are innervated by AChE. The cholinergic systems are bases on the muscarinic and nicotinic systems since they have receptors that display specificity to muscarinic alkaloids and nicotine alkaloids. The post-ganglionic parasympathetic fibers are innervated by the muscarinic sites which regulate the activity of the glands, smooth muscle of the respiratory, cardiovascular and gastrointestinal systems. Autonomic ganglia, part of the nicotinic sites are relied upon for the contractions of the skeletal muscle. When both muscarinic and nicotinic cholinergic neurotransmitter buildup it causes hyper-stimulation of the synaptic process and hence causes paralysis of the skeletal muscles. Comparably the buildup of AChE in the CNS nerve receptors leads to hyper-stimulation and paralysis cardiac brady-asystole, hyper-secretion from secretory glands, respirational collapse, seizures, coma and eventually it is fatal. A small window of opportunity allows antidote drugs, atropine and oximes to work against the inhibitor stimulated nicotinic and muscarinic cholinergic system correspondingly depending on the stage of poisoning.

CONCLUSION

NAs are highly poisonous complexes that result in fatality within mere seconds. The principal biochemical cause NAs is the capability to irreversible inhibit AChE enzyme resulting in the buildup of ACh in the synaptic cleavage. Antidotes such as atropine and oximes present a crucial windowed-opportunity to act against the inhibitor