TRACKING HEART ATTACK
by BARSANJIT MAZUMDER
Heart attack and stroke mostly originates from the abnormal behavior of the resident cells of the artery. Inside the artery a very large numbers of immune cells are present. Inflammation of these cells can rapidly change the normal architecture of the artery causing rapid proliferation. In addition, these cells rapidly capture cholesterol / lipid and form foam cells. This is the root cause of the blockage in the blood vessels. All of a sudden this process could send someone to the emergency room with severe chest pain and the kiss of death. It has been widely accepted by the expert in the field that not only the cholesterol or lipid, inflammation of the cells of blood vessel plays a major role in the Heart Attack or Stroke. More than 35 % of the patients showing up in the emergency room do not have significantly bad cholesterol profile but still they get sudden heart attack. The term “Inflammation” most of the time convey a very bad sense. However, the most interesting fact about inflammation is they are the defense against infection. The cells that protect us from infection are called immune cells and macrophage is a big part of it. Macrophage serves as a role of the Protector cells that could make highly lethal molecule by the process called inflammation. These lethal molecules are very potent to kill the invading infectious agents that could cause deadly disease. The problem starts when macrophage failed to control these deadly weapon systems. What mechanisms control the deadly weapon systems (inflammation) of the cell is largely unknown. Recently in our laboratory we have created a genetically engineered animal model by removing a critical component of the control system from macrophage. Using this animal model we discovered a defense mechanism against this uncontrolled inflammation. This work show significant promise for the development of new generation of anti-inflammatory drugs that could block inflammation. The results of these studies have been published in “JOURNAL OF IMMUNOLOGY” (March 2013 issue) a premier journal in immunological research.
My current Ph.D student Darshana Poddar has played a significant role in this work and this work wouldn’t be a reality without her relentless effort in the laboratory. I am also fortunate enough to have a wonderful team of researchers such as Dr. Abhijit Basu (Postdoctoral Fellow in my lab) and Dr. William Baldwin my collaborator from Cleveland Clinic Lerner College of Medicine. In recognition of this work Darshana has been awarded “FUTURE OF SCIENCE AWARD” from the prestigious Keystone conference of Immunology and a GRANT AWARD from American heart association. The competitive funding that I have received from NATIONAL HEART, LUNG, and BLOOD INSTITUTE of the NATIONAL INSTITUTE of HEALTH and AMERICAN HEART ASSOCIATION served as a lifeline for this research.
Barsanjit Mazumder Ph.D (Ex-student of Siksha-Bhavan, Santiniketan), Associate Professor of Molecular Genetics, Center for Gene Regulation in Health & Disease, Cleveland State University, Cleveland, OH 44138, USA
Phone: 216-687-2435 (Office), E.mail: firstname.lastname@example.org
The Article Forwarded to me by Barsanjit raised a few questions from my part, which Barsanjit answered gracefully; which are reproduced below:-
Question by Shubhashis Mitra :
Please elaborate a bit more on how lipid is collected by cells when these inflammatory cells are active; i.e, are these deadly molecules the prime cause of collection of cholesterol etc? After collection of such lipids do they get stuck to the wall of the artery?
Answer by Barsanjit Mazumder:
To make it simple and understandable to the people across the field, I did not go into the deep and complex territory of the mechanism of inflammation. Now, since you are asking I am obligated to explain it further.
Macrophages are the terminally differentiated cells, the stage of the cells immediately before the macrophage is monocytes (white blood cells). These monocytes are present in the blood circulation and synthesize in the bone marrow which is the origin of all blood cells. When the cells of the artery is under inflammation they express many sticky molecules in the external surface of the artery, these molecules captured the monocytes from the blood circulation. As a consequences these monocytes could invade the barrier of the artery and go deep in the artery cell layers. Now these monocytes differentiate into macrophages, these macrophages are inflammatory macrophages and they could produce many deadly molecules, these molecules can activate the adjacent macrophages (it is a vicious cycle that runs like a perpetual style). These activated macrophages express receptors that is highly specific for lipids/cholesterol. As a result these macrophages after engulfing the cholesterol of the lipids transform into foam cells. These cells are the major cause of formation of plaque in the artery which is responsible for heart attack or stroke.
Cholesterol only play a partial role, if the degree of inflammation is high in the macrophage, then these cells could mobilize another kind of cells in the artery called Smooth Muscle Cells, and together they could form clot in the artery even with normal cholesterol level. Inflammation is the root cause of heart disease. Our work has identified a defense mechanism adopted by macrophages through which they could block the synthesis of those deadly molecules. This is a natural defense mechanism that is protecting us from these diseases. When the protection mechanism is defective then it creates a wild wild west condition, there is no control for this molecules as a result the synthesis rates are very high. This condition could open the Gates of the Hell. I hope this will explain the issue.
Question by Shubhashis Mitra:-
“Our work has identified a defense mechanism adopted by macrophages through which they could block the synthesis of those deadly molecules. This is a natural defense mechanism that is protecting us from these diseases. When the protection mechanism is defective then it creates a wild wild west condition, there is no control for this molecules as a result the synthesis rates are very high.”
Now, if that is in fact a basic property of the above mentioned defense mechanism, and not the inflammatory one, then doesn’t it work in inflammatory conditions? What is actually the defect in that defense mechanism then, are the system of defense molecules just outnumbered? Can it be re-activated by in full steam by some medicine (or etc)? Or in short how this defense mechanism can be spruced up not allowing artery blockade in this fashion.
Answer by Barsanjit Mazumder:
You should think in this way, inflammation creates a condition that allows the cells to synthesize a plethora of deadly molecules such as cytokines, chemokines, free radicals etc. These molecules synthesized by inflammation have a very good intention, the primary job is to kill the infectious agents, however they are weapons and should not be generated in large amounts. The balance is important. We have identified a mechanism already existing inside the macrophage that is not allowing the robust synthesis of these molecules and keeping their level in the correct amount that will not kill the cell itself. In case the control mechanism is defective that condition will allow the excessive synthesis of these deadly molecules. Which not only induce the adjacent macrophage to capture more lipid/cholesterol but also kill the macrophage and other cells. These dead cells also form a considerable mass of the artery clogging plaque responsible for heart attack or stroke. Yes, this is a natural defense mechanism of the same inflammatory macrophages.
Now consider this, you are engaged in a war with your enemies, you are standing in front of enemy colonies, but those enemy colonies are also in close proximity with the colonies of your friends and family. You have a huge amount of deadly weapons and you are applying them indiscriminately, the result will be your friend and family as well as your enemies everybody will be dead, a weapon can not distinguish between who is enemy and who is friend. However, if you have a limited number of weapons then those weapons will be used with sharp precision and will only kill the enemies. Although it is a very crude analogy but thought it might help.
My response to your question: Yes, this mechanism is also active under inflammatory condition that is allowing the inflammation not to go high but sufficient enough to serve as a protective role. Yes, all currently used anti-inflammatory compounds blocks the intermediate signaling responsible for transcription (synthesis of the RNA of those deadly molecules). These compounds have very high non-specific activities because they could block the synthesis of the RNA of many beneficial and essential molecules, therefore they might cause other bad things. What we have identified recently is a specific pathway that could identify a common signature present in the RNA of these deadly molecules (only) and once this mechanism recognize this common signature, it can block the step of translation of these RNA (Translation means the synthesis of protein from RNA). This is a precise mechanism to control, may be you can consider this mechanism as a rheostat that is controlling the output. This could be used as a novel anti-inflammatory drug screening platform to search for novel compounds by looking which compound could selectively promote the ability of this defense mechanism to block the synthesis of these deadly molecules.
The readers of this article are encourage to put up a relevant questions; and Barsanjit will be happy to explain the phenomenon in further details.