Today lets talk about a subject near and dear to my heart. Blood pressure medication. Many years ago when I was a child I was diagnosed with hypertension (high blood pressure), I went through a battery of tests to determine a cause for my disease however none was able to be identified. Through the years since then physicians have continued to occasionally try to look in new areas in their quest to figure out why my blood pressure is as high as it is.
I have my doubts they ever will, who knows what precisely is the problem. Nevertheless, high blood pressure if left uncontrolled puts a lot of strain on my arteries and organs, so I must take daily medication to keep it in a normal range (please don't tell me that diet and exercise is really all that I need, do you think I haven't tried that? ONLY medication is able to keep things under control). One such compound (I take more than one) that is used to do this is called a beta blocker. As a result, I pay special attention to research that goes on with regards to these types of compounds and today's article is one that caught my eye!
Today let us discuss a work published in the journal Nature: Scientific Reports titled "Heart Failure and MEF2 Transcriptome Dynamics in Response to β-Blockers."
Disclaimer: THIS IS GOING TO BE A LONG ARTICLE
What Is A Beta-Blocker?
A beta blocker is any such compound that is a competitive agonist against the binding of the hormones adrenaline or noradrenaline to receptors called androgenic beta receptors. Okay, lets repeat that but in a less sciency way... there are receptors that adrenaline and other similar molecules interact with, these receptors are called androgenic beta receptors (androgenic refers to the compounds that bind, the adrenaline and noradrenaline). When adrenaline binds to the beta receptor it causes a response (increased heart rate, higher blood pressure etc...). Beta blockers are compounds which bind to these receptors too (however when they bind, they do NOT cause a response), and when the beta blocker is bound it will stop the adrenaline and noradrenaline from being able to bind. This is why they are called Beta blockers, because they block the binding of the normal hormones at the beta receptor.
Beta blockers have been long used to reduce blood pressure and as a treatment for people who have experienced congestive heart failure. In these cases beta blockers are associated with a much longer lifespan, as they slow the heart down, and reduce how hard it beats. [3]
What is MEF2?
In the article we are going to discuss the researchers were focused on the MEF2 or myocyte enhancer factor-2 family of proteins. This gene family (and the resulting proteins the genes encode) are transcription factors which means their whole purpose is to regulate the amount of other proteins that are produced from other genes in the genome. Now the MEF2 family is particularly important for heart functioning and development. [2] In this publication researchers showed that if you remove one of the members of the MEF2 family from the mouse genome, that the mice are born with a variety of heart defects (directly illustrating its important in heart development!). [2]
In addition to being important in heart development, it also reported to play a role in the remodeling of heart cells after heart failure. [4] it does this through its functioning as a transcription factor, aka it is able to modulate how much of other proteins are created in the heart cells.
Okay... That's A Lot of Information... What Were The Authors Looking At?
Thinking about the interplay between MEF2, heart disease, and beta blockers, the authors put forth the hypothesis that there may be a direct link between these beta blocker compounds and the functioning of this MEF2 transcription factor family. They thought perhaps the beta blockers were actually affecting MEF2 and resulting in big changes to the amounts of other proteins being expressed downstream. So they used a model mouse system where the mouse was surgically given a condition that is known as transverse aortic constriction, which causes enlarging of the heart and eventual heart failure. They then looked at the effect that a Beta blocker (in this case the compound atenolol had on the activities of the MEF2 family of proteins.
Lets Get To The Results!
Beta Blockers Reverse Symptoms Of Heart Failure
In this first figure I am showing what we are looking at is heart tissue from two different kinds of mice, one called sham which are just normal mice that did not have the transverse aortic constriction surgery, and the other which did have the surgery (TAC). The TAC mice are those modeling heart failure. Six weeks after the heart failure TAC surgery, the mice were either given a blank buffer, or one containing the beta blocker compound for an additional four weeks.
So now, if we look at the top left corner are heart cells from a healthy mice that were then treated with just a plane buffer ("solvent") not given any atenolol (the beta blocker). The top right is a sample from a TAC mouse modeling heart failure. The cells are stained (by Massons Trichrome Stain) in such a way that we can see heart cells in red, nuclei in black and collagen fibers in blue. Accumulation of these collagen fibers occurs during the "remodeling" process that happens after heart trauma. During congestive heart failure these fibers will keep accumulating. [5], [6]
What we can see is that there are a lot of collagen fibers in the TAC heart failure mouse model's cells (lots of blue), but the healthy mouse doesn't have the dense concentration of collagen, it is healthy and normal. Now looking at the bottom panels we are seeing the two classes of mice, but this time they have been treated with atenolol, there isn't any difference for the normal mice (sham) but comparing the TAC mice you can clearly see that the density of the collagen fibers is drastically reduced, and the cells look more like those from a healthy mouse heart.
Finally to the very right is a plot showing the relative area that the collagen fibers take up, for the TAC mouse that area is much lower when the mice were treated with the beta blocker (atenolol). This experiment is an example of how beta blockers are able to reverse symptoms of heart failure.
The Beta Blocker Is Able To Change Gene Expression Profiles In The TAC Mice Hearts
- The researchers looked at the amount of mRNA that was being created for various genes related to heart functioning, they found that treatment with the beta blocker compound resulted in a change in the amount of the mRNA produced for a variety of these genes (the amount of RNA made is proportional to the amount of the protein that eventually gets made). Some genes were 'up-regulated' (meaning there was more mRNA, then with out the treatment with the beta blocker) others were 'down-regulated' (meaning there was less mRNA).
- The researchers identified a subset of 32 genes that were most biologically relevant, these genes were those that (generally) were up-regulated when comparing the TAC (heart failure) mice with the wild type mice. And down-regulated when comparing the TAC mice receiving the beta blocker with those not receiving the beta blocker.
- One of the observations related to the expression levels of Hemoglobin which is increased in the TAC mice and has been previously found that high concentrations are associated with heart failure. Here they found that there were reduced hemoglobin expression levels when the beta blocker was administered. [7]
- In general their data showed that the beta blocker (atenolol) reverses the effect that TAC (heart failure) has on gene expression in the heart.
- The data also showed that the beta blocker up-regulated genes that have been observed to be correlated to better muscle functioning.
How About The Effect of the Beta Blocker on the MEF2 Proteins?
To get at this the authors turned to recombination DNA technology and a variant of a mouse that had its MEF2A gene tagged with another protein called beta galactosidase. Now this is a particularly useful tagging because it allows you to visualize the amount of a protein expressed in say... a heart. Beta galactosidase has the ability to break down beta glycosidic bonds which are found in certain sugars. There is one such sugar 5-bromo-4-chloro-3-indolyl-β-D-galactopyranoside (or as molecular biologists call it... X-gal) that when broken down produces a blue pigment. Researchers can provide this sugar to the mouse hearts and look for the regions that turn blue as they will be where the beta galactosidase - MEF2A protein is breaking the sugar down and producing the pigment.
This is what the researchers did, so what you are looking at up top are three hearts which are from mice that received the beta blocker treatment, and the bottom three are from mice that did not receive the treatment. You can see just by comparing the two sets that the top hearts are significantly less blue then the bottom hearts. This illustrates that the amount of MEF2A protein present when the animals received the beta blocker is lower, then in the animals that did not receive the beta blocker.
This result is interesting as researchers had previously shown that MEF2A actually played a protective role for heart cells (which would indicate that more would be better), however the opposite happens upon administration of the beta blocker here. [8]
Wrapping Things Up/ Some Conclusions
- This article explored why from a genetic perspective beta blockers provide protection to people who have heart disease or are experiencing heart failure. Exploring the relationship between the transcription factor family MEF2 and the drug atenolol.
- They illustrated directly through cellular assays how the drugs are able to improve the heart muscle quality after heart failure.
- The authors identified a whole host of genes related to heart failure which have altered expression levels when in the presence of the beta blocker atenolol.
- These genes and proteins could provide new avenues for the development of ways to treat heart failure/heart disease.
Sources
- https://www.nature.com/articles/s41598-017-04762-x
- http://dev.biologists.org/content/144/7/1235
- https://www.ncbi.nlm.nih.gov/pubmed/17200711
- http://www.cvri.ucsf.edu/~bblack/wp-content/uploads/2012/04/Black-2010-HeartDev-chapter.pdf
- https://link.springer.com/chapter/10.1007%2F978-1-4615-1893-8_24
- https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4409146/
- https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3969045/
- https://www.ncbi.nlm.nih.gov/pubmed/23161540
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Great workup....Are this all experiments done with atenolol only or other b blockers too?..There are other b-blockers like Carvedilol and Labetalol which have both alpha and b blocking action, is there any role of Alpha1 blocking action ? because by blocking alpha 1 there is reduced afterload to the heart.
These are excellent questions! In the article they only used atenolol. I do not know the answers to your questions about the other beta blockers, or about the involvement of alpha androgenic receptor binding unfortunately!
Thanks for the appreciation, likely they have not done experiment on other b blockers, it will be great too see how it goes.
Very interesting :)
Thanks. :)
Almost 90% of the cases of the primary hypertension are idiopathic, researches like this help us understand their genesis. I would love to see some EBM stuff like this on Steemit! :)
Upvoted & RESTEEMED :]
Thank you for your kindness @insiders
Just to balance this great article :)
Haha, I like this!
Thanks for sharing. i hope that they try to investigate the mode of action of other medications that they also treat high blood pressure like diuretics, vasodilator .. etc maybe they can find some more informations about this disease
Indeed, It was interesting to see the changes to protein expression levels in response to the drug.
Great article. I have used propranolol for years
The beta blocker I take is bisoprolol. The effective dose with this one is actually really small. I used to take a different one but this worked far better.
Yeah, bisoprolol is on the higher rank compared to others, it has both hydrophilic and lipophilic nature , doesnot have central side effect,&almost completely absorbed..
Very imp post ..thanks for sharing
Thank you for reading and your kind words :)
... I really appreciate the detailed article, but have trouble understanding the content. Could you do a "Beta Blocker" Blood Pressure Medication Modifies Expression of a Gene Involved in Heart Failure" for dummies? ;)
My apologies, this one likely isn't easy.
... maybe a 'side thing' you could add in the future. I think a lot of us common folk would love to learn the essence of the research/ information. Cheers
I generally try to write very digestible articles where I boil it down as much as possible. This one I wanted to write something a little bit more detailed then I would normally do. Perhaps it was for me, I am not sure. Rest assured that my next post will be back in a more easily digestible format.
Thanks for taking the time to give it a look all the same :)
Interested post @justtryme90, i barely known about MEF2, thanks for sharing
Thank you for reading :) most appreciated @jamhuery.
interesting :)
Thanks for reading.
Thank you soo much for sharing this information with complete details. My elder brother is also suffering from high blood pressure. I will refer him to read this blog and hopefully, this will help him out to cure..
No cure to high blood pressure from here I'm afraid. Just new understanding about how these medications protect the heart from failure after heart attack.
Ah, epigenetics. This is great stuff.
Epigenetics refers to gene regulation through methylation this is more standard regulation through a transcription factor and gene promoters. They are different and potentially complementary regulatory processes :)
Ohh ok my bad. When the post said something about gene expression the only other place I had heard that was epigenetics.
Thanks for the clarification - looks like I have some more studying to do ;)
We all have studying to do. It's the best thing about science! So many fascinating things to learn about
agreed 100%
I’m glad to see there’s hope for my mother then, whose daily life has been badly affected by high blood pressure.
I hope she is taking medication.
Thanks mate, she is indeed on the worst of days, though I don’t know what it is exactly that she’s taking.