Pathways no avoid death….

The cell, has many pathways to avoid a process called Apoptosis. In contrast to necrosis, which is a form of traumatic cell death that results from acute cellular injury, apoptosis, in general, confers advantages during an organism’s life cycle. For example, the differentiation of fingers and toes in a developing human embryo occurs because cells between the fingers apoptose; the result is that the digits are separate. Unlike necrosis, apoptosis produces cell fragments called apoptotic bodies that phagocytic cells are able to engulf and quickly remove before the contents of the cell can spill out onto surrounding cells and cause damage. But many cells, can avoid this natural pathway and keep on proliferating, growing… CAN YOU REMEMBER SOMETHING LIKE THIS?
YEAP, CANCER…. Cancer cells have the skill to runaway from apoptosis. One of the main «roads» to follow it is a pathway called: The Akt/PKB signaling pathway. Akt/PKB is a pathway in cell signaling.


Proteins involved include AKT (also known as “protein kinase B”, PKB) and phosphoinositide 3-kinase (PI3K).

PI3 Kinase is a lipid kinase that is activated (via an SH2-domain adaptor) by signals (e.g., members of the insulin-like growth factor (IGF) family of signal proteins) transmitted by many transmembrane receptors with protein kinase cytosolic domains. This activation leads to production from membrane inositol of the inositol phospholipids PtdIns(3,4,5)P3 and PtdIns(3,4)P2

As you can see on the picture, there are several molecules that naturaly follow some activating/inhibiting pathawys. This complex phosphorylates many highly significant substrates. Akt indirectly activates (not phosphorylates) mTOR, which lies at the heart of growth regulatory pathways.

mTOR promotes cell growth by:

– activating S6kinase (an activator of translation)

– activating PKC (so turning on many synthetic and secretory pathways)

– inhibiting p21 (so releasing cells from G1 arrest)

– inhibiting GSK3β (with similar effect, since GSK3β targets cyclin D for proteolysis)

Akt also phosphorylates Bad (a pro-apoptotic protein,which in its non-phosphorylated state, promotes apoptosis) which sequesters it and keeps it out of action, promoting cell survival.


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Exercise training vs Muscle gaining and loss….




Because of its high prevalence and association with several diseases,


1)Natural regulatory protein

2)Member of TGF-b family

3)Inhibits muscle growth

4)Increases with age

5)An evolutionary circuit breaker to keep muscle growth in check

Probably inhibits recruitment of muscle stem cells




Why do Our tissues and organs stop to grow? From simple stem cells into different organs…..

Animals have rapid body growth in early life stages, then the body impose limits to itself. From a single stem cell, several differente tissues (hearth, skin, eyes…) differentiate and acquire differente functions.

WHY… What promotes differentiation? Stimulus or inhibitiors? 

Recent studies and (Julian C. et al, 2011) provide insight into a long-standing this mystery of biology.

So until now, we know that here are several mechanisms involved. This mechanisms act locally and not in a systemic way. Of course that behind this control there is a genetic map where the inhibitor information is primarly imprinted. So there are several genes that are responsible for new proteins once expressed in tissues, limit the growth.

In my study, i looked for hearth and muscle growth… Imagine  that skeletal and cardiac muscle growth are negatively regulated by myostatin and the concentration  depends on muscle mass itself. Liver growth appears to be modulated by bile acid flux, a parameter that reflects organ function. In pancreas, organ size appears to be limited by the initial number of progenitor cells, suggesting a mechanism based on cell-cycle counting. Further elucidation of the fundamental mechanisms suppressing juvenile growth is likely to yield important insights into the pathophysiology of childhood growth disorders and of the unrestrained growth of cancer.

In addition, improved understanding of these growth-suppressing mechanisms may someday allow their therapy.

Growth-suppressing mechanisms may someday allow their therapeutic suspension. Maybe, in HAP we will be able to stop Smooth muscle cells to proliferate in vessels.


Changes in blood vessel diameter can stop blood flow… What controls it?

 In smooth muscle cell, there are key mediators of the proliferative effect… so the vessel has several walls that can proliferate without any control.


Several substances  stimulate smooth muscle cell growth and induces oxidative stress.

Oxidative stress is a specific cellular crisis, that can disturb normal cell rules. Oxidative stress is started by ROS (reactive oxigen species). When intracellular ROS production in  endothelial cells increases, smooth muscle starts to proliferate.    

Other factors are related with this proliferation: MMP (matrix  metalloproteinases). MMP are capable of degrading all kinds of extracellular matrix proteins associated with smooth muscle matrix cell proliferation and migration. MMP is expressed abundantly in atherosclerotic lesions and plays an important role in increasing VSMC (vessel smooth muscle cells). MMP react with inter cell matrix allowing individual cell migration.

SO… ROS allow proliferation while MMP allow migration…. we can say that «CAOS» BEGAN… Lúmen vessel get smaller and blood find a big obstacle to his passage.

In summary,  the proliferative effects of ET-1  (endothelial cells) involves an increase in the production of ROS. Further study of the signaling pathways involved may identify additional points at which ET-1-induced proliferation can be inhibited. Because antioxidants  and other these agents may be of benefit in preventing the SMC proliferation associated with pulmonary vascular diseases.

Myocardin and Smooth muscle differenciation in Hypertension

Myocardin was shown to be a specific transcription factor that plays a central role in smooth muscle differentiation….Using several assays, we could show that the myocardin is lost at the point where slow growing cells are converted into fast growers we also found that myocardin expression is essential for their differentiation (Milyavsky et al., 2007). The unique contractile properties of the SMC lineage are directed by SRF/myocardin-regulated genes encoding SMC-restricted contractile proteins…. In the next picture we can see how this differentiation happends:

The fibroblast (immature cell)when exposed to a Growth factor (TGF-β1) increases assembly of a muscle filament called F-actin, inducing the myocardin-related transcription factor (MRTF)-A/B to go into the nucleus. After enter the nucleos, MRTF binds to serum response factor (SRF), and promote expression of a contractile gene program…. Program? yes, a group of other proteins tha regulate gene cell muscle differentiation. This group is called CArG-containing genes  and the members are α-actin (SMαA), SMγA, SM22-α, h1-calponin, and vinculin. The expression of these genes causes changes to the cytoskeleton, resulting in differentiation of the myofibroblast and the development of contractile function…. so this is another way to keep studying how smooth muscle proliferates in lung vessels… is essencial to understand how this happens to keep looking  for a therapy to hypertension.

Miocardin in Pulmonary arterial hypertension

So we need to find where it starts the problem: AT THE VESSELS..AT THE SMOOTH MUSCLE.


What if we could inhibit myocardin in smooth muscle development? It would be easy for us to control PAH…

Jingjing Li and his team at The University of Calgary in Canada (2012 article), showed recently that myostatin can be inhibited by Atorvastatin (ATV), an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, is widely prescribed as a lipid-lowering drug.

So… now, we know that, a cholesterol drug can inhibit smooth muscle proliferation. But is that a role to PAH???? Is aplicable to PAH?

My study will try to focus on Myocardin and Myostatin expression in smooth muscle. Next post, i will descrive how i am thinking to test this two protein expressions….