Spike Protein Signaling and the MEK-ERK Pathway

Looking into why some are more affected than others by the Spike Protein.

One of the most frequently asked questions I receive is "Why isn't everyone affected after Spike Protein exposure?" Indeed, this is a question which I frequently asked myself. So, I decided to look into answers to this question, and I have been finding them. As the Biblical proverb states: Seek and ye shall find!

A paper was published in January 2021 which looked into Spike Protein signaling as a possible consequence of the COVID vaccines. What they found was quite interesting. When cells were exposed to the full length S1 subunit (all Spike gets cleaved) they noticed that Spike, through its signaling via interaction with the ACE2 receptor, activated the MEK-ERK pathway. And this exposure was for only 10 minutes at a very low concentration of 130pM.

In our cell culture experiments, two recombinant SARS-CoV-2 spike proteins, both of which contain the RBD, were studied. The full-length S1 subunit protein contains most of the S1 subunit (Val16–Gln690), while the RBD S1 subunit protein only contains the RBD region (Arg319–Phe541), as shown in Figure 1. Cultured primary human pulmonary artery SMCs and human pulmonary artery endothelial cells were treated with these proteins for 10 min. We found, using the phospho-specific MEK antibody, that the recombinant full-length S1 subunit of SARS-CoV-2 alone at a concentration as low as 130 pM activated MEK, the activator of extracellular signal-regulated kinase (ERK) and a well-known signal transduction mechanism for cell growth.

The authors then proceed to discuss how this can not only affect lung cells and the possible induction of Pulmonary Hypertension (PAH) but can lead to other cardiovascular diseases.

It is generally thought that the sole function of viral membrane fusion proteins is to allow the viruses to bind to the host cells for the purpose of viral entry into the cells, so that the genetic materials can be released and the viral replication and amplification can take place. However, recent observations suggest that the SARS-CoV-2 spike protein can by itself trigger cell signaling that can lead to various biological processes. It is reasonable to assume that such events, in some cases, result in the pathogenesis of certain diseases.

Our laboratory only tested the effects of the SARS-CoV-2 spike protein in lung vascular cells and those implicated in the development of PAH. However, this protein may also affect the cells of systemic and coronary vasculatures, eliciting other cardiovascular diseases such as coronary artery disease, systemic hypertension, and stroke. In addition to cardiovascular cells, other cells that express ACE2 have the potential to be affected by the SARS-CoV-2 spike protein, which may cause adverse pathological events.

SARS-CoV-2 Spike Protein Elicits Cell Signaling in Human Host Cells: Implications for Possible Consequences of COVID-19 Vaccines
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7827936/

I continued to research this mechanism in the context of the heart. What I found can offer an explanation as to why some are more affected than others by Spike Protein pathology. The activation of the MEK-ERK pathway in the heart can be benign - or even beneficial - unless you have an underlying comorbitity, such as hypertension.

Continuous hemodynamic overload induces an unfavorable hypertrophic response. The main pathway involved in hypertension is the renin–angiotensin system. Its main effector hormone is AngII, which induces physiological vasoconstriction, blood pressure regulation, and production of extracellular matrix proteins. In addition, AngII stimulates aberrant cardiac cell growth, as suggested by the high levels of AngII after myocardial infarction and during cardiac hypertrophy. The angiotensin receptors belong to the GPCRs family, in particular the most involved in hypertension is the Gq-coupled AT1R. Many studies support the observation that AngII induces the hypertrophic response on myocardial cells. AngII-mediated detrimental effects have a crucial role in various cardiac diseases, such as inflammation, atherosclerosis, hypertension, and congestive heart failure. Heart failure patients treated with inhibitors of the angiotensin system showed reduced cardiac hypertrophy and slower progression towards heart failure. These hypertrophic effects are mediated by AT1Rs, as demonstrated by the prevention of hypertrophy through AT1R antagonists. In addition, experimental studies demonstrated increased levels of AT1R in the hypertrophic process. Animal models of AT1Rs cardiac-specific overexpression showed enhanced hypertrophy leading to heart failure, in response to pressure overload. On the other hand, the cardiac knockout of AT1Rs presented improved systolic function with attenuation of AngII-mediated hypertrophic response in MI. Importantly, ERK is activated by AT1Rs and participates in the pathological hypertrophic response. In addition, it has been demonstrated that, during hypertension, ERK-induced hypertrophy can be stimulated by mechanical stretch in an AngII-dependent or independent way.

ERK: A Key Player in the Pathophysiology of Cardiac Hypertrophy
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6539093/

I will continue to look into the activation of this pathway in relation to other organs and systems. It may be that once the Spike has invaded and damaged the Endothelium, it then causes further damage by cell signaling in the invaded tissues and organs.

This also can explain why those who have chronic conditions get worse after Spike Protein exposure. If I were to look at what the Spike Protein might say for itself, the Spike Protein would be saying “kick them while they’re down…”

As always, thank you for your readership and support.