Part 10 - Other Factors in the Development of Atherosclerosis
Now that we’ve outlined the ways in which sdLDL genesis and
LDL particle modification can place one on a path to atherosclerotic disease,
let’s touch on other factors that may influence the blood vessel environment
and contribute to a person’s vascular susceptibility. These factors include:
Advanced Glycation End-Products (AGEs) – AGEs are
fats or proteins that have been structurally and functionally modified by
glycation (exposure to sugar). Perhaps usurpingly, AGEs are strongly associated
with elevated blood sugar and related health issues such as insulin resistance,
metabolic syndrome, and obesity.1–8
There is a somewhat common fallacy to conflate dietary AGEs –
those most commonly consumed via any food browned through high-temperature cooking– with
the AGEs that develop in your own body. This is an important distinction. You
do consume AGEs in your diet (this is a reason you may hear advice to avoid charring
your meat, or limiting meat in general), but the available evidence suggests
the AGEs you consume and digest are not related to the fats and proteins that
become glycated in your own body. There is scant evidence that a high AGE diet
increases AGEs in the body, and in fact it is vegetarians and those consuming higher-carbohydrate
diets (who thus typically have the most elevated blood sugar) who often tend to
have the highest AGE levels.9–16
The formation of AGEs in the body has multiple effects.
Binding of AGEs to the oh-so-cleverly named RAGE (receptor for AGEs) initiates
a cell signaling process that increases action of NF-kB, which you’ll recall from
the previous section is itself critical in the LDL particle immune response.17–20
AGEs that form in the blood vessels themselves alter bonding
of proteins such as collagen, leading to AGE-AGE cross-linking in the vessel
wall. This process can stiffen the blood vessel, leading to decreased vascular compliance,
a loss of collagen elasticity, and elevated blood pressure.21–24 AGE accumulation here also increases
the action of certain oxidized LDL receptors, potentially contributing to foam
cell development.17,25,26
One final effect is possible AGE-modification of LDL particles themselves. As suggested in the previous section, these modified LDL particles are preferential targets of the scavenger receptor LOX-1.27–31
Nitric Oxide (NO) – NO is a gaseous signaling molecule
noted for its cardioprotective effects, including the inhibition of platelet
aggregation, the suppression of VSMC lesion development, and the regulation of
blood pressure (you may previously be aware of NO as an emergency first-line cardiovascular
drug). Unsurprisingly, decreased function and availability of NO is associated with
atherosclerotic cardiovascular disease.32–35
Arguably the largest negative effects on NO function are imparted
by elevated blood sugar, as hyperglycemia inhibits the action of the enzyme (eNOS)
responsible for NO production.36–40 Glucose-triggered activation
of the transcription factor Foxo1 reduces NO availability as well. This
decreased availability meanwhile plays a reciprocal role in the formation of
oxidized LDL particles, whereby lower NO concentrations allow for increased
progression of oxidized LDL particles while the damaged particles themselves
further reduce eNOS expression and reduced NO prevalence.36,41–44
What increases NO availability? One factor is HDL, which has
been demonstrated to upregulate eNOS expression via a signaling cascade
activated by the HDL receptor SR-BI.45,46 As you’re well aware by now, sufficient
HDL and thus higher NO levels can be maintained through healthy triglyceride
utilization.
The Glycocalyx – The glycocalyx is a gummy structural
matrix lining the interior wall of the blood vessel. It plays important roles
in maintaining barrier integrity and is noted for its anti-adhesive effects on
macrophages and platelets.
Perhaps unsurprisingly, the glycocalyx offers another means
by which elevated blood sugar may contribute to potential atherosclerotic disease.
Hyperglycemia has both the capacity to break down and reduce the volume of the glycocalyx,
and to impair its formation and repair by decreasing synthesis of the glycosaminoglycan
chains that form this protective complex. 47–51
Putting It All Together
The traditional lipid-heart hypothesis suggests that elevated
LDL-C will lead to heart disease by the sheer prevalence of LDL particles that
must penetrate the wall of the blood vessel and accumulate there. However, neither
the cholesterol within these particles, nor the normal, healthy particles
themselves, appear to play any legitimate role in the propagation of atherosclerotic
disease.
Instead, we see that poor metabolic health leads to an abundance
of sdLDL particles, which are highly susceptible to modification and are a
favored target of receptors such as LOX-1. These sdLDL, along with other LDL
particles subject to oxidative stress or elevated blood sugars, are scavenged
and sequestered in the vessel wall to be acted upon by macrophages. This portion
of the immune response results in the formation of a foam cells – too many foam
cells forming too quickly overwhelm the body’s capacity to clear them, leading
to the formation of lesions that narrow the arteries and may eventually
rupture.
Meanwhile, certain long-term conditions in the bloodstream –
namely, elevated blood sugar – increase the actions of various inflammatory and
immune factors, decrease NO availability, damage the glycocalyx, and lead to blood
vessels that are narrower, stiffer, and lacking in structural integrity.
In an unhealthy person, this all happens extremely frequently
alongside elevated LDL-C. As you know, excessive carbohydrate consumption and increased
blood sugar and insulin levels are instrumental in this process, in which poor
triglyceride utilization leads to increased VLDL production at the liver. From
the perspective of an energy delivery model, then, elevated LDL-C is simply another
product of the poor metabolic health that leads to cardiovascular disease, not
the cause itself. As I wrote in the conclusion of my paper on the subject:
As we can see,
though, it is not this person’s consumption of dietary fat or cholesterol
driving their risk. Nor is their elevated LDL-C actually implicated in any way.
No, it is only an association driven by overconsumption in general and
overconsumption of carbohydrates specifically. Their risk is instead driven by
factors of hyperglycemia and insulin resistance – the increased development of
AGEs, depressed NO availability, the elevated blood pressure and lack of
vascular compliance that results from each of these, increased ROS production,
hyperglycemia-induced damage to the glycocalyx, increased cellular adhesion
molecule and monocyte signaling, poor reverse cholesterol transport, and the
formation of the glycated, oxidized, and small, dense LDL particles that form
the basis of atherosclerotic plaque.
If you’ve made it this far, you’re almost to the end of our
discussion on the shortcomings of the prevailing LDL-C paradigm. Finally, we
will examine the effects of diet on the factors and health markers implicated
in metabolic health and cardiovascular disease.
**Key Takeaways
- Elevated blood sugar damages the blood vessels through the formation of AGEs, the decreased availability of NO, and deleterious effects on the protective glycocalyx
- AGEs form in the body primarily as a result of increased exposure to sugar in the bloodstream, and can increase the action of factors, such as NF-kB and LOX-1, that play important roles in cardiovascular disease
- Small and modified LDL particles are commonly abundant in the same conditions that lead to damaged and weakened blood vessels, creating a “perfect storm” of atherosclerotic conditions
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