Beschreibung:
<jats:p>
Complex phenotypic modulation of vascular smooth muscle cells (SMCs) is a major driver of atherosclerosis. It is caused in part due to high levels of exogenous cholesterol activating the PERK arm of endoplasmic reticulum (ER) stress, which drives a component of SMC modulation and plaque formation. This is illustrated by the fact that SMC-specific deletion of
<jats:italic>Perk</jats:italic>
reduces plaque formation by up to 80% in male hypercholesterolemic (HC) mice. HC mice harboring the
<jats:italic>ACTA2</jats:italic>
p.R149C pathogenic variant (
<jats:italic>
Acta2
<jats:sup>R149C/+</jats:sup>
Apoe
<jats:sup>-/-</jats:sup>
</jats:italic>
) have 2.5-fold higher atherosclerotic plaque burden than
<jats:italic>
Apoe
<jats:sup>-/-</jats:sup>
</jats:italic>
mice despite no difference in serum lipid levels. Misfolding of mutant SM α-actin in SMCs activates heat shock factor 1 (HSF1), which upregulates HMG-CoA reductase (HMG-CoAR, coded by
<jats:italic>Hmgcr</jats:italic>
), thus increasing cholesterol biosynthesis and ER stress, activating PERK, and augmenting phenotypic modulation and plaque burden. However, it is not known if activation of the HSF1→HMG-CoAR→PERK signaling axis contributes to disease in patients with more common risk factors for atherosclerosis. Hyperhomocysteinemia (HHcy), defined as plasma homocysteine (Hcy) concentration >15μM, caused by genetic and lifestyle factors, is an independent risk factor for coronary artery disease and ischemic strokes. Wildtype SMCs were exposed to 0-500μM of Hcy in culture for 48 hours, which activated PERK signaling as indicated by increased expression and activation of its downstream targets
<jats:italic>Atf4</jats:italic>
and
<jats:italic>Klf4</jats:italic>
. Hcy treatment also caused a dose-dependent decrease in expression of contractile genes and increase in cellular migration, while expression of modulation-specific genes increased at higher concentrations of Hcy. Furthermore, exposure to Hcy increased expression and transcriptional activity of HSF1 in a dose-dependent manner. Finally, Hcy treatment caused dose-dependent upregulation of
<jats:italic>Hmgcr</jats:italic>
expression and augmented cellular cholesterol biosynthesis. Taken together, these data support the hypothesis that, similar to misfolding of the mutant SM α-actin, Hcy activation of the HSF1→HMG-CoAR→PERK pathway in SMCs leads to phenotypic modulation of SMCs and may contribute to the augmented atherosclerosis associated with HHcy.
</jats:p>