Pericentrin deficiency in smooth muscle cells augments atherosclerosis through HSF1-driven cholesterol biosynthesis and PERK activation
Suravi Majumder, … , Callie S. Kwartler, Dianna M. Milewicz
Suravi Majumder, … , Callie S. Kwartler, Dianna M. Milewicz
Published November 8, 2023
Citation Information: JCI Insight. 2023;8(21):e173247. https://doi.org/10.1172/jci.insight.173247.
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Research Article Genetics Vascular biology

Pericentrin deficiency in smooth muscle cells augments atherosclerosis through HSF1-driven cholesterol biosynthesis and PERK activation

Abstract

Microcephalic osteodysplastic primordial dwarfism type II (MOPDII) is caused by biallelic loss-of-function variants in pericentrin (PCNT), and premature coronary artery disease (CAD) is a complication of the syndrome. Histopathology of coronary arteries from patients with MOPDII who died of CAD in their 20s showed extensive atherosclerosis. Hyperlipidemic mice with smooth muscle cell–specific (SMC-specific) Pcnt deficiency (PcntSMC–/–) exhibited significantly greater atherosclerotic plaque burden compared with similarly treated littermate controls despite similar serum lipid levels. Loss of PCNT in SMCs induced activation of heat shock factor 1 (HSF1) and consequently upregulated the expression and activity of HMG-CoA reductase (HMGCR), the rate-limiting enzyme in cholesterol biosynthesis. The increased cholesterol biosynthesis in PcntSMC–/– SMCs augmented PERK signaling and phenotypic modulation compared with control SMCs. Treatment with the HMGCR inhibitor, pravastatin, blocked the augmented SMC modulation and reduced plaque burden in hyperlipidemic PcntSMC–/– mice to that of control mice. These data support the notion that Pcnt deficiency activates cellular stress to increase SMC modulation and plaque burden, and targeting this pathway with statins in patients with MOPDII has the potential to reduce CAD in these individuals. The molecular mechanism uncovered further emphasizes SMC cytosolic stress and HSF1 activation as a pathway driving atherosclerotic plaque formation independently of cholesterol levels.

Authors

Suravi Majumder, Abhijnan Chattopadhyay, Jamie M. Wright, Pujun Guan, L. Maximilian Buja, Callie S. Kwartler, Dianna M. Milewicz

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Figure 5

Pcnt deletion–induced augmented PERK signaling and SMC phenotypic modulation are HSF1 dependent.

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Pcnt deletion–induced augmented PERK signaling and SMC phenotypic modul...
(A and B) PcntSMC–/– SMCs have increased Atf4 expression and KLF4 luciferase activity (A), and increased levels of eIF2α phosphorylation, ATF4, and KLF4 (B), at baseline or with exposure to 2.5 μg/mL MBD-Chol in PcntSMC–/– SMCs, compared with 10 μg/mL MBD-Chol in WT SMCs. (C) HSF1 activity is significantly decreased in both WT and PcntSMC–/– SMCs following siRNA-mediated depletion of Hsf1. (D) Hmgcr expression, HMGCR enzymatic activity, and cholesteryl ester levels are significantly reduced in PcntSMC–/– SMCs following siRNA-mediated depletion of Hsf1. (E–G) siRNA-mediated depletion of Hsf1 reduces activation of the PERK pathway (E), and phenotypic modulation (F and G) at baseline. All gene expression data are representative of 3 independent experiments. Multiple group comparisons were analyzed by 2-way ANOVA followed by Tukey’s multiple-comparison test. Error bars represent SD. *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001. CE, cholesteryl esters.