Pericentrin deficiency in smooth muscle cells augments atherosclerosis through HSF1-driven cholesterol biosynthesis and PERK activation
Suravi Majumder, Abhijnan Chattopadhyay, Jamie M. Wright, Pujun Guan, L. Maximilian Buja, Callie S. Kwartler, Dianna M. Milewicz
Suravi Majumder, Abhijnan Chattopadhyay, Jamie M. Wright, Pujun Guan, L. Maximilian Buja, Callie S. Kwartler, Dianna M. Milewicz
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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 2

SMC-specific Pcnt-deficient mice have increased atherosclerotic plaque burden.

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SMC-specific Pcnt-deficient mice have increased atherosclerotic plaque b...
(A and B) En face Oil Red O staining of aortas shows significantly increased plaque formation in hyperlipidemic PcntSMC–/– mice placed on 12 weeks of HFD, compared with similarly treated WT mice (n = 10–12 mice per genotype per sex, Mann-Whitney U test). (C) Only male PcntSMC–/– mice had significantly higher plaque burden compared with male WT mice, and female mice showed no statistically significant difference (n = 10 males and 12 females, 2-way ANOVA followed by Tukey’s multiple-comparison test). (D–F) H&E staining (D) demonstrates that male PcntSMC−/− mice had greater atherosclerotic lesion areas in both the aortic roots (E) and ascending aortas (F) (n = 6, by unpaired, 2-tailed Student’s t test with Welch’s correction). Scale bars: 200 μm (bottom left) and 500 μm (all others). (G–I) SMA staining of the aorta (G) reveals significantly fewer SMA+ cells in the medial layer (H) but not the plaque (I) of the aortic root (n = 9, Mann-Whitney U test). Error bars represent SD. *P < 0.05, **P < 0.01, ****P < 0.0001. L, lumen; M, medial layer; P, plaque. Scale bars: 5 μm.