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 1

Characterization of coronary artery atherosclerotic lesions in patients with MOPDII.

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Characterization of coronary artery atherosclerotic lesions in patients ...
(A) Left anterior descending coronary artery from MOPDII Patient 1. Low-magnification image of Movat staining (a) reveals a large atherosclerotic plaque (P) in the left anterior descending coronary artery with a small lumen (L). Higher magnification image of the medial layer (M), shown in b and c, shows a well-formed internal elastic lamina (c, blue arrow), with an absence of cell staining in the medial layer and increased elastin deposition in the adventitial layer (Ad; the black elastin fibers are found in the adventitial layer). H&E staining (d–f) confirms loss of medial cells, along with cholesterol crystals in the atherosclerotic plaque. α-Smooth muscle actin (SMA) staining reveals large numbers of SMA-positive cells in the adventitia and fibrous cap (g and h) of the atherosclerotic plaque and an absence of SMA-positive cells in the medial layer (i). (B) Left main coronary artery bifurcation of MOPDII Patient 2. The low-magnification image of the Movat staining (a) reveals a large atherosclerotic plaque (P) with residual lumen (L). Higher-magnification images of the artery wall reveal an absence of cells in the medial layer (M) and elastosis (b and c). H&E staining (d–f) shows similar changes. SMA staining shows SMA-positive cells in a portion of the artery wall (g) and in the fibrous cap (h), with a paucity of SMA-positive cells in other areas of the medial wall (i). Scale bars: 500 μm (left), 200 μm (middle), and 50 μm (right).