PERK Is Dispensable for Smooth Muscle Cell Phenotype Switching in Atherosclerosis

Area of Science:

• Cardiovascular Research
• Cell Biology
• Atherosclerosis Research

Background:

• Smooth muscle cells (SMCs) are key in atherosclerotic lesions, influencing stability and disease outcomes.
• Unfolded protein response (UPR) markers, thin fibrous caps, and inflammation are linked to human lesion instability.
• The role of UPR in SMC modulation and its impact on atherosclerotic lesion stability is debated, though Perk (protein kinase RNA-like ER kinase) has been implicated.

Purpose of the Study:

• To investigate the role of SMC-specific Perk UPR in modulating atherosclerotic lesion stability.
• To determine if depleting SMC Perk affects lesion stability in an atherogenic mouse model.
• To assess the correlation between UPR markers and lesion stability in human carotid arteries.

Main Methods:

• Deletion of SMC Perk in adult Ldlr-/- hypercholesterolemic mice.
• Analysis of lesion stability features and single-cell differential gene expression.
• In vitro studies using Perk knockdown in primary murine SMCs.
• Assessment of UPR marker expression in human carotid lesions via scRNA-seq, bulk RNA-seq, and spatial transcriptomics.

Main Results:

• SMC Perk deletion did not alter weight gain, serum cholesterol, lesion progression, or stability in mice.
• Little UPR activity was detected in SMCs and smooth muscle-derived cells; Perk was not essential for in vitro SMC modulation.
• No correlation was found between UPR markers and human carotid lesion stability or clinical presentation; UPR markers were mainly in leukocytes, not SMCs.

Conclusions:

• SMC Perk UPR does not significantly influence atherosclerotic SMC modulation, disease progression, or lesion stability in mice.
• Perk UPR pathway markers in humans do not correlate with carotid lesion stability or clinical presentation.