Abstract Body (Do not enter title and authors here): Introduction: Acute plaque rupture followed by luminal thrombosis is a major cause of myocardial infarction and sudden cardiac death. Vulnerable plaques are characterized by a thin fibrous cap and reduced numbers of smooth muscle cells (SMCs). SMCs are essential for plaque stability, as they synthesize collagen and support fibrous cap structure. Our previous work demonstrated that insulin-like growth factor-1 enhances plaque stability by upregulating La ribonucleoprotein domain family member 6 (Larp6), a collagen mRNA-binding protein in SMCs. However, the specific role of Larp6 in atherosclerotic plaque stability remains undefined.
Hypothesis: We hypothesize that Larp6 enhances atherosclerotic plaque stability by increasing collagen synthesis and promoting SMC survival.
Methods and Results: Using the Myh11 promotor we generated SMC specific Larp6 overexpression mice on an ApoE^-/- background (SMC-Larp6) to assess effects on plaque stability. 8-wk-old SMC-Larp6 mice and littermate controls (n=20/group) were fed a Western diet for 12 wks. Tissues were harvested for assessment of atherosclerotic burden and plaque phenotype. Histological analysis showed plaques from SMC-Larp6 mice exhibited a significantly higher collagen content (22.9 ± 9.2%, P<0.05), accompanied by a thicker fibrous cap (40.6 ± 15.8%, P<0.05) and a smaller necrotic core (28.1 ± 13.2%, P<0.05), without significant changes in overall plaque burden compared to controls. Immunofluorescence staining on aortic root sections revealed elevated α-smooth muscle actin expression within plaques (80.0 ± 26.9%, P<0.01), suggesting increased SMC presence. Mechanistically, adenoviral LARP6 overexpression in human aortic SMCs significantly increased cell proliferation and survival in the presence of oxidant stress (100 μg/mL oxidized LDL). Additionally, LARP6 overexpression promoted collagen accumulation by enhancing collagen synthesis, as demonstrated by increased hydroxyproline production both in vitro and in vivo. Finally, RNA sequencing analysis of human atherosclerotic plaques (GSE120521) revealed reduced expression of LARP6 and downregulation of extracellular matrix-related pathways in unstable plaques, underscoring the clinical relevance of these findings.
Conclusions: Larp6 overexpression promotes collagen synthesis and increases smooth muscle cell survival under atherosclerotic conditions. These findings suggest that Larp6 is a potential therapeutic target for stabilization of atherosclerotic plaques.