Abstract 17777: Sorafenib Aggravates Atherosclerotic Progression Involving With Vascular Smooth Muscle Cell (VSMCs) Phenotypic Switching and Proliferation by PKM2-Mediated Glycolysis

Introduction: As a VEGF-targeting agent, sorafenib has been used to treat a number of solid tumors but can easily lead to adverse vascular effects, including hypertension, myocardiopathy and coronary artery spasm. Our previous study reveals that sorafenib impairs endothelium-dependent vasodilatation, whereas the effect of sorafenib on atherosclerotic progression has not been determined.

Hypothesis: Hence, we hypothesize that sorafenib may promote atherosclerotic progression via such adverse vascular effects.

Methods: ApoE ^-/- mice were orally administered by sorafenib for 12 weeks, indicating that sorafenib aggravates atherosclerotic progression via promoting the formation of foam cells and the accumulation of VSMCs in intima. To study the underlying mechanism, we used sorafenib to incubate VSMCs (0, 3 and 6 mg/L) for 48 h.

Results: We found that sorafenib promoted the proliferation, migration and synthetic phenotype-related gene expression in VSMCs. More importantly, sorafenib increased lactate production, the extracellular acidification rate, PKM2 expression and PK activity in VSMCs. Interestingly, after deletion of PKM2 in VSMCs by AAV-CRISPR/Cas9 system, decreased lactate production and the extracellular acidification rate were found. Meanwhile, sorafenib-induced the proliferation, migration and phenotypic switching of VSMCs were suppressed.

Conclusions: Sorafenib can aggravate atherosclerotic progression and smooth muscle cell phenotypic switching, which may be partly ascribed to PKM2-depended glycolysis.