LAUSR

Atherosclerosis is the most prevalent cause of death across the world. Numerous clinical studies have concluded that decreased plaque stability, not greater lesion size, is a better determinant of rupture and adverse thrombotic events with unstable plaques being characterized by a high ratio of macrophages to smooth muscle cells (SMCs) and little ECM deposition. During the development of atherosclerotic lesions, SMCs from the arterial wall proliferate and migrate to form a protective fibrous cap. This cap is composed of ACTA2+ SMCs and myofibroblast-like cells of undetermined origin, which secrete collagen to maintain a lesion-stabilizing extracellular matrix. Using SMC-lineage tracing mice, our lab and others have shown that SMCs undergo phenotypic transitions during atherosclerosis, fundamentally changing into myofibroblasts, macrophage-like cells, and others. After exposure to mitogens such as platelet-derived growth factor (PDGF), SMCs undergo de-differentiation causing marker genes such as Acta2 to be downregulated while collagen genes are upregulated. SMCs rely on oxidative phosphorylation to provide energy for contraction, but the energetic requirement for SMCs to undergo a phenotypic transition to a myofibroblast-like cell is not well understood. Thus, we hypothesized that fibrogenic and mitogenic stimuli force a metabolic shift in SMCs, necessary to energetically support a phenotypic transition to an atheroprotective myofibroblast-like state. Using extracellular flux analysis, we found that cultured SMCs significantly increase their capacity for aerobic glycolysis in response to PDGF and transforming growth factor-β (TGFβ). Furthermore, pharmacologically inhibiting lactate dehydrogenase, using galloflavin, not only prevents PDGF-induced aerobic glycolysis, but also abrogates PDGF-driven downregulation of Acta2. Additionally, galloflavin abrogates PDGF-induced expression of collagen genes. We conclude that a metabolic shift to aerobic glycolysis is necessary for SMCs to undergo a phenotypic transition to a myofibroblast state, and suggest that modifying SMC metabolism represents a previously undiscovered mechanism for strengthening the fibrous cap and stabilizing atherosclerotic lesions.