PKM2-dependent glycolysis promotes the proliferation and migration of vascular smooth muscle cells during atherosclerosis

摘要

Increased glycolysis is involved in the proliferation and migration of vascular smooth muscle cells (VSMCs).Pyruvate kinase isoform M2 (PKM2),a key rate-limiting enzyme in glycolysis,accelerates the proliferation and migration of tumor cells.Although the intracellular mechanisms associated with oxidized low-density lipoprotein (oxLDL)-stimulated VSMC proliferation and migration have been extensively explored,it is still unclear whether oxLDL promotes the proliferation and migration of VSMCs by enhancing PKM2-dependent glycolysis.In the present study,we detected PKM2 expression and pyruvate kinase activity in oxLDL-treated VSMCs and explored the regulation of PKM2 in oxLDL-treated VSMCs and apoE-/-mice.The results showed that PKM2 expression in VSMCs was higher in the intima than in the media in plaques from atherosclerotic rabbits.Moreover,PKM2 level in VSMCs was increased during atherosclerosis progression in apoE-/-mice.Both PKM2 expression and pyruvate kinase activity were found to be upregulated by oxLDL stimulation in VSMCs.Shikonin (SKN),a specific inhibitor of PKM2,was found to inhibit the oxLDL-induced proliferation and migration in VSMCs,in addition to delaying the atherosclerosis progression in apoE-/-mice.More importantly,oxLDL increased glucose uptake,ATP and lactate production,and the extracellular acidification rate in VSMCs,which could be reversed by SKN.Meanwhile,oxygen consumption rate was unchanged after oxLDL stimulation,suggesting that glycolysis is the main contributor to the energy supply in oxLDL-treated VSMCs.Our results suggest that oxLDL induces VSMC proliferation and migration by upregulating PKM2-dependent glycolysis,thereby contributing to the atherosclerosis progression.Thus,targeting PKM2-dependent glycolysis might provide a novel therapeutic approach for the treatment of atherosclerosis.